Genome-wide mapping of complement system proteins for islet autoimmunity in the DAISY and TEDDY children

Genome-wide mapping of complement system proteins for islet autoimmunity in the DAISY and TEDDY children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Genome-wide mapping of complement system proteins for islet autoimmunity in the DAISY and TEDDY children Xiaowei Hu, Bobbie-Jo M Webb-Robertson, Hemang M Parikh, Ernesto S Nakayasu, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5975824/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Type 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin-producing beta cells, and there is no cure yet for the disease. While islet autoantibodies are well-recognized biomarkers that mark the onset of islet autoimmunity (IA) and are predictors of T1D, few additional biomarkers are available to monitor disease progression. Recent studies have reported the involvement of complement system proteins in the initiation and progression of IA in the study of T1D. However, the genetic factors of complement system proteins at the time of triggering of IA is unknown. Results Through complement system protein quantitative trait locus (pQTL) mapping analysis of 170 participants from the Diabetes Autoimmunity Study in the Young (DAISY), we identified 240 statistically significant pQTLs (false discovery rate, FDR < 0.1) from pooled and IA case-stratified analyses. Replication analysis conducted on 385 IA cases from The Environment Determinants of Diabetes in the Young (TEDDY) study confirmed 68 significant (FDR < 0.05) pQTLs in total for C8A, C8B, CFB, C4A, and MBL2. Furthermore, all replicated pQTLs of CFB and C4A were previously reported to be associated with T1D risk. Conclusions We identified and replicated 68 pQTLs for five complement system proteins (C8A, C8B, CFB, C4A, and MBL2) in the young population. Among them, all replicated pQTLs of CFB and C4A are also associated with T1D risk. Our study provides evidence of complement system proteins as potential protein biomarkers underlying the development and progression of T1D. islet autoimmunity T1D complement system proteins protein quantitative trait locus (pQTL) DAISY TEDDY Background Type 1 diabetes (T1D) is a complex autoimmune disease where an autoimmune attack destroys the pancreatic islet beta cells, which eventually results in a complete dependency on exogenic insulin. There is no cure for T1D yet, and the disease progression is not well understood. Hence, the development of biomarkers that can help track disease progression and determine disease causes is important for T1D prevention and therapy. The islet antibodies are well-recognized and reliable diagnostic biomarkers that mark the onset of islet autoimmunity (IA), and persistent multi-positivity of islet autoantibodies can be used to predict individuals at high risk of developing T1D 1 , 2 . However, the genetic mechanisms of the initiation of IA, as well as the progression from IA to clinical diabetes, are still largely unknown. The complement system, also known as complement cascade, plays an important role in the innate immune system, which helps to fight bacterial or viral infections and promotes clearance of damaged cells 3 . Three interrelated pathways activate the complement system, specifically the classical, lectin, and alternative pathways. These activation pathways converge at the terminal pathway, where much of the effector function resides 3 . The complement system also modulates adaptive immunity through activation by antibodies, including autoantibodies 4 . Several studies have suggested that the dysregulation of the complement system contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus 5 , rheumatoid arthritis 6 , and T1D 7 , 8 . More specifically, increasing studies have reported the involvement of the complement system in the initiation and progression of IA for the study of T1D 9 , 10 . Furthermore, recent studies observed lower levels of several complement system proteins in children with islet autoantibodies compared to healthy controls 11 – 14 . However, the genetic factors that result in decreased abundance of complement system proteins at the time of triggering of IA are currently unclear 15 . Circulating plasma proteins play a fundamental role in human biological processes and are frequently the targets of pharmaceutical interventions 16 . Protein quantitative trait locus (pQTL) mapping is an approach that can identify genetic variants underlying variation of protein expression levels. In prior studies, pQTL analysis has led to critical advances in knowledge of the genetic architecture of plasma proteins and their relationship to disease 17 – 21 . In this study, we aim to improve our understanding of the genetic factors of complement system proteins at the time of triggering of IA and bring us closer to dissecting the genetic mechanisms underlying the development and progression of T1D. Here, we performed pQTL analysis of 170 participants in the Diabetes Autoimmunity Study in the Young (DAISY) to identify statistically significant pQTLs for complement system proteins. Complement system proteins for DAISY participants were measured by two different protein assay platforms, selected reaction monitoring (SRM) 22 , and Exsera Biolabs 23 (hereinafter referred to as Exsera). Complement system proteins measured by two platforms were approximately overlapped in half. Hence, using proteins from both platforms provides a more comprehensive list of complement system proteins for study. Replication analysis was then conducted on 385 IA cases in the Environment Determinants of Diabetes in the Young (TEDDY) study and the proteins were measured by SRM for TEDDY participants. Finally, we used T1D Knowledge Portal to examine replicated pQTLs for their association with T1D and other disease-relevant traits. Results Participant characteristics The demographic and clinical characteristics of study samples are summarized in Table 1 , which includes 170 samples with 131 IA cases and 39 controls for DAISY discovery analysis, and 385 IA cases for TEDDY replication analysis after combining available proteomics and genotype data ( Methods ). Overall, the participants in the DAISY study had a median age of 6.2 years which was older than TEDDY participants with a median age of 1.8 years ( Table 1 ). The percentage of first-degree relatives with T1D in DAISY was 54%, much higher than 22% from TEDDY ( Table 1 ). For the other two clinical characteristics, female (%) and self-reported Non-Hispanic White (NHW) (%), the percentages were similar between the two studies. Females accounted for 46% and 44% in DAISY and TEDDY, respectively, and NHW was the most common population in both studies. cis -pQTLs discovery analysis in DAISY We first performed cis -pQTL mapping for DAISY samples in pooled (IA cases and controls) and IA case-stratified analyses, respectively ( Methods ). There were 19 and 16 complement system proteins measured by the SRM and Exsera platform, respectively, for DAISY samples, and 10 proteins overlapped between the two platforms ( Table 2 ). We observed 14 proteins with false discovery rate (FDR)-significant (FDR<0.1) cis -pQTLs ( Table 2 ). MBL2 has the greatest number of FDR-significant cis -pQTLs with 264 and 211 cis -pQTLs identified from Exsera pooled and case-stratified analysis, respectively (Additional file 2: Table S1 ). However, there were no statistically significant cis -pQTLs of MBL2 from the SRM platform. Additionally, MBL2 had the cis -pQTLs with the greatest strength of statistical significance (chr10:52771475-T, chr10:52773600-G, chr10:52775077-T with p-value=3.12x10 -19 and p-value=5.22x10 -16 from Exsera pooled and case-stratified analysis, respectively, Additional file 2: Table S1 ). Among other genes, CFH and C4B had FDR-significant cis -pQTLs from both SRM and Exsera platforms ( Table 2 ). For six proteins that had many FDR-significant cis -pQTLs (i.e., CFH, C8A, CFB, C4A, C4B, and MBL2), we performed fine-mapping to identify potential causal cis -pQTLs for each protein ( Methods ). For the proteins C8A, CFB and C4B, we observed corresponding 95% credible sets (CS) containing 29, 26, and 9 fine-mapped variants, respectively, from the SRM pooled analysis. For CFH, we observed a single 95% CS with 69 fine-mapped variants in the pooled analysis of protein levels from the Exsera platform (Additional file 1: Fig. S1-4 ). MBL2 has fine-mapped variants from both Exsera analyses, where 14 variants were identified in two 95% CSs from pooled analysis, and 4 variants were identified in one 95% CS from case-stratified analysis (Additional file 1: Fig. S5 ). However, there were no fine-mapped variants for CFH and C4A from SRM pooled analysis (Additional file 2: Table S1 ). We used non-fine-mapped cis -pQTLs for these two proteins from the corresponding analysis. After fine-mapping analysis, we identified 240 FDR-significant (FDR<0.1) cis -pQTLs in total from DAISY discovery analysis. Replicated cis -pQTLs in TEDDY To follow up on our discovery pQTL analysis in DAISY, we performed replication analysis in TEDDY for the 240 cis -pQTLs reported in Additional file 2: Table S1 , which maps to 14 proteins. A cis -pQTL was deemed replicated if it had FDR-corrected p-value< 0.05. Of these, we observed 68 cis -pQTLs passing the replication threshold, including 27 for C8A, 23 for CFB, 12 for C4A, 4 for MBL2, and 2 for C8B, respectively. The summary of all replicated cis -pQTLs for C8B and MBL2, and top replicated cis -pQTLs for C8A, CFB and C4A is presented in Table 3 . The other replicated cis -pQTLs for C8A, CFB and C4A are presented in Additional file 3: Table S2 .The replicated cis -pQTLs of CFB, C4A, and MBL2 decreased protein expression levels, while the replicated cis -pQTLs of C8A and C8B increased protein levels.All replicated cis -pQTLs had the same direction of effect between DAISY and TEDDY. However, the replicated signals in TEDDY generally achieved a lower level of statistical significance compared to DAISY. One exception to this finding was the CFB pQTL (chr10:31562639-A: Beta (SE)=-0.45 (0.11) and p-value=3.92x10 -5 in TEDDY vs. Beta (SE)=-0.34 (0.08) and p-value=4.37x10 -5 in DAISY; Additional file 2: Table S1 ;Additional file 3: Table S2 ). Examination of association with T1D for replicated pQTL variants We further examined the association of replicated cis -pQTLs with T1D through publicly available resources. The T1D Knowledge Portal (https://t1d.hugeamp.org) enables searching of human genomic variants linked to T1D and other related phenotypes. We used the T1D Knowledge Portal and found that all 23 and 12 replicated cis -pQTLs for CFB and C4A respectively have been reported genome-wide significantly (p-value<5x10 -8 ) associated with T1D risk (Additional file 3: Table S2 ; Additional file 1: Fig. S6-7 ). The T1D association p-values were obtained from a previous T1D study 24 , and the p-values range from 1.11x10 -37 (C4A: rs9262570) to 6.29x10 -235 (CFB: rs114355928) (Additional file 3: Table S2 ). For the other replicated cis -pQTLs, we found that they were significantly associated with highlight scatter reticulocyte count (C8A and C8B, Additional file 1: Fig. S8-9 ), chronic kidney disease and reticulocyte count (MBL2, Additional file 1: Fig. S10-11 ). Discussion Previous reports have examined the involvement of the complement system in the initiation and progression of IA for the study of T1D 8 , 11 , 12 , 14 , however, the genetic factors underlying the complement system proteins at the time of triggering of IA are poorly unknown. Our study investigated genetic variants that are associated with complement system proteins in DAISY, a prospective cohort of children from the general population who either had a first degree relative with T1D or had a high-risk human leukocyte antigen (HLA) genotype. From pooled and IA case-stratified analyses with 170 participants in the DAISY, 240 significant (FDR < 0.1) cis -pQTLs were associated with 14 complement system proteins. We replicated 68 cis -pQTLs with statistical significance (FDR < 0.05) in the 385 IA cases from the TEDDY study. The 68 replicated cis -pQTLs represent C8A and C8B, CFB and C4A (within the HLA region), and MBL2. The CFB and C4A cis -pQTLs are known genetic associations with T1D. However, the strong linkage disequilibrium within the region has limited our understanding of the independent contribution of complement system to T1D risk. Our study provides new insight into the role of complement system on the disease progression. CFB (Complement Factor B) is located on chromosome 6 and between the HLA class II and class I regions 7 . The HLA region is the single most important genetic determinant of T1D susceptibility. The variability in the HLA region has been estimated to explain approximately 60% of the genetic influence of T1D 25 . CFB is a component of the alternative pathway of complement activation. The detailed function of CFB has been reported in a previous study 15 . T1D-associated genetic variants in CFB have been reported in European ancestry 26 , 27 and Northern India 28 . The 23 replicated cis -pQTLs of CFB identified in our study, which decrease protein level, are found to be significantly associated with increasing T1D risk in a large-scale genomic study of T1D 24 . The T1D association p-value ranges from 5.38x10 − 43 (rs115272033, EHMT2 intron) to 6.29x10 − 235 (rs114355928, TSBP1 intron) (Additional file 3: Table S2 ). C4A (Complement Component 4A) is also located between the HLA class II and class I regions 7 and is part of the classical and lectin pathways of activating complement system. Two functionally distinct genes, C4A and C4B, code the C4 protein together. Limited T1D association studies have been focused on the structural variation of this region 15 . The previously reported associations of genetic variants in C4A with T1D focused on European ancestry population 29 , 30 . Our study found that the 12 replicated cis -pQTLs of C4A were previously identified to be significantly associated with increasing T1D risk 24 . The T1D association p-value ranges from 1.11x10 − 37 (rs9262570, intergenic) to 1.33x10 − 88 (rs9263822, PSORS1C3 intron) (Additional file 3: Table S2 ). Our study identified three genes outside of HLA region (C8A, C8B and MBL) in addition to two genes in the HLA region. Both C8A (Complement C8 Alpha Chain) and C8B (Complement C8 Beta Chain) are located on chromosome 1 and encode Complement Component 8 (C8) protein. C8 participates in the formation of the membrane attack complex, which causes cell lysis and/or pro-inflammatory signaling 15 . MBL2 (Mannose-Binding Lectin 2) is located on chromosome 10 and is the only single gene to encode human Mannose-Binding Lectin (MBL). MBL is a soluble lectin that activates the lectin complement pathway by recognizing microorganisms through the carbohydrate-recognition domain, thereby modulating inflammation 31 . Although our replicated cis -pQTLs of MBL2 were not associated with T1D, previous studies have identified their associations with type 2 diabetes and pneumonia. For example, the variant rs1800450 has been linked to type 2 diabetes in diverse populations, including the full-heritage Pima Indians and the Old Order Amish 32 , and the North Chinese Han population 33 . Additionally, Uysalol et al. 34 reported that the rs1800450 genotypes associated with low MBL expression were significantly more common in patients with pneumonia and severe infections. Strengths of this study include being one of the very few studies that examined pQTL mapping of complement system proteins in children with high risk of developing T1D and the use of independent study data to replicate significant pQTL signals. However, some limitations warrant mentioning. First, the statistical power of identifying significant cis -pQTLs in our study is still limited due to the sample size of both discovery and replication analyses. Second, the protein assay platform in the replication analysis is different from that in the discovery analysis for the significant findings of MBL2. We only identified statistically significant cis -pQTLs in the Exsera platform for MBL2 in the DAISY discovery analysis, however, the replication analysis in TEDDY was only available to use measured protein levels from a different protein assay, the SRM platform. Hence, future validation for the identified cis -pQTLs of MBL2 needs to be conducted on measured protein levels from the Exsera platform. Lastly, the participants in our study are predominantly composed of Non-Hispanic Whites. Hence, our findings cannot be generalized to non-European ancestry populations yet. Future research focusing on non-European or diverse ancestries will help improve the understanding of genetic mechanisms underlying the complement system and provide a more comprehensive insight into the role of complement system proteins in the etiology of T1D. Conclusions In summary, this study performed pQTL mapping of complement system proteins in children at high risk of developing T1D and replicated significant signals in an independent study of children with T1D. Our study confirmed that genetic variants regulating two complement system proteins CFB and C4A, located in the HLA-region, are associated with an increased risk of T1D. Further, we identified three non-HLA-region complement system proteins (C8A, C8B, and MBL2) as potential biomarkers with a putative role in the etiology of T1D. Methods Overview of approach We performed cis -pQTL mapping for 170 samples (131 IA cases and 39 controls) in The Diabetes Autoimmunity Study in the Young (DAISY) as discovery analysis to identify statistically significant cis -pQTL variants for complement system proteins. To follow up on our pQTL analysis in DAISY, we conducted replication analysis for 385 IA samples from The Environmental Determinants of Diabetes in the Young (TEDDY) study. Finally, we used the T1D Knowledge Portal ( https://t1d.hugeamp.org/ ) to examine replicated cis -pQTLs for their association with T1D and other disease-relevant traits. DAISY: study design, proteomic profiling and genotyping Study design : DAISY is a prospective cohort of 2,547 children from the general population who either had a first degree relative with T1D or had a high-risk human leukocyte antigen (HLA) genotype. The participants were recruited in Denver, Colorado between 1993 and 2004, and followed for up to 21 years 35 , 36 . Follow-up results are available through April 4, 2022. Written informed consent was obtained from participants and parents. The Colorado Multiple Institutional Review Board approved all protocols. The primary goal of DAISY is to learn how genes and the environment interact to cause childhood T1D 35 . Proteomic profiling : The peptides of complement system proteins were measured by two different assay platforms for DAISY participants, selected reaction monitoring (SRM)-based 22 , and Exsera Biolabs-based (referred herein as Exsera) 23 . The Exsera targeted proteomics use commercial immunoassays in a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-accredited laboratory. The details of two protein assay platforms for DAISY participants are described in a previous study 14 . Genotype quality control and imputation : Genome-wide genotyping was performed using the custom designed Infinium TEDDY-T1D Exome array (Illumina) and was genotyped at the University of Virginia (UVA) Genome Sciences Laboratory following the manufacturer’s protocol (Illumina). The following quality control (QC) criteria were applied: 1) samples with a genotype call rate < 0.95 were removed; and 2) single nucleotide polymorphism (SNP) level QC included removal of monomorphic SNPs, and removal of SNPs that deviated from Hardy-Weiberg equilibrium (p-value < 1x10 − 20 at the HLA region or p-value < 1x10 − 6 otherwise). Genome-wide imputation used the Trans-Omics for Precision Medicine (TOPMed) multi-ancestry reference panel (version R2). The SNP was selected if minor allele frequency (MAF) ≥ 0.05 and imputation quality R 2 ≥ 0.7. The details of QC criteria of genomic variants used in this study are provided in a previous study 37 . TEDDY: study design, proteomic profiling and genotyping Study design : TEDDY is an international prospective study that was designed to identify T1D-associated environmental factors in children who carry a high genetic risk for the disease 38 . The participating clinical centers include Colorado, Georgia/Florida, and Washington in the US, and Finland, Germany, and Sweden in Europe. We only reported summary statistics of self-reported Non-Hispanic White (NHW) from US centers for TEDDY as many missing or unknown race/ethnicity were reported from European centers. For TEDDY study, all procedures were approved by the ethics committees / institutional review boards including Colorado Multiple Institutional Review Board (04-0361); Medical College of Georgia Human Assurance Committee (2004–2010)/Georgia Health Sciences University Human Assurance Committee (2011–2012)/Georgia Regents University Institutional Review Board (2013–2017)/Augusta University Institutional Review Board (2017-present) (HAC 0405380); University of Florida Health Center Institutional Review Board (IRB201600277); Washington State Institutional Review Board (2004–2012)/Western Institutional Review Board (2013–present) (20130211); Ethics Committee of the Hospital District of Southwest Finland (Dnro168/2004); Bayerischen Landesärztekammer (Bavarian Medical Association) Ethics Committee (04089); and Regional Ethics Board in Lund, Section 2 (2004–2012)/Lund University Committee for Continuing Ethical Review (2013-present) (217/2004). In addition, TEDDY is monitored by an external evaluation committee formed by the National Institutes of Health, Bethesda, MD, U.S.A. Proteomic profiling and genotyping : Both proteomics and imputed genotype data were provided by the TEDDY Data Coordinating Center. The peptides of complement system proteins for TEDDY participants were measured by SRM-based assay. The details of the protein assay for TEDDY are described in a previous study 13 . SNPs were genotyped using the ImmunoChip and/or the TEDDY-T1DexomeChip at the Center for Public Health Genomics at the UVA, US. GWAS imputation analysis was conducted using the TOPMed Version R2 (built from 97,256 deeply sequenced human genomes containing 308,107,085 genetic variants), the 1000 Genomes, and a subset of the TEDDY subjects (n = 1,119) with the whole-genome sequencing data as reference panels. MetaMinimac2 was used to combine genotype data imputed against these three reference panels. For imputed genotype data, we retained rare variants with MAF > 0.05 in unrelated controls with European ancestry and with imputation quality R 2 > 0.50. cis -pQTL mapping in DAISY A cis -pQTL mapping is to test the association between measured protein levels and cis -pQTL genomic variants via statistical model. We defined a cis -pQTL genomic variant as a SNP within +/- 1Mb of the transcription start site (TSS) of the corresponding protein-coding gene. We applied a linear mixed model adjusted for age, sex, self-reported race/ethnicity, protein plate effects, first-degree relative with T1D (yes or no), the first two principal components (PCs) of genetic ancestry, and genetic relationship matrix (GRM) to perform cis -pQTL mapping in our study. The association analyses were conducted using R/GENESIS 39 . The mapping results were then filtered on 1) expected heterozygosity count (EHC) > 6 for WGS data, and 2) imputation quality > 0.3 and EHC > 6 for imputation genotypes by using R/EasyQC 40 . We first performed cis -pQTL mapping on DAISY participants with Islet autoimmunity (IA), referred herein as IA cases. Participants were considered to have IA if they were positive for one or more islet autoantibodies tests on two or more consecutive visits or being autoantibody positive with a diagnosis of diabetes at the next visit by the American Diabetes Association criteria 41 . For protein levels of IA cases, 1) we averaged measured peptides if a participant had multiple peptides at one time point, and 2) we used the earliest time point if a participant had multiple visits for peptide measures. We then applied log2-transformation on the selected peptides and treated the transformed peptides as outcome variables for the linear mixed model. Due to limited IA cases in DAISY, we also conducted case-control pooled analysis for DAISY with additional group adjustment (i.e., case or control) to increase statistical power of cis -pQTL mapping. For protein levels of controls, we followed the same procedure as IA cases except for the selection of time points for controls who have multiple peptides by different visits. To obtain a similar age as IA cases for most controls, we selected the closest time point to the median age of selected visits of IA cases for controls. Finally, we applied false discovery rate (FDR) correction (Benjamini-Hochberg) at 10% on cis -pQTL mapping results to identify statistically significant cis -pQTLs in DAISY by different protein assay platforms and by different stratified analyses respectively. For proteins with many FDR-significant cis -pQTLs, we further performed fine-mapping using SuSiE 42 to identify potential causal cis -pQTLs. The variant clustered in a 95% credible set (CS) is considered as a fine-mapped variant 42 . Replication analysis in TEDDY To follow-up on statistically significant cis -pQTLs identified in DAISY discovery analysis, we applied a linear mixed model adjusted for age, sex, protein plate effects, clinical centers, first-degree relative with T1D (yes or no), the first two PCs of ancestry, and GRM to test association between DAISY FDR-significant cis -pQTLs and log2-transformed peptides for TEDDY IA cases. We then applied FDR correction at 5% on TEDDY mapping results to identify replicated cis -pQTLs. PheWAS of replicated cis -pQTLs The T1D Knowledge Portal ( https://t1d.hugeamp.org ) enables searching of human genomic variants linked to T1D and other related phenotypes. We used T1D Knowledge Portal to examine replicated cis -pQTLs for their association with T1D and other disease-relevant traits. Declarations Acknowledgements The authors acknowledge Research Computing at The University of Virginia for providing computational resources and technical support that have contributed to the results reported within this manuscript. URL:https://rc.virginia.edu. The authors also acknowledge the TEDDY Study Group as follows: Colorado Clinical Center: Marian Rewers, M.D., Ph.D., PI 1,4,6,9,10 , Kimberly Bautista 11 , Judith Baxter 8,911 , Daniel Felipe-Morales, Brigitte I. Frohnert, M.D., Ph.D. 2,13 , Marisa Stahl, M.D. 12 , Isabel Flores Garcia, Patricia Gesualdo 2, 6,11,13 , Sierra Hays, Michelle Hoffman 11,12,13 , Randi Johnson, Ph.D. 2,3 , Rachel Karban 11 , Edwin Liu, M.D. 12 , Leila Loaiza, Jill Norris, Ph.D. 2,3,11 , Holly O’Donnell, Ph.D. 8 , Andrea Steck, M.D. 3,13 , Kathleen Waugh 6,7,11 . University of Colorado, Anschutz Medical Campus, Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA. Finland Clinical Center: Jorma Toppari, M.D., Ph.D., PI ¥^1,4,10,13 ,Olli G. Simell, M.D., Ph.D., Annika Adamsson, Ph.D. ^11 , Suvi Ahonen* ±§ , Mari Åkerlund* ±§ , Sirpa Anttila µ¤ , Leena Hakola, Ph.D.* ± , Sanni Heikura µ¤ , Tiia Honkanen µ¤ , Heikki Hyöty, M.D., Ph.D.* ±6 , Jorma Ilonen, M.D., Ph.D. ¥3 , Saori Itoshima, M.D. ¥^ , Minna Jokipolvi *± , Sanna Jokipuu ^ , Taru Karjalainen µ¤ , Leena Karlsson ^ , Pieta Kemppainen µ¤ , Jukka Kero, M.D., Ph.D. ¥^3, 13 , Marika Korpela µ¤ , Jaakko J. Koskenniemi M.D., Ph.D. ¥^ , Miia Kähönen µ¤11,13 , Mikael Knip, M.D., Ph.D.* ± , Minna-Liisa Koivikko µ¤ , Katja Kokkonen* ± , Merja Koskinen* ± , Mirva Koreasalo* ±§2 , Kalle Kurppa, M.D., Ph.D.* ±12 , Salla Kuusela, M.D. µ¤ , Jarita Kytölä *± , Jutta Laiho, Ph.D.* 6 , Tiina Latva-aho µ¤ , Siiri Leisku *± , Laura Leppänen ^ , Katri Lindfors, Ph.D.* 12 , Maria Lönnrot, M.D., Ph.D.* ±6 , Elina Mäntymäki ^ , Markus Mattila, Ph.D.* ±2 , Maija E. Miettinen, Ph.D. §2 , Teija Mykkänen µ¤ , Tiina Niininen ± * 11 , Sari Niinistö, Ph.D. §2 , Noora Nurminen *± , Sami Oikarinen, Ph.D.* ±6 , Hanna-Leena Oinas* ± , Paula Ollikainen µ ¤ , Zhian Othmani ¥ , Sirpa Pohjola µ¤ , Jenna Rautanen § , Mia Rein µ¤ , Minna Romo ^ , Juulia Rönkä µ¤ , Nelli Rönkä µ¤ , Noora Ruotsalainen µ¤ , Satu Simell, M.D., Ph.D. ¥12 , Päivi Tossavainen, M.D. µ¤ , Erika Turtinen µ¤ , Mari Vähä-Mäkilä ¥ , Eeva Varjonen ^11 , Riitta Veijola, M.D., Ph.D. µ¤13 , Irene Viinikangas µ¤ , Suvi M. Virtanen, M.D., Ph.D.* ±§2 . ¥ University of Turku, Turku, Finland, *Tampere University, Tampere, Finland, µ University of Oulu, Oulu, Finland, ^ Turku University Hospital, Wellbeing Services County of Southwest Finland, Turku, Finland, ± Tampere University Hospital, Wellbeing Services County of Pirkanmaa, Tampere, Finland, ¤ Oulu University Hospital, Wellbeing Services County of North Ostrobothia, Oulu, Finland, § Finnish Institute for Health and Welfare, Helsinki, Finland. Georgia/Florida Clinical Center: Richard McIndoe, Ph.D., PI ^4,10 , Desmond Schatz*, M.D.* 4,7,8 , Diane Hopkins ^11 , Michael Haller, M.D.* 13 , Melissa Gardiner ^11 , Ashok Sharma ^ , Ph.D. ^ , Laura Jacobsen, M.D.* 13 , Percy Gordon ^ , Jennifer Hosford*,. ^ Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, USA. *University of Florida, Pediatric Endocrinology, Gainesville, FL, USA. Germany Clinical Center: Anette G. Ziegler, M.D., PI 1,3,4,10 , Ezio Bonifacio Ph.D.*, Cigdem Sanverdi, Anja Heublein, Sandra Hummel, Ph.D. 2 , Annette Knopff 7 , Melanie Köger, Sibylle Koletzko, M.D. ¶12 , Claudia Ramminger 11 , Roswith Roth, Ph.D. 8 , Jennifer Schmidt, Marlon Scholz, Joanna Stock 8,11,13 , Katharina Warncke, M.D. 13 , Lorena Müller, Christiane Winkler, Ph.D. 2,11 . Forschergruppe Diabetes e.V. and Institute of Diabetes Research, Helmholtz Zentrum München, Forschergruppe Diabetes, and Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany. *Center for Regenerative Therapies, TU Dresden, Dresden, Germany, ¶ Dr. von Hauner Children’s Hospital, Department of Gastroenterology, Ludwig Maximillians University Munich, Munich, Germany. Sweden Clinical Center: Åke Lernmark, Ph.D., PI 1,3,4,5,6,8,9,10 , Daniel Agardh, M.D., Ph.D. 6,12 , Carin Andrén Aronsson, Ph.D. 2,11,12 , Rasmus Bennet, Corrado Cilio, Ph.D., M.D. 6 , Susanne Dahlberg, Malin Goldman Tsubarah, Emelie Ericson-Hallström, Lina Fransson, Emina Halilovic, Susanne Hyberg, Berglind Jonsdottir, M.D., Ph.D. 11 , Naghmeh Karimi, Helena Elding Larsson, M.D., Ph.D. 6,13 , Marielle Lindström, Markus Lundgren, M.D., Ph.D. 13 , Jessica Melin, Ph.D. 11 , Kobra Rahmati, Anita Ramelius, Falastin Salami, Ph.D., Anette Sjöberg, Evelyn Tekum Amboh, Carina Törn, Ph.D. 3 , Ulrika Ulvenhag, Terese Wiktorsson, Åsa Wimar 13 . Lund University, Lund, Sweden. Past staff: Eva Andersson, Marie Andersson Turpeinen, Rawya Antar, Maria Ask, Jenny Bremer, Sylvia Bianconi Svensson, Ulla-Marie Carlsson, Magdalena Delikat Kulinski, Annika Fors, Ulla Fält, Thomas Gard, Joanna Gerardsson, Monika Hansen, Anna Hansson, Carina Hansson, Gertie Hansson, Elin M. Hård af Segerstad, Ph.D. 2 , Hanna Jisser, Fredrik Johansen, Linda Jonsson, Silvija Jovic, Sigrid Lenrick Forss, Barbro Lernmark, Ph.D. 8 , Maria Markan, Theodosia Massadakis, Marlena Maziarz, Ph.D., Zeliha Mestan, Maria Månsson Martinez, Caroline Nilsson, Emma Nilsson, Yohanna Nordh, Karin Ottosson, Sara Rang, Anna Rosenquist, Monika Sedig Järvirova, Sara Sibthorpe, Birgitta Sjöberg, Ulrika Swartling Ph.D. 8 , Erika Trulsson, Anne Wallin, Ingrid Wigheden, Sofie Åberg. Washington Clinical Center: William A. Hagopian, M.D., Ph.D., PI ^1,3,4,6,7,10,12,13 , Michael Killian* 6,7,11,12 , Claire Cowen Crouch* 11,13 , Jennifer Skidmore* 2 , Ben Kim*, Cody McCall*, Arlene Meyer*, Jared Radtke*, Shreya Roy*. ^ Indiana University, Indianapolis, IN, USA. *Pacific Northwest Research Institute, Seattle, WA, USA. Pennsylvania Satellite Center: Dorothy Becker, M.D., Margaret Franciscus, MaryEllen Dalmagro-Elias Smith 2 , Ashi Daftary, M.D., Mary Beth Klein, Chrystal Yates. Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. Data Coordinating Center: Jeffrey P. Krischer, Ph.D., PI 1,4,5,9,10 , Rajesh Adusumali, Sarah Austin-Gonzalez, Maryouri Avendano, Sandra Baethke, Brant Burkhardt, Ph.D. 6 , Martha Butterworth 2 , Nicholas Cadigan, Joanna Clasen, Ph.D., Kevin Counts, Laura Gandolfo, Jennifer Garmeson, Veena Gowda, Shu Liu, Xiang Liu, Ph.D. 2,3,8,13 , Kristian Lynch, Ph.D. 6,8 , Jamie Malloy, Lazarus Mramba, Ph.D. 2 , Cristina McCarthy 11 , Hemang M. Parikh, Ph.D. 3,8 , Cassandra Remedios, Chris Shaffer, Susan Smith 11 , Noah Sulman, Ph.D., Roy Tamura, Ph.D. 1,2,11,12,13 , Dena Tewey, Henri Thuma, Michael Toth, Ulla Uusitalo, Ph.D. 2 , Kendra Vehik, Ph.D. 4,5,6,8,13 , Ponni Vijayakandipan, Melissa Wroble, Jimin Yang, Ph.D., R.D. 2 , Kenneth Young, Ph.D. Past staff: Michael Abbondondolo, Lori Ballard, Rasheedah Brown, David Cuthbertson, Stephen Dankyi, Christopher Eberhard, Steven Fiske, David Hadley, Ph.D., Kathleen Heyman, Belinda Hsiao, Christina Karges, Francisco Perez Laras, Hye-Seung Lee, Ph.D., Qian Li, Ph.D., Colleen Maguire, Wendy McLeod, Aubrie Merrell, Steven Meulemans, Jose Moreno, Ryan Quigley, Laura Smith, Ph.D. University of South Florida, Tampa, FL, USA. Project scientist: Beena Akolkar, Ph.D. 1,3,4,5,6,7,9,10 . National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA. Other contributors: Thomas Briese, Ph.D. 6 , Columbia University, New York, NY, USA. Todd Brusko, Ph.D. 5 , University of Florida, Gainesville, FL, USA. Teresa Buckner, Ph.D. 2 , University of Northern Colorado, Greeley, CO, USA. Suzanne Bennett Johnson, Ph.D. 8,11 , Florida State University, Tallahassee, FL, USA. Eoin McKinney, Ph.D. 5 , University of Cambridge, Cambridge, UK. Tomi Pastinen, M.D., Ph.D. 5 , The Children’s Mercy Hospital, Kansas City, MO, USA. Steffen Ullitz Thorsen, M.D., Ph.D. 2 , Department of Clinical Immunology, University of Copenhagen, Copenhagen, Denmark, and Department of Pediatrics and Adolescents, Copenhagen University Hospital, Herlev, Denmark. Eric Triplett, Ph.D. 6 , University of Florida, Gainesville, FL, USA. Committees: 1 Ancillary Studies, 2 Diet, 3 Genetics, 4 Human Subjects/Publicity/Publications, 5 Immune Markers, 6 Infectious Agents, 7 Laboratory Implementation, 8 Psychosocial, 9 Quality Assurance, 10 Steering, 11 Study Coordinators, 12 Celiac Disease, 13 Clinical Implementation. Authors’ contributions XW, AM, and MJR designed the study. BJMWR, AFA, ESN, TOM, and MJR provided DAISY proteomics data. SOG, WMC, and SSR provided DAISY genotype data. HMP provided TEDDY proteomics and genotype data. XW performed statistical analyses and wrote the manuscript. XW, AM, BJMWR, ESN, SOG, SSR, and MJR interpreted results. All authors read, reviewed, and approved the final manuscript for publication. Funding This work was funded by Leona M. and Harry B. Helmsley Charitable Trust grants 2018PG-T1D017 and G-2103-05121. The TEDDY Study is funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and Breakthrough T1D (formerly JDRF). This work is supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR002535). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Availability of data and materials The TEDDY Immunochip (SNP) data that support the findings of this study have been deposited in NCBI’s database of Genotypes and Phenotypes (dbGaP) with the primary accession code phs001442.v4.p3. The TEDDY-T1DExome Array data that support the findings of this study have been deposited in NCBI’s database of Genotypes and Phenotypes (dbGaP) with the primary accession code phs001442.v4.p3. The TEDDY Whole Genome Sequencing (WGS) data that support the findings of this study have been deposited in NCBI’s database of Genotypes and Phenotypes (dbGaP) with the primary accession code phs001442.v4.p3. The TEDDY Proteomics Discovery Phase data that support the findings of this study are available from the Mass Spectrometry Interactive Virtual Environment (MassIVE) repository https://massive.ucsd.edu/ via its dataset identifier MSV000091560 (https://doi.org/doi:10.25345/C5V11VW3F). The TEDDY Proteomics Validation Phase data that support the findings of this study are available from the Mass Spectrometry Interactive Virtual Environment (MassIVE) repository https://massive.ucsd.edu/ via its dataset identifier MSV000091562 (https://doi.org/doi:10.25345/C5KH0F84V). Ethics approval and consent to participate For DAISY cohort, written informed consent was obtained from participants and parents. The Colorado Multiple Institutional Review Board approved all protocols of DAISY cohort. For TEDDY study, all procedures were approved by the ethics committees / institutional review boards including Colorado Multiple Institutional Review Board (04-0361); Medical College of Georgia Human Assurance Committee (2004–2010)/Georgia Health Sciences University Human Assurance Committee (2011–2012)/Georgia Regents University Institutional Review Board (2013–2017)/Augusta University Institutional Review Board (2017-present) (HAC 0405380); University of Florida Health Center Institutional Review Board (IRB201600277); Washington State Institutional Review Board (2004–2012)/Western Institutional Review Board (2013–present) (20130211); Ethics Committee of the Hospital District of Southwest Finland (Dnro168/2004); Bayerischen Landesärztekammer (Bavarian Medical Association) Ethics Committee (04089); and Regional Ethics Board in Lund, Section 2 (2004–2012)/Lund University Committee for Continuing Ethical Review (2013-present) (217/2004). In addition, TEDDY is monitored by an external evaluation committee formed by the National Institutes of Health, Bethesda, MD, U.S.A. Competing interests The authors declare no competing interests. References Eringsmark Regnéll, S. & Lernmark, A. The environment and the origins of islet autoimmunity and Type 1 diabetes. Diabet. Med. J. Br. Diabet. Assoc. 30 , 155–160 (2013). Krischer, J. P. et al. Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study. Diabetologia 64 , 2247–2257 (2021). Holers, V. M. Complement and its receptors: new insights into human disease. Annu. Rev. Immunol. 32 , 433–459 (2014). Radillo, O. et al. Complement-Fixing Islet Cell Antibodies in Type-1 Diabetes Can Trigger the Assembly of the Terminal Complement Complex on Human Islet Cells and Are Potentially Cytotoxic. Clin. Immunol. Immunopathol. 79 , 217–223 (1996). Chen, M., Daha, M. R. & Kallenberg, C. G. M. The complement system in systemic autoimmune disease. J. Autoimmun. 34 , J276-286 (2010). Sturfelt, G. & Truedsson, L. Complement in the immunopathogenesis of rheumatic disease. Nat. Rev. Rheumatol. 8 , 458–468 (2012). Törn, C. et al. Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study. Sci. Rep. 6 , 27887 (2016). Ajjan, R. A. & Schroeder, V. Role of complement in diabetes. Mol. Immunol. 114 , 270–277 (2019). Zhang, Q. et al. Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes. J. Exp. Med. 210 , 191–203 (2013). Sarkar, S. et al. Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response. Clin. Proteomics 20 , 38 (2023). Moulder, R. et al. Serum Proteomes Distinguish Children Developing Type 1 Diabetes in a Cohort With HLA-Conferred Susceptibility. Diabetes 64 , 2265–2278 (2015). von Toerne, C. et al. Peptide serum markers in islet autoantibody-positive children. Diabetologia 60 , 287–295 (2017). Nakayasu, E. S. et al. Plasma protein biomarkers predict the development of persistent autoantibodies and type 1 diabetes 6 months prior to the onset of autoimmunity. Cell Rep. Med. 4 , 101093 (2023). Webb-Robertson, B.-J. M. et al. Decrease in multiple complement proteins associated with development of islet autoimmunity and type 1 diabetes. iScience 27 , (2024). Onengut-Gumuscu, S. et al. Genetic variants in the complement system and their potential link in the aetiology of type 1 diabetes. Diabetes Metab. Res. Rev. 40 , e3716 (2024). Sun, B. B. et al. Genomic atlas of the human plasma proteome. Nature 558 , 73–79 (2018). Suhre, K. et al. Connecting genetic risk to disease end points through the human blood plasma proteome. Nat. Commun. 8 , 14357 (2017). Yao, C. et al. Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease. Nat. Commun. 9 , 3268 (2018). Yang, Z. et al. Genetic Landscape of the ACE2 Coronavirus Receptor. Circulation 145 , 1398–1411 (2022). Katz, D. H. et al. Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease. Circulation 145 , 357–370 (2022). Jiang, M.-Z. et al. Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium. Hum. Mol. Genet. 33 , 1429–1441 (2024). Nakayasu, E. S. et al. Tutorial: best practices and considerations for mass-spectrometry-based protein biomarker discovery and validation. Nat. Protoc. 16 , 3737–3760 (2021). Prohászka, Z., Nilsson, B., Frazer-Abel, A. & Kirschfink, M. Complement analysis 2016: Clinical indications, laboratory diagnostics and quality control. Immunobiology 221 , 1247–1258 (2016). Chiou, J. et al. Interpreting type 1 diabetes risk with genetics and single-cell epigenomics. Nature 594 , 398–402 (2021). Lambert, A. P. et al. Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. J. Clin. Endocrinol. Metab. 89 , 4037–4043 (2004). McCluskey, J. et al. HLA and complement allotypes in Type 1 (insulin-dependent) diabetes. Diabetologia 24 , 162–165 (1983). Alper, C. A., Awdeh, Z. L. & Yunis, E. J. Complotypes and extended haplotypes in laboratory medicine. Complement Inflamm. 6 , 8–18 (1989). Kumar, N., Kaur, G., Tandon, N. & Mehra, N. K. Allotyping human complement factor B in Asian Indian type 1 diabetic patients. Tissue Antigens 72 , 517–524 (2008). Bertrams, J., Hintzen, U., Schlicht, V. & Schoeps, S. C4: another marker for type I diabetes. Lancet Lond. Engl. 1 , 41 (1982). Bertrams, J. et al. Gene and haplotype frequencies of the fourth component of complement (C4) in type 1 diabetics and normal controls. Immunobiology 166 , 335–344 (1984). Choteau, L. et al. Role of mannose-binding lectin in intestinal homeostasis and fungal elimination. Mucosal Immunol. 9 , 767–776 (2016). Muller, Y. L. et al. Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish. Diabetes 59 , 2080–2085 (2010). Zhang, N. et al. Association of levels of mannose-binding lectin and the MBL2 gene with type 2 diabetes and diabetic nephropathy. PloS One 8 , e83059 (2013). Uysalol, M. et al. Importance of mannose-binding lectin2 polymorphism (rs1800450) in infections in children. Biomarkers (2022). Rewers, M. et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia 39 , 807–812 (1996). Frohnert, B. I. et al. Late-onset islet autoimmunity in childhood: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 60 , 998–1006 (2017). Buckner, T. et al. Genome-wide analysis of oxylipins and oxylipin profiles in a pediatric population. Front. Nutr. 10 , (2023). TEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr. Diabetes 8 , 286–298 (2007). Gogarten, S. M. et al. Genetic association testing using the GENESIS R/Bioconductor package. Bioinformatics 35 , 5346–5348 (2019). Winkler, T. W. et al. Quality control and conduct of genome-wide association meta-analyses. Nat. Protoc. 9 , 1192–1212 (2014). American Diabetes Association. 2. Classification and Diagnosis of Diabetes. Diabetes Care 39 , S13–S22 (2015). Wang, G., Sarkar, A., Carbonetto, P. & Stephens, M. A simple new approach to variable selection in regression, with application to genetic fine mapping. J. R. Stat. Soc. Ser. B Stat. Methodol. 82 , 1273–1300 (2020). Tables Table 1 Clinical characteristics of samples in DAISY and TEDDY. median ± standard deviation; DAISY, the Diabetes Autoimmunity Study in the Young study; TEDDY, The Environment Determinants of Diabetes in the Young study; IA, islet autoimmunity; # age matches with sample’s protein collection time; T1D, type 1 diabetes; NHW, Non-Hispanic White; *TEDDY participants are from three United States (US) clinical centers (Colorado, Georgia/Florida, Washington) and three European clinical centers (Finland, Germany, Sweden), the summary statistics are from three US clinical centers as European clinical centers report many missing or unknown race/ethnicity. Table 2 Summary of FDR-significant (FDR<0.1) cis -pQTLs identified in DAISY. DAISY, the Diabetes Autoimmunity Study in the Young study; 10 overlapped proteins between SRM and Exsera are highlighted in bold; SRM, selected reaction monitoring mass spectrometry assay; FDR, false discovery rate; Total, union of significant cis -pQTLs after fine mapping from pooled and case-stratified analyses; –, protein data was not available in the corresponding assay. Table 3 Summary of replicated cis -pQTLs in TEDDY. Chr, chromosome; FDR, false discovery rate; Beta (SE)/P-value, cis -pQTL mapping effect size (standard error)/P-value for 385 TEDDY IA cases; TEDDY, The Environment Determinants of Diabetes in the Young study; IA, islet autoimmunity; T1D, type 1 diabetes; *, top pQTL variant, see Supplementary Table S2 for full replicated cis -pQTL list. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTables.xlsx Additional file 2: Table S1. FDR-significant (FDR<0.1) cis -pQTLs in DAISY. Additional file 3: Table S2. FDR-significant (FDR<0.05) replicated cis -pQTLs in TEDDY. SupplementaryInformation.docx Supplementary Information Additional file 1: Supplementary Information for Figure S1-S11. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5975824","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":412530136,"identity":"f1508286-8952-4c96-9d20-a33a93fd146f","order_by":0,"name":"Xiaowei 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15:19:06","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":70607,"visible":true,"origin":"","legend":"\u003cp\u003eAdditional file 2: Table S1. FDR-significant (FDR\u0026lt;0.1) \u003cem\u003ecis\u003c/em\u003e-pQTLs in DAISY.\u003c/p\u003e\n\u003cp\u003eAdditional file 3: Table S2. FDR-significant (FDR\u0026lt;0.05) replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs in TEDDY.\u003c/p\u003e","description":"","filename":"SupplementaryTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5975824/v1/cd4cc2ca43b31f124611ec0c.xlsx"},{"id":75926312,"identity":"4ac2372e-2f38-4796-bc48-67aa217fd966","added_by":"auto","created_at":"2025-02-10 15:19:05","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2190265,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional file 1: Supplementary Information for Figure S1-S11.\u003c/p\u003e","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-5975824/v1/692058271210708bcfd5d05e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genome-wide mapping of complement system proteins for islet autoimmunity in the DAISY and TEDDY children","fulltext":[{"header":"Background","content":"\u003cp\u003eType 1 diabetes (T1D) is a complex autoimmune disease where an autoimmune attack destroys the pancreatic islet beta cells, which eventually results in a complete dependency on exogenic insulin. There is no cure for T1D yet, and the disease progression is not well understood. Hence, the development of biomarkers that can help track disease progression and determine disease causes is important for T1D prevention and therapy. The islet antibodies are well-recognized and reliable diagnostic biomarkers that mark the onset of islet autoimmunity (IA), and persistent multi-positivity of islet autoantibodies can be used to predict individuals at high risk of developing T1D\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. However, the genetic mechanisms of the initiation of IA, as well as the progression from IA to clinical diabetes, are still largely unknown.\u003c/p\u003e \u003cp\u003eThe complement system, also known as complement cascade, plays an important role in the innate immune system, which helps to fight bacterial or viral infections and promotes clearance of damaged cells\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Three interrelated pathways activate the complement system, specifically the classical, lectin, and alternative pathways. These activation pathways converge at the terminal pathway, where much of the effector function resides\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The complement system also modulates adaptive immunity through activation by antibodies, including autoantibodies\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Several studies have suggested that the dysregulation of the complement system contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, rheumatoid arthritis\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, and T1D\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. More specifically, increasing studies have reported the involvement of the complement system in the initiation and progression of IA for the study of T1D\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Furthermore, recent studies observed lower levels of several complement system proteins in children with islet autoantibodies compared to healthy controls\u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. However, the genetic factors that result in decreased abundance of complement system proteins at the time of triggering of IA are currently unclear\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCirculating plasma proteins play a fundamental role in human biological processes and are frequently the targets of pharmaceutical interventions\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Protein quantitative trait locus (pQTL) mapping is an approach that can identify genetic variants underlying variation of protein expression levels. In prior studies, pQTL analysis has led to critical advances in knowledge of the genetic architecture of plasma proteins and their relationship to disease\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, we aim to improve our understanding of the genetic factors of complement system proteins at the time of triggering of IA and bring us closer to dissecting the genetic mechanisms underlying the development and progression of T1D. Here, we performed pQTL analysis of 170 participants in the Diabetes Autoimmunity Study in the Young (DAISY) to identify statistically significant pQTLs for complement system proteins. Complement system proteins for DAISY participants were measured by two different protein assay platforms, selected reaction monitoring (SRM)\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, and Exsera Biolabs\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e (hereinafter referred to as Exsera). Complement system proteins measured by two platforms were approximately overlapped in half. Hence, using proteins from both platforms provides a more comprehensive list of complement system proteins for study. Replication analysis was then conducted on 385 IA cases in the Environment Determinants of Diabetes in the Young (TEDDY) study and the proteins were measured by SRM for TEDDY participants. Finally, we used T1D Knowledge Portal to examine replicated pQTLs for their association with T1D and other disease-relevant traits.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eParticipant characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe demographic and clinical characteristics of study samples are summarized in \u003cstrong\u003eTable 1\u003c/strong\u003e, which includes 170 samples with 131 IA cases and 39 controls for DAISY discovery analysis, and 385 IA cases for TEDDY replication analysis after combining available proteomics and genotype data (\u003cstrong\u003eMethods\u003c/strong\u003e). Overall, the participants in the DAISY study had a median age of 6.2 years which was older than TEDDY participants with a median age of 1.8 years (\u003cstrong\u003eTable 1\u003c/strong\u003e). The percentage of first-degree relatives with T1D in DAISY was 54%, much higher than 22% from TEDDY (\u003cstrong\u003eTable 1\u003c/strong\u003e). For the other two clinical characteristics, female (%) and self-reported Non-Hispanic White (NHW) (%), the percentages were similar between the two studies. Females accounted for 46% and 44% in DAISY and TEDDY, respectively, and NHW was the most common population in both studies. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ecis\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-pQTLs discovery analysis in DAISY \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe first performed \u003cem\u003ecis\u003c/em\u003e-pQTL mapping for DAISY samples in pooled (IA cases and controls) and IA case-stratified analyses, respectively (\u003cstrong\u003eMethods\u003c/strong\u003e). There were 19 and 16 complement system proteins measured by the SRM and Exsera platform, respectively, for DAISY samples, and 10 proteins overlapped between the two platforms (\u003cstrong\u003eTable 2\u003c/strong\u003e). We observed 14 proteins with false discovery rate (FDR)-significant (FDR\u0026lt;0.1)\u003cem\u003e cis\u003c/em\u003e-pQTLs (\u003cstrong\u003eTable 2\u003c/strong\u003e). MBL2 has the greatest number of FDR-significant \u003cem\u003ecis\u003c/em\u003e-pQTLs with 264 and 211 \u003cem\u003ecis\u003c/em\u003e-pQTLs identified from Exsera pooled and case-stratified analysis, respectively (Additional file 2: \u003cstrong\u003eTable S1\u003c/strong\u003e). However, there were no statistically significant \u003cem\u003ecis\u003c/em\u003e-pQTLs of MBL2 from the SRM platform. Additionally, MBL2 had the \u003cem\u003ecis\u003c/em\u003e-pQTLs with the greatest strength of statistical significance (chr10:52771475-T, chr10:52773600-G, chr10:52775077-T with p-value=3.12x10\u003csup\u003e-19\u003c/sup\u003e and p-value=5.22x10\u003csup\u003e-16\u003c/sup\u003e from Exsera pooled and case-stratified analysis, respectively, Additional file 2: \u003cstrong\u003eTable S1\u003c/strong\u003e). Among other genes, CFH and C4B had FDR-significant \u003cem\u003ecis\u003c/em\u003e-pQTLs from both SRM and Exsera platforms (\u003cstrong\u003eTable 2\u003c/strong\u003e). \u003c/p\u003e\n\u003cp\u003eFor six proteins that had many FDR-significant \u003cem\u003ecis\u003c/em\u003e-pQTLs (i.e., CFH, C8A, CFB, C4A, C4B, and MBL2), we performed fine-mapping to identify potential causal \u003cem\u003ecis\u003c/em\u003e-pQTLs for each protein (\u003cstrong\u003eMethods\u003c/strong\u003e). For the proteins C8A, CFB and C4B, we observed corresponding 95% credible sets (CS) containing 29, 26, and 9 fine-mapped variants, respectively, from the SRM pooled analysis. For CFH, we observed a single 95% CS with 69 fine-mapped variants in the pooled analysis of protein levels from the Exsera platform (Additional file 1: \u003cstrong\u003eFig. S1-4\u003c/strong\u003e). MBL2 has fine-mapped variants from both Exsera analyses, where 14 variants were identified in two 95% CSs from pooled analysis, and 4 variants were identified in one 95% CS from case-stratified analysis (Additional file 1: \u003cstrong\u003eFig. S5\u003c/strong\u003e). However, there were no fine-mapped variants for CFH and C4A from SRM pooled analysis (Additional file 2: \u003cstrong\u003eTable S1\u003c/strong\u003e). We used non-fine-mapped \u003cem\u003ecis\u003c/em\u003e-pQTLs for these two proteins from the corresponding analysis. After fine-mapping analysis, we identified 240 FDR-significant (FDR\u0026lt;0.1) \u003cem\u003ecis\u003c/em\u003e-pQTLs in total from DAISY discovery analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReplicated \u003cem\u003ecis\u003c/em\u003e-pQTLs in TEDDY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo follow up on our discovery pQTL analysis in DAISY, we performed replication analysis in TEDDY for the 240 \u003cem\u003ecis\u003c/em\u003e-pQTLs reported in Additional file 2: \u003cstrong\u003eTable S1\u003c/strong\u003e, which maps to 14 proteins. A \u003cem\u003ecis\u003c/em\u003e-pQTL was deemed replicated if it had FDR-corrected p-value\u0026lt; 0.05. Of these, we observed 68 \u003cem\u003ecis\u003c/em\u003e-pQTLs passing the replication threshold, including 27 for C8A, 23 for CFB, 12 for C4A, 4 for MBL2, and 2 for C8B, respectively. The summary of all replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs for C8B and MBL2, and top replicated\u003cem\u003e cis\u003c/em\u003e-pQTLs for C8A, CFB and C4A is presented in \u003cstrong\u003eTable 3\u003c/strong\u003e. The other replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs for C8A, CFB and C4A are presented in Additional file 3: \u003cstrong\u003eTable S2\u003c/strong\u003e.The replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs of CFB, C4A, and MBL2 decreased protein expression levels, while the replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs of C8A and C8B increased protein levels.All replicated\u003cem\u003e cis\u003c/em\u003e-pQTLs had the same direction of effect between DAISY and TEDDY. However, the replicated signals in TEDDY generally achieved a lower level of statistical significance compared to DAISY. One exception to this finding was the CFB pQTL (chr10:31562639-A: Beta (SE)=-0.45 (0.11) and p-value=3.92x10\u003csup\u003e-5\u003c/sup\u003e in TEDDY vs. Beta (SE)=-0.34 (0.08) and p-value=4.37x10\u003csup\u003e-5\u003c/sup\u003e in DAISY; Additional file 2: \u003cstrong\u003eTable S1\u003c/strong\u003e;Additional file 3: \u003cstrong\u003eTable S2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExamination of association with T1D for replicated pQTL variants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe further examined the association of replicated\u003cem\u003e cis\u003c/em\u003e-pQTLs with T1D through publicly available resources. The T1D Knowledge Portal (https://t1d.hugeamp.org) enables searching of human genomic variants linked to T1D and other related phenotypes. We used the T1D Knowledge Portal and found that all 23 and 12 replicated\u003cem\u003e cis\u003c/em\u003e-pQTLs for CFB and C4A respectively have been reported genome-wide significantly (p-value\u0026lt;5x10\u003csup\u003e-8\u003c/sup\u003e) associated with T1D risk (Additional file 3: \u003cstrong\u003eTable S2\u003c/strong\u003e; Additional file 1: \u003cstrong\u003eFig. S6-7\u003c/strong\u003e). The T1D association p-values were obtained from a previous T1D study\u003csup\u003e24\u003c/sup\u003e, and the p-values range from 1.11x10\u003csup\u003e-37\u003c/sup\u003e (C4A: rs9262570) to 6.29x10\u003csup\u003e-235\u003c/sup\u003e (CFB: rs114355928) (Additional file 3: \u003cstrong\u003eTable S2\u003c/strong\u003e). For the other replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs, we found that they were significantly associated with highlight scatter reticulocyte count (C8A and C8B, Additional file 1: \u003cstrong\u003eFig. S8-9\u003c/strong\u003e), chronic kidney disease and reticulocyte count (MBL2, Additional file 1: \u003cstrong\u003eFig. S10-11\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrevious reports have examined the involvement of the complement system in the initiation and progression of IA for the study of T1D\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, however, the genetic factors underlying the complement system proteins at the time of triggering of IA are poorly unknown. Our study investigated genetic variants that are associated with complement system proteins in DAISY, a prospective cohort of children from the general population who either had a first degree relative with T1D or had a high-risk human leukocyte antigen (HLA) genotype. From pooled and IA case-stratified analyses with 170 participants in the DAISY, 240 significant (FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.1) \u003cem\u003ecis\u003c/em\u003e-pQTLs were associated with 14 complement system proteins. We replicated 68 \u003cem\u003ecis\u003c/em\u003e-pQTLs with statistical significance (FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in the 385 IA cases from the TEDDY study. The 68 replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs represent C8A and C8B, CFB and C4A (within the HLA region), and MBL2. The CFB and C4A \u003cem\u003ecis\u003c/em\u003e-pQTLs are known genetic associations with T1D. However, the strong linkage disequilibrium within the region has limited our understanding of the independent contribution of complement system to T1D risk. Our study provides new insight into the role of complement system on the disease progression.\u003c/p\u003e \u003cp\u003eCFB (Complement Factor B) is located on chromosome 6 and between the HLA class II and class I regions\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The HLA region is the single most important genetic determinant of T1D susceptibility. The variability in the HLA region has been estimated to explain approximately 60% of the genetic influence of T1D\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. CFB is a component of the alternative pathway of complement activation. The detailed function of CFB has been reported in a previous study\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. T1D-associated genetic variants in CFB have been reported in European ancestry\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and Northern India\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. The 23 replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs of CFB identified in our study, which decrease protein level, are found to be significantly associated with increasing T1D risk in a large-scale genomic study of T1D\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. The T1D association p-value ranges from 5.38x10\u003csup\u003e\u0026minus;\u0026thinsp;43\u003c/sup\u003e (rs115272033, \u003cem\u003eEHMT2\u003c/em\u003e intron) to 6.29x10\u003csup\u003e\u0026minus;\u0026thinsp;235\u003c/sup\u003e (rs114355928, \u003cem\u003eTSBP1\u003c/em\u003e intron) (Additional file 3: \u003cb\u003eTable \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eC4A (Complement Component 4A) is also located between the HLA class II and class I regions\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and is part of the classical and lectin pathways of activating complement system. Two functionally distinct genes, C4A and C4B, code the C4 protein together. Limited T1D association studies have been focused on the structural variation of this region\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The previously reported associations of genetic variants in C4A with T1D focused on European ancestry population\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Our study found that the 12 replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs of C4A were previously identified to be significantly associated with increasing T1D risk\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. The T1D association p-value ranges from 1.11x10\u003csup\u003e\u0026minus;\u0026thinsp;37\u003c/sup\u003e (rs9262570, intergenic) to 1.33x10\u003csup\u003e\u0026minus;\u0026thinsp;88\u003c/sup\u003e (rs9263822, \u003cem\u003ePSORS1C3\u003c/em\u003e intron) (Additional file 3: \u003cb\u003eTable \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eOur study identified three genes outside of HLA region (C8A, C8B and MBL) in addition to two genes in the HLA region. Both C8A (Complement C8 Alpha Chain) and C8B (Complement C8 Beta Chain) are located on chromosome 1 and encode Complement Component 8 (C8) protein. C8 participates in the formation of the membrane attack complex, which causes cell lysis and/or pro-inflammatory signaling\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eMBL2 (Mannose-Binding Lectin 2) is located on chromosome 10 and is the only single gene to encode human Mannose-Binding Lectin (MBL). MBL is a soluble lectin that activates the lectin complement pathway by recognizing microorganisms through the carbohydrate-recognition domain, thereby modulating inflammation\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Although our replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs of MBL2 were not associated with T1D, previous studies have identified their associations with type 2 diabetes and pneumonia. For example, the variant rs1800450 has been linked to type 2 diabetes in diverse populations, including the full-heritage Pima Indians and the Old Order Amish\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e, and the North Chinese Han population\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Additionally, Uysalol et al.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e reported that the rs1800450 genotypes associated with low MBL expression were significantly more common in patients with pneumonia and severe infections.\u003c/p\u003e \u003cp\u003eStrengths of this study include being one of the very few studies that examined pQTL mapping of complement system proteins in children with high risk of developing T1D and the use of independent study data to replicate significant pQTL signals. However, some limitations warrant mentioning. First, the statistical power of identifying significant \u003cem\u003ecis\u003c/em\u003e-pQTLs in our study is still limited due to the sample size of both discovery and replication analyses. Second, the protein assay platform in the replication analysis is different from that in the discovery analysis for the significant findings of MBL2. We only identified statistically significant \u003cem\u003ecis\u003c/em\u003e-pQTLs in the Exsera platform for MBL2 in the DAISY discovery analysis, however, the replication analysis in TEDDY was only available to use measured protein levels from a different protein assay, the SRM platform. Hence, future validation for the identified \u003cem\u003ecis\u003c/em\u003e-pQTLs of MBL2 needs to be conducted on measured protein levels from the Exsera platform. Lastly, the participants in our study are predominantly composed of Non-Hispanic Whites. Hence, our findings cannot be generalized to non-European ancestry populations yet. Future research focusing on non-European or diverse ancestries will help improve the understanding of genetic mechanisms underlying the complement system and provide a more comprehensive insight into the role of complement system proteins in the etiology of T1D.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, this study performed pQTL mapping of complement system proteins in children at high risk of developing T1D and replicated significant signals in an independent study of children with T1D. Our study confirmed that genetic variants regulating two complement system proteins CFB and C4A, located in the HLA-region, are associated with an increased risk of T1D. Further, we identified three non-HLA-region complement system proteins (C8A, C8B, and MBL2) as potential biomarkers with a putative role in the etiology of T1D.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOverview of approach\u003c/h2\u003e \u003cp\u003eWe performed \u003cem\u003ecis\u003c/em\u003e-pQTL mapping for 170 samples (131 IA cases and 39 controls) in The Diabetes Autoimmunity Study in the Young (DAISY) as discovery analysis to identify statistically significant \u003cem\u003ecis\u003c/em\u003e-pQTL variants for complement system proteins. To follow up on our pQTL analysis in DAISY, we conducted replication analysis for 385 IA samples from The Environmental Determinants of Diabetes in the Young (TEDDY) study. Finally, we used the T1D Knowledge Portal (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://t1d.hugeamp.org/\u003c/span\u003e\u003cspan address=\"https://t1d.hugeamp.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to examine replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs for their association with T1D and other disease-relevant traits.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDAISY: study design, proteomic profiling and genotyping\u003c/h3\u003e\n\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy design\u003c/span\u003e: DAISY is a prospective cohort of 2,547 children from the general population who either had a first degree relative with T1D or had a high-risk human leukocyte antigen (HLA) genotype. The participants were recruited in Denver, Colorado between 1993 and 2004, and followed for up to 21 years\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Follow-up results are available through April 4, 2022. Written informed consent was obtained from participants and parents. The Colorado Multiple Institutional Review Board approved all protocols. The primary goal of DAISY is to learn how genes and the environment interact to cause childhood T1D\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eProteomic profiling\u003c/span\u003e: The peptides of complement system proteins were measured by two different assay platforms for DAISY participants, selected reaction monitoring (SRM)-based\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, and Exsera Biolabs-based (referred herein as Exsera)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The Exsera targeted proteomics use commercial immunoassays in a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-accredited laboratory. The details of two protein assay platforms for DAISY participants are described in a previous study\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eGenotype quality control and imputation\u003c/span\u003e: Genome-wide genotyping was performed using the custom designed Infinium TEDDY-T1D Exome array (Illumina) and was genotyped at the University of Virginia (UVA) Genome Sciences Laboratory following the manufacturer\u0026rsquo;s protocol (Illumina). The following quality control (QC) criteria were applied: 1) samples with a genotype call rate\u0026thinsp;\u0026lt;\u0026thinsp;0.95 were removed; and 2) single nucleotide polymorphism (SNP) level QC included removal of monomorphic SNPs, and removal of SNPs that deviated from Hardy-Weiberg equilibrium (p-value\u0026thinsp;\u0026lt;\u0026thinsp;1x10\u003csup\u003e\u0026minus;\u0026thinsp;20\u003c/sup\u003e at the HLA region or p-value\u0026thinsp;\u0026lt;\u0026thinsp;1x10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e otherwise). Genome-wide imputation used the Trans-Omics for Precision Medicine (TOPMed) multi-ancestry reference panel (version R2). The SNP was selected if minor allele frequency (MAF)\u0026thinsp;\u0026ge;\u0026thinsp;0.05 and imputation quality R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026ge;\u0026thinsp;0.7. The details of QC criteria of genomic variants used in this study are provided in a previous study\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eTEDDY: study design, proteomic profiling and genotyping\u003c/h3\u003e\n\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy design\u003c/span\u003e: TEDDY is an international prospective study that was designed to identify T1D-associated environmental factors in children who carry a high genetic risk for the disease\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. The participating clinical centers include Colorado, Georgia/Florida, and Washington in the US, and Finland, Germany, and Sweden in Europe. We only reported summary statistics of self-reported Non-Hispanic White (NHW) from US centers for TEDDY as many missing or unknown race/ethnicity were reported from European centers. For TEDDY study, all procedures were approved by the ethics committees / institutional review boards including Colorado Multiple Institutional Review Board (04-0361); Medical College of Georgia Human Assurance Committee (2004\u0026ndash;2010)/Georgia Health Sciences University Human Assurance Committee (2011\u0026ndash;2012)/Georgia Regents University Institutional Review Board (2013\u0026ndash;2017)/Augusta University Institutional Review Board (2017-present) (HAC 0405380); University of Florida Health Center Institutional Review Board (IRB201600277); Washington State Institutional Review Board (2004\u0026ndash;2012)/Western Institutional Review Board (2013\u0026ndash;present) (20130211); Ethics Committee of the Hospital District of Southwest Finland (Dnro168/2004); Bayerischen Landes\u0026auml;rztekammer (Bavarian Medical Association) Ethics Committee (04089); and Regional Ethics Board in Lund, Section 2 (2004\u0026ndash;2012)/Lund University Committee for Continuing Ethical Review (2013-present) (217/2004). In addition, TEDDY is monitored by an external evaluation committee formed by the National Institutes of Health, Bethesda, MD, U.S.A.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eProteomic profiling and genotyping\u003c/span\u003e: Both proteomics and imputed genotype data were provided by the TEDDY Data Coordinating Center. The peptides of complement system proteins for TEDDY participants were measured by SRM-based assay. The details of the protein assay for TEDDY are described in a previous study\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. SNPs were genotyped using the ImmunoChip and/or the TEDDY-T1DexomeChip at the Center for Public Health Genomics at the UVA, US. GWAS imputation analysis was conducted using the TOPMed Version R2 (built from 97,256 deeply sequenced human genomes containing 308,107,085 genetic variants), the 1000 Genomes, and a subset of the TEDDY subjects (n\u0026thinsp;=\u0026thinsp;1,119) with the whole-genome sequencing data as reference panels. MetaMinimac2 was used to combine genotype data imputed against these three reference panels. For imputed genotype data, we retained rare variants with MAF\u0026thinsp;\u0026gt;\u0026thinsp;0.05 in unrelated controls with European ancestry and with imputation quality R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.50.\u003c/p\u003e \u003cp\u003e \u003cb\u003ecis\u003c/b\u003e \u003cb\u003e-pQTL mapping in DAISY\u003c/b\u003e \u003c/p\u003e \u003cp\u003eA \u003cem\u003ecis\u003c/em\u003e-pQTL mapping is to test the association between measured protein levels and \u003cem\u003ecis\u003c/em\u003e-pQTL genomic variants via statistical model. We defined a \u003cem\u003ecis\u003c/em\u003e-pQTL genomic variant as a SNP within +/- 1Mb of the transcription start site (TSS) of the corresponding protein-coding gene. We applied a linear mixed model adjusted for age, sex, self-reported race/ethnicity, protein plate effects, first-degree relative with T1D (yes or no), the first two principal components (PCs) of genetic ancestry, and genetic relationship matrix (GRM) to perform \u003cem\u003ecis\u003c/em\u003e-pQTL mapping in our study. The association analyses were conducted using R/GENESIS\u003csup\u003e39\u003c/sup\u003e. The mapping results were then filtered on 1) expected heterozygosity count (EHC)\u0026thinsp;\u0026gt;\u0026thinsp;6 for WGS data, and 2) imputation quality\u0026thinsp;\u0026gt;\u0026thinsp;0.3 and EHC\u0026thinsp;\u0026gt;\u0026thinsp;6 for imputation genotypes by using R/EasyQC\u003csup\u003e40\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe first performed \u003cem\u003ecis\u003c/em\u003e-pQTL mapping on DAISY participants with Islet autoimmunity (IA), referred herein as IA cases. Participants were considered to have IA if they were positive for one or more islet autoantibodies tests on two or more consecutive visits or being autoantibody positive with a diagnosis of diabetes at the next visit by the American Diabetes Association criteria\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. For protein levels of IA cases, 1) we averaged measured peptides if a participant had multiple peptides at one time point, and 2) we used the earliest time point if a participant had multiple visits for peptide measures. We then applied log2-transformation on the selected peptides and treated the transformed peptides as outcome variables for the linear mixed model. Due to limited IA cases in DAISY, we also conducted case-control pooled analysis for DAISY with additional group adjustment (i.e., case or control) to increase statistical power of \u003cem\u003ecis\u003c/em\u003e-pQTL mapping. For protein levels of controls, we followed the same procedure as IA cases except for the selection of time points for controls who have multiple peptides by different visits. To obtain a similar age as IA cases for most controls, we selected the closest time point to the median age of selected visits of IA cases for controls. Finally, we applied false discovery rate (FDR) correction (Benjamini-Hochberg) at 10% on \u003cem\u003ecis\u003c/em\u003e-pQTL mapping results to identify statistically significant \u003cem\u003ecis\u003c/em\u003e-pQTLs in DAISY by different protein assay platforms and by different stratified analyses respectively. For proteins with many FDR-significant \u003cem\u003ecis\u003c/em\u003e-pQTLs, we further performed fine-mapping using SuSiE\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e to identify potential causal \u003cem\u003ecis\u003c/em\u003e-pQTLs. The variant clustered in a 95% credible set (CS) is considered as a fine-mapped variant\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eReplication analysis in TEDDY\u003c/h2\u003e \u003cp\u003eTo follow-up on statistically significant \u003cem\u003ecis\u003c/em\u003e-pQTLs identified in DAISY discovery analysis, we applied a linear mixed model adjusted for age, sex, protein plate effects, clinical centers, first-degree relative with T1D (yes or no), the first two PCs of ancestry, and GRM to test association between DAISY FDR-significant \u003cem\u003ecis\u003c/em\u003e-pQTLs and log2-transformed peptides for TEDDY IA cases. We then applied FDR correction at 5% on TEDDY mapping results to identify replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePheWAS of replicated\u003c/b\u003e \u003cb\u003ecis\u003c/b\u003e\u003cb\u003e-pQTLs\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe T1D Knowledge Portal (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://t1d.hugeamp.org\u003c/span\u003e\u003cspan address=\"https://t1d.hugeamp.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e)\u003c/span\u003e enables searching of human genomic variants linked to T1D and other related phenotypes. We used T1D Knowledge Portal to examine replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs for their association with T1D and other disease-relevant traits.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge Research Computing at The University of Virginia for providing computational resources and technical support that have contributed to the results reported within this manuscript. URL:https://rc.virginia.edu.\u003c/p\u003e\n\u003cp\u003eThe authors also acknowledge the \u003cstrong\u003eTEDDY Study Group\u003c/strong\u003e as follows:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eColorado Clinical Center:\u003c/u\u003e\u003c/strong\u003e Marian Rewers, M.D., Ph.D., PI\u003csup\u003e1,4,6,9,10\u003c/sup\u003e, Kimberly Bautista\u003csup\u003e11\u003c/sup\u003e, Judith Baxter\u003csup\u003e8,911\u003c/sup\u003e, Daniel Felipe-Morales, Brigitte I. Frohnert, M.D., Ph.D.\u003csup\u003e2,13\u003c/sup\u003e, Marisa Stahl, M.D.\u003csup\u003e12\u003c/sup\u003e, Isabel Flores Garcia, Patricia Gesualdo\u003csup\u003e2,\u003c/sup\u003e\u003csup\u003e6,11,13\u003c/sup\u003e, Sierra Hays, Michelle Hoffman\u003csup\u003e11,12,13\u003c/sup\u003e, Randi Johnson, Ph.D.\u003csup\u003e2,3\u003c/sup\u003e, Rachel Karban\u003csup\u003e11\u003c/sup\u003e, Edwin Liu, M.D.\u003csup\u003e12\u003c/sup\u003e, Leila Loaiza, Jill Norris, Ph.D.\u003csup\u003e2,3,11\u003c/sup\u003e, Holly O\u0026rsquo;Donnell, Ph.D.\u003csup\u003e8\u003c/sup\u003e, Andrea Steck, M.D.\u003csup\u003e3,13\u003c/sup\u003e, Kathleen Waugh\u003csup\u003e6,7,11\u003c/sup\u003e. University of Colorado, Anschutz Medical Campus, Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFinland Clinical Center:\u003c/u\u003e\u003c/strong\u003e Jorma Toppari, M.D., Ph.D., PI\u003csup\u003e\u0026yen;^1,4,10,13\u003c/sup\u003e,Olli G. Simell, M.D., Ph.D., Annika Adamsson, Ph.D.\u003csup\u003e^11\u003c/sup\u003e, Suvi Ahonen*\u003csup\u003e\u0026plusmn;\u0026sect;\u003c/sup\u003e, Mari \u0026Aring;kerlund*\u003csup\u003e\u0026plusmn;\u0026sect;\u003c/sup\u003e, Sirpa Anttila\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e, Leena Hakola, Ph.D.*\u003csup\u003e\u0026plusmn;\u003c/sup\u003e, Sanni Heikura\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e, Tiia Honkanen\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Heikki Hy\u0026ouml;ty, M.D., Ph.D.*\u003csup\u003e\u0026plusmn;6\u003c/sup\u003e, Jorma Ilonen, M.D., Ph.D.\u003csup\u003e\u0026yen;3\u003c/sup\u003e, Saori Itoshima, M.D.\u003csup\u003e\u0026yen;^\u003c/sup\u003e, Minna Jokipolvi\u003csup\u003e*\u0026plusmn;\u003c/sup\u003e, Sanna Jokipuu\u003csup\u003e^\u003c/sup\u003e, Taru Karjalainen\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Leena Karlsson\u003csup\u003e^\u003c/sup\u003e, Pieta Kemppainen\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Jukka Kero, M.D., Ph.D.\u003csup\u003e\u0026yen;^3, 13\u003c/sup\u003e, Marika Korpela\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Jaakko J. Koskenniemi M.D., Ph.D.\u003csup\u003e\u0026yen;^\u003c/sup\u003e, Miia K\u0026auml;h\u0026ouml;nen\u003csup\u003e\u0026micro;\u0026curren;11,13\u003c/sup\u003e, Mikael Knip, M.D., Ph.D.*\u003csup\u003e\u0026plusmn;\u003c/sup\u003e, Minna-Liisa Koivikko\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e, Katja Kokkonen*\u003csup\u003e\u0026plusmn;\u003c/sup\u003e, Merja Koskinen*\u003csup\u003e\u0026plusmn;\u003c/sup\u003e, Mirva Koreasalo*\u003csup\u003e\u0026plusmn;\u0026sect;2\u003c/sup\u003e, Kalle Kurppa, M.D., Ph.D.*\u003csup\u003e\u0026plusmn;12\u003c/sup\u003e, Salla Kuusela, M.D.\u003csup\u003e\u0026nbsp;\u0026micro;\u0026curren;\u003c/sup\u003e, Jarita Kyt\u0026ouml;l\u0026auml;\u003csup\u003e*\u0026plusmn;\u003c/sup\u003e, Jutta Laiho, Ph.D.*\u003csup\u003e6\u003c/sup\u003e, Tiina Latva-aho\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e, Siiri Leisku\u003csup\u003e*\u0026plusmn;\u003c/sup\u003e, Laura Lepp\u0026auml;nen\u003csup\u003e^\u003c/sup\u003e, Katri Lindfors, Ph.D.*\u003csup\u003e12\u003c/sup\u003e, Maria L\u0026ouml;nnrot, M.D., Ph.D.*\u003csup\u003e\u0026plusmn;6\u003c/sup\u003e, Elina M\u0026auml;ntym\u0026auml;ki\u003csup\u003e^\u003c/sup\u003e, Markus Mattila, Ph.D.*\u003csup\u003e\u0026plusmn;2\u003c/sup\u003e, Maija E. Miettinen, Ph.D.\u003csup\u003e\u0026sect;2\u003c/sup\u003e, Teija Mykk\u0026auml;nen\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Tiina Niininen\u003csup\u003e\u0026plusmn;\u003c/sup\u003e*\u003csup\u003e11\u003c/sup\u003e, Sari Niinist\u0026ouml;, Ph.D.\u003csup\u003e\u0026sect;2\u003c/sup\u003e, Noora Nurminen\u003csup\u003e*\u0026plusmn;\u003c/sup\u003e, Sami Oikarinen, Ph.D.*\u003csup\u003e\u0026plusmn;6\u003c/sup\u003e, Hanna-Leena Oinas*\u003csup\u003e\u0026plusmn;\u003c/sup\u003e, Paula Ollikainen\u003csup\u003e\u0026micro;\u003c/sup\u003e\u003csup\u003e\u0026curren;\u003c/sup\u003e, Zhian Othmani\u003csup\u003e\u0026yen;\u003c/sup\u003e, Sirpa Pohjola\u003csup\u003e\u0026nbsp;\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Jenna Rautanen\u003csup\u003e\u0026sect;\u003c/sup\u003e, Mia Rein\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Minna Romo\u003csup\u003e^\u003c/sup\u003e, Juulia R\u0026ouml;nk\u0026auml;\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e, Nelli R\u0026ouml;nk\u0026auml;\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Noora Ruotsalainen\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Satu Simell, M.D., Ph.D.\u003csup\u003e\u0026yen;12\u003c/sup\u003e, P\u0026auml;ivi Tossavainen, M.D.\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e, Erika Turtinen\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e,\u0026nbsp;Mari V\u0026auml;h\u0026auml;-M\u0026auml;kil\u0026auml;\u003csup\u003e\u0026yen;\u003c/sup\u003e, Eeva Varjonen\u003csup\u003e^11\u003c/sup\u003e, Riitta Veijola, M.D., Ph.D.\u003csup\u003e\u0026micro;\u0026curren;13\u003c/sup\u003e, Irene Viinikangas\u003csup\u003e\u0026micro;\u0026curren;\u003c/sup\u003e, Suvi M. Virtanen, M.D., Ph.D.*\u003csup\u003e\u0026plusmn;\u0026sect;2\u003c/sup\u003e. \u003csup\u003e\u0026yen;\u003c/sup\u003eUniversity of Turku, Turku, Finland, *Tampere University, Tampere, Finland, \u003csup\u003e\u0026micro;\u003c/sup\u003eUniversity of Oulu, Oulu, Finland, \u003csup\u003e^\u003c/sup\u003eTurku University Hospital,\u0026nbsp;Wellbeing Services County of Southwest Finland, Turku, Finland,\u003csup\u003e\u0026nbsp;\u0026plusmn;\u003c/sup\u003eTampere University Hospital, Wellbeing Services County of Pirkanmaa, Tampere, Finland, \u003csup\u003e\u0026curren;\u003c/sup\u003eOulu University Hospital, Wellbeing Services County of North Ostrobothia, Oulu, Finland, \u003csup\u003e\u0026sect;\u003c/sup\u003eFinnish Institute for Health and Welfare, Helsinki, Finland.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eGeorgia/Florida Clinical Center:\u003c/u\u003e\u003c/strong\u003e Richard McIndoe, Ph.D., PI\u003csup\u003e^4,10\u003c/sup\u003e, Desmond Schatz*, M.D.*\u003csup\u003e4,7,8\u003c/sup\u003e, Diane Hopkins\u003csup\u003e^11\u003c/sup\u003e, Michael Haller, M.D.*\u003csup\u003e13\u003c/sup\u003e, Melissa Gardiner\u003csup\u003e^11\u003c/sup\u003e, Ashok Sharma\u003csup\u003e^\u003c/sup\u003e, Ph.D.\u003csup\u003e^\u003c/sup\u003e, Laura Jacobsen, M.D.*\u003csup\u003e13\u003c/sup\u003e, Percy Gordon\u003csup\u003e^\u003c/sup\u003e, Jennifer Hosford*,. \u003csup\u003e^\u003c/sup\u003eCenter for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, USA. *University of Florida, Pediatric Endocrinology, Gainesville, FL, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eGermany Clinical Center:\u003c/u\u003e\u003c/strong\u003e Anette G. Ziegler, M.D., PI\u003csup\u003e1,3,4,10\u003c/sup\u003e, Ezio Bonifacio Ph.D.*, Cigdem Sanverdi, Anja Heublein, Sandra Hummel, Ph.D.\u003csup\u003e2\u003c/sup\u003e, Annette Knopff\u003csup\u003e7\u003c/sup\u003e, Melanie K\u0026ouml;ger, Sibylle Koletzko, M.D.\u003csup\u003e\u0026para;12\u003c/sup\u003e, Claudia Ramminger\u003csup\u003e11\u003c/sup\u003e, Roswith Roth, Ph.D.\u003csup\u003e8\u003c/sup\u003e, Jennifer Schmidt, Marlon Scholz, Joanna Stock\u003csup\u003e8,11,13\u003c/sup\u003e, Katharina Warncke, M.D.\u003csup\u003e13\u003c/sup\u003e, Lorena M\u0026uuml;ller, Christiane Winkler, Ph.D.\u003csup\u003e2,11\u003c/sup\u003e. Forschergruppe Diabetes e.V. and Institute of Diabetes Research, Helmholtz Zentrum M\u0026uuml;nchen, Forschergruppe Diabetes, and Klinikum rechts der Isar, Technische Universit\u0026auml;t M\u0026uuml;nchen, Neuherberg, Germany. *Center for Regenerative Therapies, TU Dresden, Dresden, Germany, \u003csup\u003e\u0026para;\u003c/sup\u003eDr. von Hauner Children\u0026rsquo;s Hospital, Department of Gastroenterology, Ludwig Maximillians University Munich, Munich, Germany.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eSweden Clinical Center:\u003c/u\u003e\u003c/strong\u003e \u0026Aring;ke Lernmark, Ph.D., PI\u003csup\u003e1,3,4,5,6,8,9,10\u003c/sup\u003e, Daniel Agardh, M.D., Ph.D.\u003csup\u003e6,12\u003c/sup\u003e, Carin Andr\u0026eacute;n Aronsson, Ph.D.\u003csup\u003e2,11,12\u003c/sup\u003e, Rasmus Bennet, Corrado Cilio, Ph.D., M.D.\u003csup\u003e6\u003c/sup\u003e, Susanne Dahlberg, Malin Goldman Tsubarah, Emelie Ericson-Hallstr\u0026ouml;m, Lina Fransson, Emina Halilovic, Susanne Hyberg, Berglind Jonsdottir, M.D., Ph.D.\u003csup\u003e11\u003c/sup\u003e, Naghmeh Karimi, Helena Elding Larsson, M.D., Ph.D.\u003csup\u003e6,13\u003c/sup\u003e, Marielle Lindstr\u0026ouml;m, Markus Lundgren, M.D., Ph.D.\u003csup\u003e13\u003c/sup\u003e, Jessica Melin, Ph.D.\u003csup\u003e11\u003c/sup\u003e, Kobra Rahmati, Anita Ramelius, Falastin Salami, Ph.D., Anette Sj\u0026ouml;berg, Evelyn Tekum Amboh, Carina T\u0026ouml;rn, Ph.D.\u003csup\u003e3\u003c/sup\u003e, Ulrika Ulvenhag, Terese Wiktorsson, \u0026Aring;sa Wimar\u003csup\u003e13\u003c/sup\u003e. Lund University, Lund, Sweden.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePast staff: Eva Andersson, Marie Andersson Turpeinen, Rawya Antar, Maria Ask, Jenny Bremer, Sylvia Bianconi Svensson, Ulla-Marie Carlsson, Magdalena Delikat Kulinski, Annika Fors, Ulla F\u0026auml;lt, Thomas Gard, Joanna Gerardsson, Monika Hansen, Anna Hansson, Carina Hansson, Gertie Hansson, Elin M. H\u0026aring;rd af Segerstad, Ph.D.\u003csup\u003e2\u003c/sup\u003e, Hanna Jisser, Fredrik Johansen, Linda Jonsson, Silvija Jovic, Sigrid Lenrick Forss, Barbro Lernmark, Ph.D.\u003csup\u003e8\u003c/sup\u003e, Maria Markan, Theodosia Massadakis, Marlena Maziarz, Ph.D., Zeliha Mestan, Maria M\u0026aring;nsson Martinez, Caroline Nilsson, Emma Nilsson, Yohanna Nordh, Karin Ottosson, Sara Rang, Anna Rosenquist, Monika Sedig J\u0026auml;rvirova, Sara Sibthorpe, Birgitta Sj\u0026ouml;berg, Ulrika Swartling Ph.D.\u003csup\u003e8\u003c/sup\u003e, Erika Trulsson, Anne Wallin, Ingrid Wigheden, Sofie \u0026Aring;berg.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eWashington Clinical Center:\u003c/u\u003e\u003c/strong\u003e William A. Hagopian, M.D., Ph.D., PI\u003csup\u003e^1,3,4,6,7,10,12,13\u003c/sup\u003e, Michael Killian*\u003csup\u003e6,7,11,12\u003c/sup\u003e, Claire Cowen Crouch*\u003csup\u003e11,13\u003c/sup\u003e, Jennifer Skidmore*\u003csup\u003e2\u003c/sup\u003e, Ben Kim*, Cody McCall*, Arlene Meyer*, Jared Radtke*, Shreya Roy*. \u003csup\u003e^\u003c/sup\u003eIndiana University, Indianapolis, IN, USA. *Pacific Northwest Research Institute, Seattle, WA, USA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003ePennsylvania Satellite Center:\u003c/u\u003e\u003c/strong\u003eDorothy Becker, M.D., Margaret Franciscus, MaryEllen Dalmagro-Elias Smith\u003csup\u003e2\u003c/sup\u003e, Ashi Daftary, M.D., Mary Beth Klein, Chrystal Yates. Children\u0026rsquo;s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eData Coordinating Center:\u003c/u\u003e\u003c/strong\u003e Jeffrey P. Krischer, Ph.D., PI\u003csup\u003e1,4,5,9,10\u003c/sup\u003e, Rajesh Adusumali, Sarah Austin-Gonzalez, Maryouri Avendano, Sandra Baethke, Brant Burkhardt, Ph.D.\u003csup\u003e6\u003c/sup\u003e, Martha Butterworth\u003csup\u003e2\u003c/sup\u003e, Nicholas Cadigan, Joanna Clasen, Ph.D., Kevin Counts, Laura Gandolfo, Jennifer Garmeson, Veena Gowda, Shu Liu, Xiang Liu, Ph.D.\u003csup\u003e2,3,8,13\u003c/sup\u003e, Kristian Lynch, Ph.D.\u003csup\u003e\u0026nbsp;6,8\u003c/sup\u003e, Jamie Malloy, Lazarus Mramba, Ph.D.\u003csup\u003e2\u003c/sup\u003e, Cristina McCarthy\u003csup\u003e11\u003c/sup\u003e, Hemang M. Parikh, Ph.D.\u003csup\u003e3,8\u003c/sup\u003e, Cassandra Remedios, Chris Shaffer, Susan Smith\u003csup\u003e11\u003c/sup\u003e, Noah Sulman, Ph.D., Roy Tamura, Ph.D.\u003csup\u003e1,2,11,12,13\u003c/sup\u003e, Dena Tewey, Henri Thuma, Michael Toth, Ulla Uusitalo, Ph.D.\u003csup\u003e2\u003c/sup\u003e, Kendra Vehik, Ph.D.\u003csup\u003e4,5,6,8,13\u003c/sup\u003e, Ponni Vijayakandipan, Melissa Wroble, Jimin Yang, Ph.D., R.D.\u003csup\u003e2\u003c/sup\u003e, Kenneth Young, Ph.D. \u003cem\u003ePast staff: Michael Abbondondolo, Lori Ballard, Rasheedah Brown, David Cuthbertson, Stephen Dankyi, Christopher Eberhard, Steven Fiske, David Hadley, Ph.D., Kathleen Heyman, Belinda Hsiao, Christina Karges, Francisco Perez Laras, Hye-Seung Lee, Ph.D., Qian Li, Ph.D., Colleen Maguire, Wendy McLeod, Aubrie Merrell, Steven Meulemans, Jose Moreno, Ryan Quigley, Laura Smith, Ph.D.\u003c/em\u003e University of South Florida, Tampa, FL, USA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eProject scientist:\u003c/u\u003e\u003c/strong\u003eBeena Akolkar, Ph.D.\u003csup\u003e1,3,4,5,6,7,9,10\u003c/sup\u003e. National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eOther contributors:\u003c/u\u003e\u003c/strong\u003eThomas Briese, Ph.D.\u003csup\u003e6\u003c/sup\u003e, Columbia University, New York, NY, USA. Todd Brusko, Ph.D.\u003csup\u003e5\u003c/sup\u003e, University of Florida, Gainesville, FL, USA. Teresa Buckner, Ph.D.\u003csup\u003e2\u003c/sup\u003e, University of Northern Colorado, Greeley, CO, USA. Suzanne Bennett Johnson, Ph.D.\u003csup\u003e8,11\u003c/sup\u003e, Florida State University, Tallahassee, FL, USA. Eoin McKinney, Ph.D.\u003csup\u003e5\u003c/sup\u003e, University of Cambridge, Cambridge, UK. Tomi Pastinen, M.D., Ph.D.\u003csup\u003e5\u003c/sup\u003e, The Children\u0026rsquo;s Mercy Hospital, Kansas City, MO, USA. Steffen Ullitz Thorsen, M.D., Ph.D.\u003csup\u003e2\u003c/sup\u003e, Department of Clinical Immunology, University of Copenhagen, Copenhagen, Denmark, and Department of Pediatrics and Adolescents, Copenhagen University Hospital, Herlev, Denmark. Eric Triplett, Ph.D.\u003csup\u003e6\u003c/sup\u003e, University of Florida, Gainesville, FL, USA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCommittees:\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eAncillary Studies, \u003csup\u003e2\u003c/sup\u003eDiet, \u003csup\u003e3\u003c/sup\u003eGenetics, \u003csup\u003e4\u003c/sup\u003eHuman Subjects/Publicity/Publications, \u003csup\u003e5\u003c/sup\u003eImmune Markers, \u003csup\u003e6\u003c/sup\u003eInfectious Agents, \u003csup\u003e7\u003c/sup\u003eLaboratory Implementation, \u003csup\u003e8\u003c/sup\u003ePsychosocial, \u003csup\u003e9\u003c/sup\u003eQuality Assurance, \u003csup\u003e10\u003c/sup\u003eSteering, \u003csup\u003e11\u003c/sup\u003eStudy Coordinators, \u003csup\u003e12\u003c/sup\u003eCeliac Disease, \u003csup\u003e13\u003c/sup\u003eClinical Implementation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXW, AM, and MJR designed the study. BJMWR, AFA, ESN, TOM, and MJR provided DAISY proteomics data. SOG, WMC, and SSR provided DAISY genotype data. HMP provided TEDDY proteomics and genotype data. XW performed statistical analyses and wrote the manuscript. XW, AM, BJMWR, ESN, SOG, SSR, and MJR interpreted results. All authors read, reviewed, and approved the final manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by Leona M. and Harry B. Helmsley Charitable Trust grants 2018PG-T1D017 and G-2103-05121. The TEDDY Study is funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and Breakthrough T1D (formerly JDRF). This work is supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR002535). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe TEDDY Immunochip (SNP) data that support the findings of this study have been deposited in NCBI\u0026rsquo;s database of Genotypes and Phenotypes (dbGaP) with the primary accession code phs001442.v4.p3. The TEDDY-T1DExome Array data that support the findings of this study have been deposited in NCBI\u0026rsquo;s database of Genotypes and Phenotypes (dbGaP) with the primary accession code phs001442.v4.p3. The TEDDY Whole Genome Sequencing (WGS) data that support the findings of this study have been deposited in NCBI\u0026rsquo;s database of Genotypes and Phenotypes (dbGaP) with the primary accession code phs001442.v4.p3. The TEDDY Proteomics Discovery Phase data that support the findings of this study are available from the Mass Spectrometry Interactive Virtual Environment (MassIVE) repository https://massive.ucsd.edu/ via its dataset identifier MSV000091560 (https://doi.org/doi:10.25345/C5V11VW3F). The TEDDY Proteomics Validation Phase data that support the findings of this study are available from the Mass Spectrometry Interactive Virtual Environment (MassIVE) repository https://massive.ucsd.edu/ via its dataset identifier MSV000091562 (https://doi.org/doi:10.25345/C5KH0F84V).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor DAISY cohort, written informed consent was obtained from participants and parents. The Colorado Multiple Institutional Review Board approved all protocols of DAISY cohort.\u003c/p\u003e\n\u003cp\u003eFor TEDDY study, all procedures were approved by the ethics committees / institutional review boards including Colorado Multiple Institutional Review Board (04-0361); Medical College of Georgia Human Assurance Committee (2004\u0026ndash;2010)/Georgia Health Sciences University Human Assurance Committee (2011\u0026ndash;2012)/Georgia Regents University Institutional Review Board (2013\u0026ndash;2017)/Augusta University Institutional Review Board (2017-present) (HAC 0405380); University of Florida Health Center Institutional Review Board (IRB201600277); Washington State Institutional Review Board (2004\u0026ndash;2012)/Western Institutional Review Board (2013\u0026ndash;present) (20130211); Ethics Committee of the Hospital District of Southwest Finland (Dnro168/2004); Bayerischen Landes\u0026auml;rztekammer (Bavarian Medical Association) Ethics Committee (04089); and Regional Ethics Board in Lund, Section 2 (2004\u0026ndash;2012)/Lund University Committee for Continuing Ethical Review (2013-present) (217/2004). In addition, TEDDY is monitored by an external evaluation committee formed by the National Institutes of Health, Bethesda, MD, U.S.A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEringsmark Regn\u0026eacute;ll, S. \u0026amp; Lernmark, A. The environment and the origins of islet autoimmunity and Type 1 diabetes. \u003cem\u003eDiabet. Med. J. Br. Diabet. Assoc. \u003c/em\u003e\u003cstrong\u003e30\u003c/strong\u003e, 155\u0026ndash;160 (2013).\u003c/li\u003e\n\u003cli\u003eKrischer, J. P. \u003cem\u003eet al.\u003c/em\u003e Characteristics of children diagnosed with type 1 diabetes before vs after 6 years of age in the TEDDY cohort study. \u003cem\u003eDiabetologia \u003c/em\u003e\u003cstrong\u003e64\u003c/strong\u003e, 2247\u0026ndash;2257 (2021).\u003c/li\u003e\n\u003cli\u003eHolers, V. M. Complement and its receptors: new insights into human disease. \u003cem\u003eAnnu. Rev. Immunol. \u003c/em\u003e\u003cstrong\u003e32\u003c/strong\u003e, 433\u0026ndash;459 (2014).\u003c/li\u003e\n\u003cli\u003eRadillo, O. \u003cem\u003eet al.\u003c/em\u003e Complement-Fixing Islet Cell Antibodies in Type-1 Diabetes Can Trigger the Assembly of the Terminal Complement Complex on Human Islet Cells and Are Potentially Cytotoxic. \u003cem\u003eClin. Immunol. Immunopathol. \u003c/em\u003e\u003cstrong\u003e79\u003c/strong\u003e, 217\u0026ndash;223 (1996).\u003c/li\u003e\n\u003cli\u003eChen, M., Daha, M. R. \u0026amp; Kallenberg, C. G. M. The complement system in systemic autoimmune disease. \u003cem\u003eJ. Autoimmun. \u003c/em\u003e\u003cstrong\u003e34\u003c/strong\u003e, J276-286 (2010).\u003c/li\u003e\n\u003cli\u003eSturfelt, G. \u0026amp; Truedsson, L. Complement in the immunopathogenesis of rheumatic disease. \u003cem\u003eNat. Rev. Rheumatol. \u003c/em\u003e\u003cstrong\u003e8\u003c/strong\u003e, 458\u0026ndash;468 (2012).\u003c/li\u003e\n\u003cli\u003eT\u0026ouml;rn, C. \u003cem\u003eet al.\u003c/em\u003e Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study. \u003cem\u003eSci. Rep. \u003c/em\u003e\u003cstrong\u003e6\u003c/strong\u003e, 27887 (2016).\u003c/li\u003e\n\u003cli\u003eAjjan, R. A. \u0026amp; Schroeder, V. Role of complement in diabetes. \u003cem\u003eMol. Immunol. \u003c/em\u003e\u003cstrong\u003e114\u003c/strong\u003e, 270\u0026ndash;277 (2019).\u003c/li\u003e\n\u003cli\u003eZhang, Q. \u003cem\u003eet al.\u003c/em\u003e Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes. \u003cem\u003eJ. Exp. Med. \u003c/em\u003e\u003cstrong\u003e210\u003c/strong\u003e, 191\u0026ndash;203 (2013).\u003c/li\u003e\n\u003cli\u003eSarkar, S. \u003cem\u003eet al.\u003c/em\u003e Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response. \u003cem\u003eClin. Proteomics \u003c/em\u003e\u003cstrong\u003e20\u003c/strong\u003e, 38 (2023).\u003c/li\u003e\n\u003cli\u003eMoulder, R. \u003cem\u003eet al.\u003c/em\u003e Serum Proteomes Distinguish Children Developing Type 1 Diabetes in a Cohort With HLA-Conferred Susceptibility. \u003cem\u003eDiabetes \u003c/em\u003e\u003cstrong\u003e64\u003c/strong\u003e, 2265\u0026ndash;2278 (2015).\u003c/li\u003e\n\u003cli\u003evon Toerne, C. \u003cem\u003eet al.\u003c/em\u003e Peptide serum markers in islet autoantibody-positive children. \u003cem\u003eDiabetologia \u003c/em\u003e\u003cstrong\u003e60\u003c/strong\u003e, 287\u0026ndash;295 (2017).\u003c/li\u003e\n\u003cli\u003eNakayasu, E. S. \u003cem\u003eet al.\u003c/em\u003e Plasma protein biomarkers predict the development of persistent autoantibodies and type 1 diabetes 6 months prior to the onset of autoimmunity. \u003cem\u003eCell Rep. Med. \u003c/em\u003e\u003cstrong\u003e4\u003c/strong\u003e, 101093 (2023).\u003c/li\u003e\n\u003cli\u003eWebb-Robertson, B.-J. M. \u003cem\u003eet al.\u003c/em\u003e Decrease in multiple complement proteins associated with development of islet autoimmunity and type 1 diabetes. \u003cem\u003eiScience \u003c/em\u003e\u003cstrong\u003e27\u003c/strong\u003e, (2024).\u003c/li\u003e\n\u003cli\u003eOnengut-Gumuscu, S. \u003cem\u003eet al.\u003c/em\u003e Genetic variants in the complement system and their potential link in the aetiology of type 1 diabetes. \u003cem\u003eDiabetes Metab. Res. Rev. \u003c/em\u003e\u003cstrong\u003e40\u003c/strong\u003e, e3716 (2024).\u003c/li\u003e\n\u003cli\u003eSun, B. B. \u003cem\u003eet al.\u003c/em\u003e Genomic atlas of the human plasma proteome. \u003cem\u003eNature \u003c/em\u003e\u003cstrong\u003e558\u003c/strong\u003e, 73\u0026ndash;79 (2018).\u003c/li\u003e\n\u003cli\u003eSuhre, K. \u003cem\u003eet al.\u003c/em\u003e Connecting genetic risk to disease end points through the human blood plasma proteome. \u003cem\u003eNat. Commun. \u003c/em\u003e\u003cstrong\u003e8\u003c/strong\u003e, 14357 (2017).\u003c/li\u003e\n\u003cli\u003eYao, C. \u003cem\u003eet al.\u003c/em\u003e Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease. \u003cem\u003eNat. Commun. \u003c/em\u003e\u003cstrong\u003e9\u003c/strong\u003e, 3268 (2018).\u003c/li\u003e\n\u003cli\u003eYang, Z. \u003cem\u003eet al.\u003c/em\u003e Genetic Landscape of the ACE2 Coronavirus Receptor. \u003cem\u003eCirculation \u003c/em\u003e\u003cstrong\u003e145\u003c/strong\u003e, 1398\u0026ndash;1411 (2022).\u003c/li\u003e\n\u003cli\u003eKatz, D. H. \u003cem\u003eet al.\u003c/em\u003e Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease. \u003cem\u003eCirculation \u003c/em\u003e\u003cstrong\u003e145\u003c/strong\u003e, 357\u0026ndash;370 (2022).\u003c/li\u003e\n\u003cli\u003eJiang, M.-Z. \u003cem\u003eet al.\u003c/em\u003e Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium. \u003cem\u003eHum. Mol. Genet. \u003c/em\u003e\u003cstrong\u003e33\u003c/strong\u003e, 1429\u0026ndash;1441 (2024).\u003c/li\u003e\n\u003cli\u003eNakayasu, E. S. \u003cem\u003eet al.\u003c/em\u003e Tutorial: best practices and considerations for mass-spectrometry-based protein biomarker discovery and validation. \u003cem\u003eNat. Protoc. \u003c/em\u003e\u003cstrong\u003e16\u003c/strong\u003e, 3737\u0026ndash;3760 (2021).\u003c/li\u003e\n\u003cli\u003eProh\u0026aacute;szka, Z., Nilsson, B., Frazer-Abel, A. \u0026amp; Kirschfink, M. Complement analysis 2016: Clinical indications, laboratory diagnostics and quality control. \u003cem\u003eImmunobiology \u003c/em\u003e\u003cstrong\u003e221\u003c/strong\u003e, 1247\u0026ndash;1258 (2016).\u003c/li\u003e\n\u003cli\u003eChiou, J. \u003cem\u003eet al.\u003c/em\u003e Interpreting type 1 diabetes risk with genetics and single-cell epigenomics. \u003cem\u003eNature \u003c/em\u003e\u003cstrong\u003e594\u003c/strong\u003e, 398\u0026ndash;402 (2021).\u003c/li\u003e\n\u003cli\u003eLambert, A. P. \u003cem\u003eet al.\u003c/em\u003e Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. \u003cem\u003eJ. Clin. Endocrinol. Metab. \u003c/em\u003e\u003cstrong\u003e89\u003c/strong\u003e, 4037\u0026ndash;4043 (2004).\u003c/li\u003e\n\u003cli\u003eMcCluskey, J. \u003cem\u003eet al.\u003c/em\u003e HLA and complement allotypes in Type 1 (insulin-dependent) diabetes. \u003cem\u003eDiabetologia \u003c/em\u003e\u003cstrong\u003e24\u003c/strong\u003e, 162\u0026ndash;165 (1983).\u003c/li\u003e\n\u003cli\u003eAlper, C. A., Awdeh, Z. L. \u0026amp; Yunis, E. J. Complotypes and extended haplotypes in laboratory medicine. \u003cem\u003eComplement Inflamm. \u003c/em\u003e\u003cstrong\u003e6\u003c/strong\u003e, 8\u0026ndash;18 (1989).\u003c/li\u003e\n\u003cli\u003eKumar, N., Kaur, G., Tandon, N. \u0026amp; Mehra, N. K. Allotyping human complement factor B in Asian Indian type 1 diabetic patients. \u003cem\u003eTissue Antigens \u003c/em\u003e\u003cstrong\u003e72\u003c/strong\u003e, 517\u0026ndash;524 (2008).\u003c/li\u003e\n\u003cli\u003eBertrams, J., Hintzen, U., Schlicht, V. \u0026amp; Schoeps, S. C4: another marker for type I diabetes. \u003cem\u003eLancet Lond. Engl. \u003c/em\u003e\u003cstrong\u003e1\u003c/strong\u003e, 41 (1982).\u003c/li\u003e\n\u003cli\u003eBertrams, J. \u003cem\u003eet al.\u003c/em\u003e Gene and haplotype frequencies of the fourth component of complement (C4) in type 1 diabetics and normal controls. \u003cem\u003eImmunobiology \u003c/em\u003e\u003cstrong\u003e166\u003c/strong\u003e, 335\u0026ndash;344 (1984).\u003c/li\u003e\n\u003cli\u003eChoteau, L. \u003cem\u003eet al.\u003c/em\u003e Role of mannose-binding lectin in intestinal homeostasis and fungal elimination. \u003cem\u003eMucosal Immunol. \u003c/em\u003e\u003cstrong\u003e9\u003c/strong\u003e, 767\u0026ndash;776 (2016).\u003c/li\u003e\n\u003cli\u003eMuller, Y. L. \u003cem\u003eet al.\u003c/em\u003e Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish. \u003cem\u003eDiabetes \u003c/em\u003e\u003cstrong\u003e59\u003c/strong\u003e, 2080\u0026ndash;2085 (2010).\u003c/li\u003e\n\u003cli\u003eZhang, N. \u003cem\u003eet al.\u003c/em\u003e Association of levels of mannose-binding lectin and the MBL2 gene with type 2 diabetes and diabetic nephropathy. \u003cem\u003ePloS One \u003c/em\u003e\u003cstrong\u003e8\u003c/strong\u003e, e83059 (2013).\u003c/li\u003e\n\u003cli\u003eUysalol, M. \u003cem\u003eet al.\u003c/em\u003e Importance of mannose-binding lectin2 polymorphism (rs1800450) in infections in children. \u003cem\u003eBiomarkers\u003c/em\u003e (2022).\u003c/li\u003e\n\u003cli\u003eRewers, M. \u003cem\u003eet al.\u003c/em\u003e Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). \u003cem\u003eDiabetologia \u003c/em\u003e\u003cstrong\u003e39\u003c/strong\u003e, 807\u0026ndash;812 (1996).\u003c/li\u003e\n\u003cli\u003eFrohnert, B. I. \u003cem\u003eet al.\u003c/em\u003e Late-onset islet autoimmunity in childhood: the Diabetes Autoimmunity Study in the Young (DAISY). \u003cem\u003eDiabetologia \u003c/em\u003e\u003cstrong\u003e60\u003c/strong\u003e, 998\u0026ndash;1006 (2017).\u003c/li\u003e\n\u003cli\u003eBuckner, T. \u003cem\u003eet al.\u003c/em\u003e Genome-wide analysis of oxylipins and oxylipin profiles in a pediatric population. \u003cem\u003eFront. Nutr. \u003c/em\u003e\u003cstrong\u003e10\u003c/strong\u003e, (2023).\u003c/li\u003e\n\u003cli\u003eTEDDY Study Group. The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. \u003cem\u003ePediatr. Diabetes \u003c/em\u003e\u003cstrong\u003e8\u003c/strong\u003e, 286\u0026ndash;298 (2007).\u003c/li\u003e\n\u003cli\u003eGogarten, S. M. \u003cem\u003eet al.\u003c/em\u003e Genetic association testing using the GENESIS R/Bioconductor package. \u003cem\u003eBioinformatics \u003c/em\u003e\u003cstrong\u003e35\u003c/strong\u003e, 5346\u0026ndash;5348 (2019).\u003c/li\u003e\n\u003cli\u003eWinkler, T. W. \u003cem\u003eet al.\u003c/em\u003e Quality control and conduct of genome-wide association meta-analyses. \u003cem\u003eNat. Protoc. \u003c/em\u003e\u003cstrong\u003e9\u003c/strong\u003e, 1192\u0026ndash;1212 (2014).\u003c/li\u003e\n\u003cli\u003eAmerican Diabetes Association. 2. Classification and Diagnosis of Diabetes. \u003cem\u003eDiabetes Care \u003c/em\u003e\u003cstrong\u003e39\u003c/strong\u003e, S13\u0026ndash;S22 (2015).\u003c/li\u003e\n\u003cli\u003eWang, G., Sarkar, A., Carbonetto, P. \u0026amp; Stephens, M. A simple new approach to variable selection in regression, with application to genetic fine mapping. \u003cem\u003eJ. R. Stat. Soc. Ser. B Stat. Methodol. \u003c/em\u003e\u003cstrong\u003e82\u003c/strong\u003e, 1273\u0026ndash;1300 (2020).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 Clinical characteristics of samples in DAISY and TEDDY.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"554\" 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\" alt=\"image\" height=\"105\"\u003e\u003c/p\u003e\n\u003cp\u003emedian \u0026plusmn; standard deviation; DAISY, the Diabetes Autoimmunity Study in the Young study; TEDDY, The Environment Determinants of Diabetes in the Young study; IA, islet autoimmunity; \u003csup\u003e#\u003c/sup\u003eage matches with sample\u0026rsquo;s protein collection time; T1D, type 1 diabetes; NHW, Non-Hispanic White; *TEDDY participants are from three United States (US) clinical centers (Colorado, Georgia/Florida, Washington) and three European clinical centers (Finland, Germany, Sweden), the summary statistics are from three US clinical centers as European clinical centers report many missing or unknown race/ethnicity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Summary of FDR-significant (FDR\u0026lt;0.1) \u003cem\u003ecis\u003c/em\u003e-pQTLs identified in DAISY.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"530\" 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\" alt=\"image\" height=\"431\"\u003e\u003c/p\u003e\n\u003cp\u003eDAISY, the Diabetes Autoimmunity Study in the Young study; 10 overlapped proteins between SRM\u003c/p\u003e\n\u003cp\u003eand Exsera are highlighted in bold; SRM, selected reaction monitoring mass spectrometry assay;\u003c/p\u003e\n\u003cp\u003eFDR, false discovery rate; Total, union of significant \u003cem\u003ecis\u003c/em\u003e-pQTLs after fine mapping from pooled and case-stratified analyses; \u0026ndash;, protein data was not available in the corresponding assay.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3 Summary of replicated \u003cem\u003ecis\u003c/em\u003e-pQTLs in TEDDY.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" alt=\"image\" width=\"554\" height=\"105\"\u003eChr, chromosome; FDR, false discovery rate; Beta (SE)/P-value, \u003cem\u003ecis\u003c/em\u003e-pQTL mapping effect size (standard error)/P-value for 385 TEDDY IA cases; TEDDY, The Environment Determinants of Diabetes in the Young study; IA, islet autoimmunity; T1D, type 1 diabetes; *, top pQTL variant, see Supplementary Table S2 for full replicated \u003cem\u003ecis\u003c/em\u003e-pQTL list.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"islet autoimmunity, T1D, complement system proteins, protein quantitative trait locus (pQTL), DAISY, TEDDY","lastPublishedDoi":"10.21203/rs.3.rs-5975824/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5975824/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eType 1 diabetes (T1D) is characterized by the autoimmune destruction of the insulin-producing beta cells, and there is no cure yet for the disease. While islet autoantibodies are well-recognized biomarkers that mark the onset of islet autoimmunity (IA) and are predictors of T1D, few additional biomarkers are available to monitor disease progression. Recent studies have reported the involvement of complement system proteins in the initiation and progression of IA in the study of T1D. However, the genetic factors of complement system proteins at the time of triggering of IA is unknown.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThrough complement system protein quantitative trait locus (pQTL) mapping analysis of 170 participants from the Diabetes Autoimmunity Study in the Young (DAISY), we identified 240 statistically significant pQTLs (false discovery rate, FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.1) from pooled and IA case-stratified analyses. Replication analysis conducted on 385 IA cases from The Environment Determinants of Diabetes in the Young (TEDDY) study confirmed 68 significant (FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.05) pQTLs in total for C8A, C8B, CFB, C4A, and MBL2. Furthermore, all replicated pQTLs of CFB and C4A were previously reported to be associated with T1D risk.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWe identified and replicated 68 pQTLs for five complement system proteins (C8A, C8B, CFB, C4A, and MBL2) in the young population. Among them, all replicated pQTLs of CFB and C4A are also associated with T1D risk. Our study provides evidence of complement system proteins as potential protein biomarkers underlying the development and progression of T1D.\u003c/p\u003e","manuscriptTitle":"Genome-wide mapping of complement system proteins for islet autoimmunity in the DAISY and TEDDY children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-10 15:19:00","doi":"10.21203/rs.3.rs-5975824/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"942eca39-ec6f-40f5-b2cf-771fb73d9b60","owner":[],"postedDate":"February 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-13T23:08:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-10 15:19:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5975824","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5975824","identity":"rs-5975824","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}