Genetic polymorphisms are associated with imatinib plasma levels and periorbital edema in Chinese patients with gastrointestinal stromal tumors receiving adjuvant imatinib

Genetic polymorphisms are associated with imatinib plasma levels and periorbital edema in Chinese patients with gastrointestinal stromal tumors receiving adjuvant imatinib | 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 Genetic polymorphisms are associated with imatinib plasma levels and periorbital edema in Chinese patients with gastrointestinal stromal tumors receiving adjuvant imatinib Xuehui Jiang, Qun Fu, Ying Kong, Hong Liu, Kaisaner Rexiti, Xiaohua Wei, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1994623/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 Purpose Imatinib mesylate (IM) offers a significant survival benefit to patients with gastrointestinal stromal tumors (GIST). However, the clinical responses of IM vary drastically between individuals. Therefore, this study aimed to assess the role of genetic polymorphisms of metabolic enzymes, transporters and drug targets in IM plasma levels and adverse reactions in Chinese patients with GIST. Methods The dose-adjusted trough plasma levels (C 0 /D) of IM in 95 patients were quantified using two-dimensional liquid chromatography. Nine SNPs in six genes were detected. The relationships between C 0 /D, single nucleotide polymorphisms (SNPs) and adverse reactions were tested. Logistic regression was used to test the risk factors for IM-related grade ≥ 2 periorbital edema. Results A range of C 0 /D from 1.33 to 7.04 ng/mL·mg -1 for the 95 patients was found. G allele carriers (CG+GG) of SLC22A1 rs683369 and T allele carriers (GT+TT) of ABCG2 rs2231142 had significantly higher C 0 /D. For all grades of periorbital edema, an increase in incidence with age was found, while this differed from more severe periorbital edema. Grade ≥ 2 periorbital edema was related to the carriership of two C-alleles in EGFR rs2072454 with an adjusted OR of 2.85 (95% CI=1.10–7.40; P =0.032), two T-alleles in SLC22A1 rs1867351 with an adjusted OR of 3.42 (95% CI=1.32–8.88; P =0.010) and two A-alleles in CYP1A2 rs11636419 with an adjusted OR of 3.15 (95% CI=1.08–9.20; P =0.036). None of the nine SNPs was found to be related to gastrointestinal reactions. Conclusions Rs683369 and rs2231142 have an impact on the metabolism of IM; rs2072454, rs1867351, and rs11636419 are linked to grade ≥ 2 periorbital edema. These SNPs may be biomarkers for IM dose adjustment and IM-related grade ≥ 2 periorbital edema. IM GIST Genetic polymorphisms Periorbital edema Plasma levels Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Gastrointestinal stromal tumors (GIST), derived from precursors of the interstitial cells of Cajal, are the most frequent subset of all sarcomas of the gastrointestinal tract, with an incidence of approximately 1.2/100000 per year [ 1 , 2 ]. Before 2002, surgery was the exclusive treatment for GIST. However, the recurrence and mortality rates remain high even with complete resection, and the 5-year survival rate is only 54% [ 3 ]. Since the introduction of tyrosine kinase inhibitors (TKIs), the treatment paradigm for GIST has shifted from a predominantly surgical approach to a combination of surgery and drugs. IM, a typical TKI, is the first-line agent for unresectable or metastatic GIST and is used as an adjuvant treatment for GIST in patients with an intermediate or high risk of relapse after surgery. IM is a targeted antitumor agent that offers a significant survival benefit for patients with GIST, and the 5-year survival rate has increased to approximately 80% [ 4 , 5 ]. IM is metabolized to N-demethylated piperazine derivative (CGP74588), its active metabolite, in the liver [ 6 ]. IM displays significant interpatient variability, ranging from 38–75% [ 7 ]. Genetic polymorphisms have been found to dramatically influence inter-individual variations in drug distribution, metabolism, and response, including adverse reactions [ 8 ], and have been recognized as biomarkers to adjust drug dosage and predict adverse effects [ 9 ]. The genetic marker system of single nucleotide polymorphisms (SNPs) was proposed in 1996. SNPs are scattered single-base substitutions, belonging to di-allelic polymorphic markers [ 10 ]. Since SNPs can reflect genetic variations among individuals, the impact of genetic factors on adverse drug reactions can be elucidated using correlation studies between SNPs and adverse reactions to drugs. Efficacy is the primary goal in the introduction of anticancer drugs, yet toxicity poses a barrier to the implementation of many targeted anticancer drugs [ 11 ], and managing toxicity is critical to achieving long-term therapeutic outcomes, which also applies to IM. Adverse reactions attributed to IM are widespread and include edema, gastrointestinal reactions, and rashes. Continuous administration of IM and good compliance contribute to disease management. However, due to adverse reactions caused by IM, many patients reduce their dosage on their own, and about 30% of patients who suffer serious adverse reactions have to withdraw from the drug [ 12 , 13 ], making it difficult to achieve a favorable outcome. Edema, mainly in the periorbital area, is the most common adverse reaction to IM, with an approximate occurrence rate of 70% [ 14 ], and is reportedly associated with SNPs [ 13 , 15 ]. Adverse reactions caused by IM are often mild, but it can cause grade 2 and 3 edema in the periorbital area. More severe edema has the potential to induce or aggravate heart failure, and patients with a history of heart disease or heart failure should be monitored closely [ 16 ]. Further studies have not been conducted to explore the relationship between more severe periorbital edema and SNPs, and sufficient covariates were not captured in the primary screen, which tends to omit potential factors. Additionally, most of the current studies were conducted by combining preoperative and postoperative patients without considering postoperative patients separately. There is a pressing need to uncover the factors underlying IM plasma levels and the role of gene polymorphisms in more severe periorbital edema secondary to IM. Therefore, this study sought to test the relationship between genetic polymorphisms and grade 2 or 3 periorbital edema attributed to IM in a surgically treated population. We selected nine SNPs in six genes (influx- and efflux-transporters, metabolic enzymes and drug targets). This study was designed to investigate the differences in distribution, metabolism, and toxic reactions among individuals, and to provide a foundation for choosing an appropriate drug treatment regimen according to the differences in individual genetic backgrounds; thus, the clinical practice of both medicine and pharmacology in GIST can be made more effective. Ultimately, the goal of achieving better therapeutic effects and lower toxicity can be achieved. Materials And Methods Patients All surgically treated GIST patients, receiving 200–600 mg IM, were recruited from the First Affiliated Hospital of Nanchang University. The inclusion criteria were as follows: (1) patients with histologically confirmed GIST; (2) age ≥ 18 years at the time of operation; (3) patients categorized as having an intermediate or high risk of relapse after surgery and had been taking IM regularly for at least one month; and (4) patients with normal liver and kidney functions [alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than twice the upper limit of normal (ULN), total bilirubin in serum less than 1.25 times the ULN, and serum creatinine less than 1.5 times the ULN]. Patients who (1) showed poor adherence to treatment; (2) were lost to follow-up; and (3) received co-administration of CYP3A4 and CYP3A5 inhibitors or inducers were excluded from this study. Finally, 95 patients were enrolled in this study. Ethical approval for this study was granted by the First Affiliated Hospital of Nanchang University Ethics Committee [(2021) Medical Research Ethics No. (12 − 001)], and informed consent was obtained from all patients. Periorbital edema were recorded during regular follow-up and then evaluated and graded according to the NCI Common Toxicity Criteria of Adverse Events (NCI CTCAE v5.0). According to the document, periorbital edema was classified into four grades: without periorbital edema, grade 0; soft or non-punctate, grade 1; hard or punctate edema and requiring local treatment, grade 2; edema with visual disturbance or elevated intraocular pressure and requiring diuretics, grade 3. Of these, grades 2 and 3 were defined as periorbital edema that required manual intervention, which was the focus of this study. Gastrointestinal reactions (including nausea, vomiting, abdominal pain and diarrhea in this study) were recored, too. Quantitation of IM concentration Blood samples were collected in EDTA anticoagulant tubes from patients who had been taking IM regularly for 30 days and 24 ± 2 h after IM dosing. Samples were pre-purified via protein precipitation, centrifuged at 3000 r for 5 min for plasma separation, and frozen at -80°C. Two-dimensional liquid chromatography was used to determine the IM concentration. The inter- and intra-day relative standard deviations (SD) were less than 4.0%. SNP selection and genotyping Most candidate genes were selected from IM metabolism and transport pathways. The 1000 Genomes database and Haploview software version 4.2 ( https://www.broadinstitute.org/haploview/haploview ) were used to screen SNPs, and the minor allele frequency of SNPs was at least 0.1 (MAF ≥ 0.1). In addition, NCBI dbSNP was used to select non-synonymous coding SNPs, synonymous coding SNPs, and SNPs located in the 3'UTR and 5'UTR. DNA was isolated from the blood samples of 95 patients with GIST using the TIANamp blood DNA kit (Tiangen Biotech, Co., Ltd., Beijing, China). MassARRAY technology was used by Shanghai Bohao Biological Corporation to genotype selected SNPs. Statistical analysis Statistical analyses were performed using SPSS version 22.0 (IBM, Armonk, NY, USA) and, to a lesser extent, SAS version 9.4 (SAS Institute, Cary, NC, USA). Descriptive statistics were used to analyze patient characteristics. The normality of continuous variables was tested using the Shapiro-Wilk normality test, and normally distributed data were expressed as mean ± SD (range), while non-normally distributed data were expressed as the median (interquartile range, IQR). Hardy-Weinberg equilibrium (HWE) was tested using the Chi-square test for genotype and allele frequencies of all selected SNPs. SNPs with genotype distributions that were not in Hardy-Weinberg equilibrium ( P < 0.05) were excluded from the analysis. Pairwise linkage disequilibrium for the investigated SNPs was estimated using the SHEsisPlus platform ( http://shesisplus.bio-x.cn/SHEsis.html ). Nonparametric tests were applied to continuous variables that were non-normally distributed. The independent samples t -test was used to analyze the association between continuous variables that were normally distributed and adverse reactions, and Chi-square or Fisher’s exact tests were used to test the association between adverse reactions and categorical variables, such as gender, SNPs, and primary tumor sites. Significantly correlated factors of more severe periorbital edema was identified as confounding factors using binary logistic regression. All statistical tests were two-sided, and P -values < 0.05 were considered statistically significant. Results Patient characteristics and adverse reactions of IM The GIST patients comprised a cohort of 95 Chinese patients who had undergone surgery. The characteristics of the study population are presented in Table 1 . There were 46 (48.4%) men and 49 (51.6%) women. The patients were divided into four groups according to age, namely 18–40, 41–55, 56–70, and > 70 years, and included 6 (6.3%), 35 (36.8%), 40 (42.1%), and 14 (14.7%) patients, respectively. Of all grades of periorbital edema, there were remarkable differences between the 18–40-year-old group and other groups, except for the 56–70-year-old group ( P < 0.05 after Bonferroni correction). Figure 1 a reveals a marked increase in the incidence of periorbital edema with age ( P for trend < 0.05), suggesting that older people may be more likely to develop periorbital edema. The incidence of gastrointestinal reactions in the 41–55-year-old group was much higher than in the 56–70-year-old group after Bonferroni correction ( P 0.05 (Fig. 1 b). A significant inter-individual variation in C 0 /D was found, which ranged from 1.33 to 7.04 ng/mL·mg − 1 , but the relationship between C 0 /D and patient characteristics was not significant. This study also demonstrated that the C 0 /D of IM did not affect the incidence of grade ≥ 2 periorbital edema or gastrointestinal reactions, at least in the range of 1.33 to 7.04 ng/mL·mg − 1 . Table 1 Characteristics of study population Characteristics Number C 0 /D Periorbital edema Grade ≥ 2 Gastrointestinal reactions P N P N P Gender Male 46(48.4%) 0.174 9 0.040 * 17 0.700 Female 49(51.6%) 19 20 BMI a 21.89 ± 3.00(14.61–30.47) 0.250 0.468 0.818 C 0 /D b 3.50(2.80–4.41) — 0.278 0.287 Age at surgery 18–40 6(6.3%) 0.381 0 0.160 1 0.011 * 41–55 35(36.8%) 10 21 56–70 40(42.1%) 11 10 > 70 14(14.7%) 7 5 Primary site Stomach 36(37.8%) 0.316 8 0.339 16 0.685 Small intestine 50(52.6%) 18 18 Other 9(9.5%) 2 3 * Represent P < 0.05 a Normally distributed data was expressed as mean ± SD (range) b Non-normally distributed data was expressed as medium (IQR) Abbreviation: BMI: body mass index Genotype Frequencies The frequencies of the nine SNPs are listed in Supplementary Table 1. All SNPs met the Hardy-Weinberg equilibrium ( P > 0.05). None of the nine SNPs were in linkage disequilibrium (Fig. 2 ). Genotypes and IM plasma trough levels SLC22A1 rs683369 and ABCG2 rs2231142 were significantly correlated with C 0 /D of IM (Table 2 and Fig. 3 ). Patients with the rs683369 CC genotype (3.57±1.21 ng/mL⋅mg − 1 ) appeared to have lower IM trough plasm levels than G allele carriers (4.32±1.60 ng/mL⋅mg − 1 ), which may be because CC genotype patients metabolized IM faster than G allele carriers. The C 0 /D of IM appeared higher in patients with the rs2231142 mutant T allele (3.98±1.36 ng/mL⋅mg − 1 ) than that in wild-type GG genotype patients (3.40±1.21 ng/mL⋅mg − 1 ). Table 2 The association of SNPs and side effects Genotypes and adverse reactions For adverse reactions to IM, the study focused on the adverse reactions that are common but exert great influence on the life of patients, such as grade 2 or 3 periorbital edema and gastrointestinal reactions. In this study, women were more likely to develop more severe periorbital edema due to IM ( P 0.05). After discovering that older individuals are more likely to develop periorbital edema related to IM, those that require human intervention were not observed to be age-related; thus, genetic polymorphisms may be potential influencing factors. Further studies were conducted based on these findings. The results of further analyses are shown in Fig. 4 . Polymorphisms in EGFR , SLC22A1 , and CYP1A2 were found to be associated with grade ≥ 2 periorbital edema. All odds ratios (OR) were adjusted for factors (C 0 /D, BMI and gender). The rs2072454 CC genotype manifested as a risk factor for grade ≥ 2 periorbital edema compared to T carriers (CT + TT) with an adjusted OR of 2.85 (95% CI = 1.10–7.40, P = 0.032). The adjusted OR was 3.42 (95% CI = 1.32–8.88, P = 0.010) for the SLC22A1 rs1867351 TT genotype compared to C carriers (CT + TT), and 3.15 (95% CI = 1.08–9.20, P = 0.036) for two A-alleles in CYP1A2 rs11636419 compared to that of G allele carriers. In the logistic regression analysis, the rs2282143 CC genotype of SLC22A1 and GG genotype of EGFR were not protective factors, as expected ( P > 0.05). No correlation was found between gastrointestinal reactions and SNPs. Discussion For GIST, it has been reported that the stomach (60–65%) is the most frequent primary site, followed by the small intestine (20–25%), and other sites are much less common [ 1 , 18 ]. In this study, the proportion of primary sites in the small intestine and other sites (52.6%) was greater than that in the stomach (37.8%), as all members of the population were surgically treated and categorized as having an intermediate or high risk of relapse, and the prognosis of non-gastric cancer is expected to be worse than that of gastric primary [ 19 ] with a higher risk of recurrence [ 20 ]. The etiology of the periorbital edema caused by IM remains unclear. The most accepted view currently involves platelet-derived growth factor receptor (PDGFR), which is one of the targets of IM. PDGFR is highly expressed in the skin around the eyes and maintains interstitial fluid homeostasis by regulating the tension between the extracellular matrix structures and cells [ 21 , 22 ]. PDGFR inhibition leads to decreased interstitial pressure, increased capillary permeability, and fluid extravasation [ 23 , 14 ]. There is also a complex network of connections between the lower eyelid skin and infraorbital wall, forming an enclosed space, which may allow for easier fluid collection and edema formation [ 22 ]. The incidence of IM-induced periorbital edema was similar to that reported in other studies; however, the ratio of more severe periorbital edema was much higher in this study [ 5 , 14 ]. This may be attributed to the fact that the population in this study was postoperative, showing an intermediate or high risk of recurrence, and physiological statuses differed from patients in other studies. Additionally, the present study focused on late toxicity instead of early toxicity, as it has been reported that approximately half of the patients developed grade ≥ 2 toxicities attributed to TKIs after the first cycle [ 24 ]. Periorbital edema can be resolved by discontinuing IM, but this does not appear to be a reasonable option for most patients and is not recommended in situations where IM may markedly extend the recurrence-free survival of patients [ 25 , 26 ] and when therapeutic alternatives are limited. The risk of relapse increased after discontinuation, as shown in the BRF 14-trial, which highlighted that most patients relapsed or progressed after interruption of IM treatment [ 27 ]. In the event of a relapse, all previous efforts were lost. For mild edema, there is no need to take any steps, but to weigh and monitor regularly to detect any unusual weight gain or severe fluid retention [ 28 ]. In cases of grade 2 periorbital edema that poses difficulties in daily life, symptomatic treatment may be available, such as salt restriction and topical steroids. Diuretics or surgical intervention may be feasible approaches for grade 3 periorbital edema cases [ 22 ]. A researcher from Canada reported a patient with type 2 diabetes mellitus (T2DM) and GIST who developed grade 3 periorbital edema immediately after IM treatment. This greatly affected the patient’s life. However, it was only two days after replacing metformin with canagliflozin that the periorbital edema appeared markedly alleviated, and completely subsided after one week [ 29 ]. Canagliflozin is a new antihyperglycemic drug that inhibits glucose reabsorption in the proximal tubule by inhibiting sodium-glucose cotransporter-2 (SGLT-2). There are no prospective clinical trials of a certain scale to confirm this effect and clarify the mechanism, but an SGLT-2 inhibitor may be a good option for GIST patients with T2DM who are taking IM. More severe periorbital edema did not correlate with C 0 /D ( P > 0.05), as described in a previous study [ 15 ]. The present study also indicates that genetic polymorphisms of ABCG2 rs2231142 and SLC22A1 rs683369 may influence the trough plasma levels of IM. Genetic polymorphisms of SLC22A1 rs1867351, EGFR rs2072454, and CYP1A2 rs11636419 have been found to play roles in IM-induced grade ≥ 2 periorbital edema. ABCG2 functions as a xenobiotic transporter and may play a major role in multi-drug resistance. ABCG2 plays a role in the transportation of many drugs, including IM [ 30 ], and has attracted considerable interest. The present study found that polymorphisms in ABCG2 rs2231142 significantly affected IM transport. ABCG2 rs2231142 is a non-synonymous coding SNP that converts the originally encoded glutamine to another amino acid, and may have significantly affected ABCG2 activity, thereby affecting the plasma concentration of the drug. Many endogenous small organic cations, as well as a wide range of drugs and environmental toxins, are eliminated by organic cation transporters encoded by SLC22A1 . This was confirmed by the fact that polymorphisms in SLC22A1 were linked to grade ≥ 2 periorbital edema and IM trough plasma levels in this study. Gene polymorphisms can affect toxicity by influencing drug exposure or the ability of transporters to eliminate drug toxicity. Its impact on IM toxicity in this study was similar to that reported in a 2017 study [ 15 ]. EGFR , an oncogene, encodes a receptor for members of the epidermal growth factor family and plays an essential role in cell proliferation. This study describes the influence of EGFR rs2072454 on adverse reactions of IM for the first time. In the present study, the rs2072454 CC genotype represented an adjusted OR of 2.85 (95% CI = 1.10–7.40, P = 0.032) for grade ≥ 2 periorbital edema compared to T carriers (CT + TT). The receptor, expressed in the ocular structure, is also a receptor for IM [ 31 ], and toxicity may be a consequence of IM inhibition in this region. CYP1A2 encodes a member of the cytochrome P450 superfamily of enzymes localized to the endoplasmic reticulum. Polymorphisms in CYP1A2 were identified to be associated with more severe periorbital edema, and the gene was also found to be related to the need for dose reduction due to IM toxicity [ 4 ]. This was thought to result from the inconsistent metabolic rates of IM between different genotypes. However, other genes may compensate for this. The sample size of this study was limited and the results may be biased. Additional research with larger samples size and prospective clinical trials are required to confirm the findings of this study. Additionally, the identification of haplotype-tagged SNP (htSNP) genotypes guarantees that all common variants can be captured in gene-drug response correlation studies, whereas single SNP-based correlation studies are difficult to achieve. Nonetheless, this study revealed several SNPs associated with individual treatments, which will facilitate research to identify better treatments and help to optimize individualized medical treatment. Declarations Authors’ Contributions All authors contributed to the manuscript. Xuehui Jiang designed this study and drafted the manuscript. Imatinib concentration quantification was done by Ying Kong and Hong Liu. Statistical analysis of data was conducted by Xuehui Jiang and Qun Fu. Kaisaner Rexiti reviewed data for this study. Xiaohua Wei, Pin Xiao and Hongwei Peng critically revised the manuscript. Acknowledgments and funding information Acknowledgments The authors would like to thank the provision of financial support by Jiangxi Provincial Department of Science and Technology and technical support by Shanghai Bohao Biological Corporation. Funding This study was supported by Jiangxi Provincial Department of Science and Technology (No. 20201BBG71008). Conflict of interest All the authors declare they have no conflict of interest in this work. Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the First Affiliated Hospital of Nanchang University ethics committee [(2021) Medical Research Ethics No. (12-001)] and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individuals included in the study. 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Ann Oncol 24 (4):1087–1093. https://doi.org/10.1093/annonc/mds587 Joensuu H, Trent JC, Reichardt P (2011) Practical management of tyrosine kinase inhibitor-associated side effects in GIST. Cancer treatment reviews 37 (1):75–88. https://doi.org/10.1016/j.ctrv.2010.04.008 Chin-Yee B, Xenocostas A (2022) Successful treatment of imatinib-induced periorbital edema with a sodium-glucose cotransporter-2 inhibitor. Ann Hematol. https://doi.org/10.1007/s00277-021-04741-3 Koo DH, Ryu MH, Ryoo BY, Beck MY, Na YS, Shin JG, Lee SS, Kim EY, Kang YK (2015) Association of ABCG2 polymorphism with clinical efficacy of imatinib in patients with gastrointestinal stromal tumor. Cancer Chemother Pharmacol 75 (1):173–182. https://doi.org/10.1007/s00280-014-2630-6 Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2 (5):561–566. https://doi.org/10.1038/nm0596-561 Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx 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-1994623","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":131472924,"identity":"47317ce4-0bb8-43ed-9be4-2808acfca969","order_by":0,"name":"Xuehui Jiang","email":"","orcid":"","institution":"Nanchang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xuehui","middleName":"","lastName":"Jiang","suffix":""},{"id":131472925,"identity":"a486b155-6bf3-4155-a20b-b4c1d26a275d","order_by":1,"name":"Qun Fu","email":"","orcid":"","institution":"Jiangxi Provincial Drug Administration","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qun","middleName":"","lastName":"Fu","suffix":""},{"id":131472926,"identity":"49149f6b-863e-414e-a3bf-86ed90d93eef","order_by":2,"name":"Ying Kong","email":"","orcid":"","institution":"the First Affiliated Hospital of Nanchang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Kong","suffix":""},{"id":131472927,"identity":"ecd7cd53-2fe5-4a17-ac74-3d736099feff","order_by":3,"name":"Hong Liu","email":"","orcid":"","institution":"the First Affiliated Hospital of Nanchang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Liu","suffix":""},{"id":131472928,"identity":"2509c81b-5392-4ae0-ae4c-39c6f55ee4a9","order_by":4,"name":"Kaisaner Rexiti","email":"","orcid":"","institution":"Nanchang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kaisaner","middleName":"","lastName":"Rexiti","suffix":""},{"id":131472929,"identity":"f2cb7b1e-38c8-4590-93eb-d42c21ac6136","order_by":5,"name":"Xiaohua Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYFACHgZmBgYLGQb2xsaHH0jQIsHDwHO42ViCNC0S6W0CPMRoMLiRe4C5oEKCh1/yYRuDBIOdnG4DIS1nziUwzzgjwSM5O7HtQQFDsrHZAQJazI73mP/mbZPgMbid2G4gwXAgcRtBLYd5DJh5/wG13DwI1EiUluM9QC0NQC03GInUYn/mjAEzzzGgX3oSgYFsQIRfJGfkALXU2Mjxsx9/+PBDhZ0cQS1owIA05aNgFIyCUTAKcAAAaag5OlEcBwIAAAAASUVORK5CYII=","orcid":"","institution":"the First Affiliated Hospital of Nanchang University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Xiaohua","middleName":"","lastName":"Wei","suffix":""},{"id":131472930,"identity":"d4cb469f-1060-487d-ad9b-af7150db77f1","order_by":6,"name":"Pin Xiao","email":"","orcid":"","institution":"Hospital of Jiangxi Provincial Armed Police Corps","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pin","middleName":"","lastName":"Xiao","suffix":""},{"id":131472931,"identity":"39914f56-187d-466c-90fe-e1c942156895","order_by":7,"name":"Hongwei Peng","email":"","orcid":"","institution":"the First Affiliated Hospital of Nanchang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hongwei","middleName":"","lastName":"Peng","suffix":""}],"badges":[],"createdAt":"2022-08-24 15:14:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1994623/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1994623/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":25728826,"identity":"c1cee8c4-045f-4cd8-81fa-1b4c06a1138d","added_by":"auto","created_at":"2022-08-26 18:27:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":136825,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations of different age groups with adverse reactions are illustrated. The \u003cem\u003eP\u003c/em\u003e-value was adjusted by Bonferroni correction. Correlations between age groups and (\u003cstrong\u003ea\u003c/strong\u003e) ratio of edema (\u003cem\u003eP\u003c/em\u003e for trend=0.016), (\u003cstrong\u003eb\u003c/strong\u003e) ratio of gastrointestinal reactions (\u003cem\u003eP\u003c/em\u003e for trend=0.178)\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"OnlineFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-1994623/v1/c687fef7060f8b4d3ddc788e.png"},{"id":25728135,"identity":"750590dd-c75b-49f9-8344-43d237c68a52","added_by":"auto","created_at":"2022-08-26 18:17:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":481189,"visible":true,"origin":"","legend":"\u003cp\u003ePairwise linkage profiles of rs11636419, rs1867351, rs683369, rs2282143, rs10841803, rs2231142, rs1800860, rs2072454 and rs2227983. The number inside the rhombus indicates the R\u003csup\u003e2 \u003c/sup\u003eof the specific linkage of two SNPs, R\u003csup\u003e2 \u003c/sup\u003e\u0026gt; 0.8 is thought linked\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"OnlineFig2.png","url":"https://assets-eu.researchsquare.com/files/rs-1994623/v1/d336277e350d34d9df9de5fe.png"},{"id":25728137,"identity":"dbd0023f-b62e-406f-a18e-5322116df99e","added_by":"auto","created_at":"2022-08-26 18:17:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":145360,"visible":true,"origin":"","legend":"\u003cp\u003eThe steady-state IM trough plasm levels related to (\u003cstrong\u003ea\u003c/strong\u003e) \u003cem\u003eSLC22A1\u003c/em\u003e rs683369 (\u003cem\u003eP\u003c/em\u003e=0.039) and (\u003cstrong\u003eb\u003c/strong\u003e) \u003cem\u003eABCG2\u003c/em\u003e rs2231142 (\u003cem\u003eP\u003c/em\u003e=0.018). The IM trough plasm levels were adjusted by dose\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"OnlineFig3.png","url":"https://assets-eu.researchsquare.com/files/rs-1994623/v1/bd1b2a2ff87dc89b3bc4de68.png"},{"id":25728139,"identity":"a31645c8-453b-497b-9cfe-bd12cd41781e","added_by":"auto","created_at":"2022-08-26 18:17:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":152927,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of risks of different SNPs in IM-related periorbital edema that requiring human intervention. The intersection of horizontal bars and the vertical line (OR=1) indicates insignificance\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"OnlineFig4.png","url":"https://assets-eu.researchsquare.com/files/rs-1994623/v1/5037ff66fc3247f31d1ca7cb.png"},{"id":25976276,"identity":"5e3080e6-1d76-4424-8d90-6672c0b8fc2d","added_by":"auto","created_at":"2022-09-02 10:59:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":746418,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1994623/v1/92c163a2-2d97-47c8-bbbd-9314ee23b820.pdf"},{"id":25728303,"identity":"dd78d2d3-cae1-4f55-8cba-f354b6d98d75","added_by":"auto","created_at":"2022-08-26 18:22:46","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":21177,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-1994623/v1/a8e85f05f397e38ecaa4d89b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Genetic polymorphisms are associated with imatinib plasma levels and periorbital edema in Chinese patients with gastrointestinal stromal tumors receiving adjuvant imatinib","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastrointestinal stromal tumors (GIST), derived from precursors of the interstitial cells of Cajal, are the most frequent subset of all sarcomas of the gastrointestinal tract, with an incidence of approximately 1.2/100000 per year [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Before 2002, surgery was the exclusive treatment for GIST. However, the recurrence and mortality rates remain high even with complete resection, and the 5-year survival rate is only 54% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Since the introduction of tyrosine kinase inhibitors (TKIs), the treatment paradigm for GIST has shifted from a predominantly surgical approach to a combination of surgery and drugs. IM, a typical TKI, is the first-line agent for unresectable or metastatic GIST and is used as an adjuvant treatment for GIST in patients with an intermediate or high risk of relapse after surgery. IM is a targeted antitumor agent that offers a significant survival benefit for patients with GIST, and the 5-year survival rate has increased to approximately 80% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. IM is metabolized to N-demethylated piperazine derivative (CGP74588), its active metabolite, in the liver [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. IM displays significant interpatient variability, ranging from 38\u0026ndash;75% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Genetic polymorphisms have been found to dramatically influence inter-individual variations in drug distribution, metabolism, and response, including adverse reactions [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and have been recognized as biomarkers to adjust drug dosage and predict adverse effects [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The genetic marker system of single nucleotide polymorphisms (SNPs) was proposed in 1996. SNPs are scattered single-base substitutions, belonging to di-allelic polymorphic markers [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Since SNPs can reflect genetic variations among individuals, the impact of genetic factors on adverse drug reactions can be elucidated using correlation studies between SNPs and adverse reactions to drugs.\u003c/p\u003e \u003cp\u003eEfficacy is the primary goal in the introduction of anticancer drugs, yet toxicity poses a barrier to the implementation of many targeted anticancer drugs [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and managing toxicity is critical to achieving long-term therapeutic outcomes, which also applies to IM. Adverse reactions attributed to IM are widespread and include edema, gastrointestinal reactions, and rashes. Continuous administration of IM and good compliance contribute to disease management. However, due to adverse reactions caused by IM, many patients reduce their dosage on their own, and about 30% of patients who suffer serious adverse reactions have to withdraw from the drug [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], making it difficult to achieve a favorable outcome. Edema, mainly in the periorbital area, is the most common adverse reaction to IM, with an approximate occurrence rate of 70% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and is reportedly associated with SNPs [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Adverse reactions caused by IM are often mild, but it can cause grade 2 and 3 edema in the periorbital area. More severe edema has the potential to induce or aggravate heart failure, and patients with a history of heart disease or heart failure should be monitored closely [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Further studies have not been conducted to explore the relationship between more severe periorbital edema and SNPs, and sufficient covariates were not captured in the primary screen, which tends to omit potential factors. Additionally, most of the current studies were conducted by combining preoperative and postoperative patients without considering postoperative patients separately.\u003c/p\u003e \u003cp\u003eThere is a pressing need to uncover the factors underlying IM plasma levels and the role of gene polymorphisms in more severe periorbital edema secondary to IM. Therefore, this study sought to test the relationship between genetic polymorphisms and grade 2 or 3 periorbital edema attributed to IM in a surgically treated population. We selected nine SNPs in six genes (influx- and efflux-transporters, metabolic enzymes and drug targets). This study was designed to investigate the differences in distribution, metabolism, and toxic reactions among individuals, and to provide a foundation for choosing an appropriate drug treatment regimen according to the differences in individual genetic backgrounds; thus, the clinical practice of both medicine and pharmacology in GIST can be made more effective. Ultimately, the goal of achieving better therapeutic effects and lower toxicity can be achieved.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003ePatients\u003c/p\u003e \u003cp\u003eAll surgically treated GIST patients, receiving 200\u0026ndash;600 mg IM, were recruited from the First Affiliated Hospital of Nanchang University. The inclusion criteria were as follows: (1) patients with histologically confirmed GIST; (2) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years at the time of operation; (3) patients categorized as having an intermediate or high risk of relapse after surgery and had been taking IM regularly for at least one month; and (4) patients with normal liver and kidney functions [alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than twice the upper limit of normal (ULN), total bilirubin in serum less than 1.25 times the ULN, and serum creatinine less than 1.5 times the ULN]. Patients who (1) showed poor adherence to treatment; (2) were lost to follow-up; and (3) received co-administration of CYP3A4 and CYP3A5 inhibitors or inducers were excluded from this study. Finally, 95 patients were enrolled in this study.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthical approval\u003c/strong\u003e \u003cp\u003e for this study was granted by the First Affiliated Hospital of Nanchang University Ethics Committee [(2021) Medical Research Ethics No. (12\u0026thinsp;\u0026minus;\u0026thinsp;001)], and informed consent was obtained from all patients. Periorbital edema were recorded during regular follow-up and then evaluated and graded according to the NCI Common Toxicity Criteria of Adverse Events (NCI CTCAE v5.0). According to the document, periorbital edema was classified into four grades: without periorbital edema, grade 0; soft or non-punctate, grade 1; hard or punctate edema and requiring local treatment, grade 2; edema with visual disturbance or elevated intraocular pressure and requiring diuretics, grade 3. Of these, grades 2 and 3 were defined as periorbital edema that required manual intervention, which was the focus of this study. Gastrointestinal reactions (including nausea, vomiting, abdominal pain and diarrhea in this study) were recored, too.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eQuantitation of IM concentration\u003c/p\u003e \u003cp\u003eBlood samples were collected in EDTA anticoagulant tubes from patients who had been taking IM regularly for 30 days and 24\u0026thinsp;\u0026plusmn;\u0026thinsp;2 h after IM dosing. Samples were pre-purified via protein precipitation, centrifuged at 3000 r for 5 min for plasma separation, and frozen at -80\u0026deg;C. Two-dimensional liquid chromatography was used to determine the IM concentration. The inter- and intra-day relative standard deviations (SD) were less than 4.0%.\u003c/p\u003e \u003cp\u003eSNP selection and genotyping\u003c/p\u003e \u003cp\u003eMost candidate genes were selected from IM metabolism and transport pathways. The 1000 Genomes database and Haploview software version 4.2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.broadinstitute.org/haploview/haploview\u003c/span\u003e\u003cspan address=\"https://www.broadinstitute.org/haploview/haploview\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) were used to screen SNPs, and the minor allele frequency of SNPs was at least 0.1 (MAF\u0026thinsp;\u0026ge;\u0026thinsp;0.1). In addition, NCBI dbSNP was used to select non-synonymous coding SNPs, synonymous coding SNPs, and SNPs located in the 3'UTR and 5'UTR. DNA was isolated from the blood samples of 95 patients with GIST using the TIANamp blood DNA kit (Tiangen Biotech, Co., Ltd., Beijing, China). MassARRAY technology was used by Shanghai Bohao Biological Corporation to genotype selected SNPs.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS version 22.0 (IBM, Armonk, NY, USA) and, to a lesser extent, SAS version 9.4 (SAS Institute, Cary, NC, USA). Descriptive statistics were used to analyze patient characteristics. The normality of continuous variables was tested using the Shapiro-Wilk normality test, and normally distributed data were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range), while non-normally distributed data were expressed as the median (interquartile range, IQR). Hardy-Weinberg equilibrium (HWE) was tested using the Chi-square test for genotype and allele frequencies of all selected SNPs. SNPs with genotype distributions that were not in Hardy-Weinberg equilibrium (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were excluded from the analysis. Pairwise linkage disequilibrium for the investigated SNPs was estimated using the SHEsisPlus platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://shesisplus.bio-x.cn/SHEsis.html\u003c/span\u003e\u003cspan address=\"http://shesisplus.bio-x.cn/SHEsis.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Nonparametric tests were applied to continuous variables that were non-normally distributed. The independent samples \u003cem\u003et\u003c/em\u003e-test was used to analyze the association between continuous variables that were normally distributed and adverse reactions, and Chi-square or Fisher\u0026rsquo;s exact tests were used to test the association between adverse reactions and categorical variables, such as gender, SNPs, and primary tumor sites. Significantly correlated factors of more severe periorbital edema was identified as confounding factors using binary logistic regression. All statistical tests were two-sided, and \u003cem\u003eP\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics and adverse reactions of IM\u003c/p\u003e\n\u003cp\u003eThe GIST patients comprised a cohort of 95 Chinese patients who had undergone surgery. The characteristics of the study population are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There were 46 (48.4%) men and 49 (51.6%) women. The patients were divided into four groups according to age, namely 18\u0026ndash;40, 41\u0026ndash;55, 56\u0026ndash;70, and \u0026gt;\u0026thinsp;70 years, and included 6 (6.3%), 35 (36.8%), 40 (42.1%), and 14 (14.7%) patients, respectively. Of all grades of periorbital edema, there were remarkable differences between the 18\u0026ndash;40-year-old group and other groups, except for the 56\u0026ndash;70-year-old group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 after Bonferroni correction). Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea reveals a marked increase in the incidence of periorbital edema with age (\u003cem\u003eP\u003c/em\u003e for trend\u0026thinsp;\u0026lt;\u0026thinsp;0.05), suggesting that older people may be more likely to develop periorbital edema. The incidence of gastrointestinal reactions in the 41\u0026ndash;55-year-old group was much higher than in the 56\u0026ndash;70-year-old group after Bonferroni correction (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but there was no trend, with a \u003cem\u003eP\u003c/em\u003e-value\u0026thinsp;\u0026gt;\u0026thinsp;0.05 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb). A significant inter-individual variation in C\u003csub\u003e0\u003c/sub\u003e/D was found, which ranged from 1.33 to 7.04 ng/mL\u0026middot;mg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, but the relationship between C\u003csub\u003e0\u003c/sub\u003e/D and patient characteristics was not significant. This study also demonstrated that the C\u003csub\u003e0\u003c/sub\u003e/D of IM did not affect the incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;2 periorbital edema or gastrointestinal reactions, at least in the range of 1.33 to 7.04 ng/mL\u0026middot;mg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of study population\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNumber\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eC\u003csub\u003e0\u003c/sub\u003e/D\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePeriorbital edema\u003c/p\u003e\n\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;2\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eGastrointestinal reactions\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGender\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e46(48.4%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.174\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.040\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.700\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49(51.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.89\u0026thinsp;\u0026plusmn;\u0026thinsp;3.00(14.61\u0026ndash;30.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.250\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.468\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.818\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eC\u003csub\u003e0\u003c/sub\u003e/D\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.50(2.80\u0026ndash;4.41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026mdash;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.278\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.287\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at surgery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u0026ndash;40\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6(6.3%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e0.381\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e0.160\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\n\u003cp\u003e0.011\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41\u0026ndash;55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35(36.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e56\u0026ndash;70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40(42.1%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026gt;\u0026thinsp;70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14(14.7%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrimary site\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStomach\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36(37.8%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e0.316\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e0.339\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e0.685\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSmall intestine\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50(52.6%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9(9.5%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003e \u003cem\u003eRepresent P\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eNormally distributed data was expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eNon-normally distributed data was expressed as medium (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003eAbbreviation: BMI: body mass index\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGenotype Frequencies\u003c/p\u003e\n\u003cp\u003eThe frequencies of the nine SNPs are listed in Supplementary Table\u0026nbsp;1. All SNPs met the Hardy-Weinberg equilibrium (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). None of the nine SNPs were in linkage disequilibrium (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eGenotypes and IM plasma trough levels\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSLC22A1\u003c/em\u003e rs683369 and \u003cem\u003eABCG2\u003c/em\u003e rs2231142 were significantly correlated with C\u003csub\u003e0\u003c/sub\u003e/D of IM (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Patients with the rs683369 CC genotype (3.57\u0026plusmn;1.21 ng/mL\u0026sdot;mg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) appeared to have lower IM trough plasm levels than G allele carriers (4.32\u0026plusmn;1.60 ng/mL\u0026sdot;mg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e), which may be because CC genotype patients metabolized IM faster than G allele carriers. The C\u003csub\u003e0\u003c/sub\u003e/D of IM appeared higher in patients with the rs2231142 mutant T allele (3.98\u0026plusmn;1.36 ng/mL\u0026sdot;mg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) than that in wild-type GG genotype patients (3.40\u0026plusmn;1.21 ng/mL\u0026sdot;mg\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\nTable 2 The association of SNPs and side effects\u003c/div\u003e\n\u003cp\u003e\u003cimg 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\" alt=\"\" /\u003e\u003c/p\u003e\n\u003cp\u003eGenotypes and adverse reactions\u003c/p\u003e\n\u003cp\u003eFor adverse reactions to IM, the study focused on the adverse reactions that are common but exert great influence on the life of patients, such as grade 2 or 3 periorbital edema and gastrointestinal reactions. In this study, women were more likely to develop more severe periorbital edema due to IM (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), which was consistent with an earlier report [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]; however, this factor was not significant in the logistic regression (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). After discovering that older individuals are more likely to develop periorbital edema related to IM, those that require human intervention were not observed to be age-related; thus, genetic polymorphisms may be potential influencing factors. Further studies were conducted based on these findings. The results of further analyses are shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Polymorphisms in \u003cem\u003eEGFR\u003c/em\u003e, \u003cem\u003eSLC22A1\u003c/em\u003e, and \u003cem\u003eCYP1A2\u003c/em\u003e were found to be associated with grade\u0026thinsp;\u0026ge;\u0026thinsp;2 periorbital edema. All odds ratios (OR) were adjusted for factors (C\u003csub\u003e0\u003c/sub\u003e/D, BMI and gender). The rs2072454 CC genotype manifested as a risk factor for grade\u0026thinsp;\u0026ge;\u0026thinsp;2 periorbital edema compared to T carriers (CT\u0026thinsp;+\u0026thinsp;TT) with an adjusted OR of 2.85 (95% CI\u0026thinsp;=\u0026thinsp;1.10\u0026ndash;7.40, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032). The adjusted OR was 3.42 (95% CI\u0026thinsp;=\u0026thinsp;1.32\u0026ndash;8.88, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) for the \u003cem\u003eSLC22A1\u003c/em\u003e rs1867351 TT genotype compared to C carriers (CT\u0026thinsp;+\u0026thinsp;TT), and 3.15 (95% CI\u0026thinsp;=\u0026thinsp;1.08\u0026ndash;9.20, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036) for two A-alleles in \u003cem\u003eCYP1A2\u003c/em\u003e rs11636419 compared to that of G allele carriers. In the logistic regression analysis, the rs2282143 CC genotype of \u003cem\u003eSLC22A1\u003c/em\u003e and GG genotype of \u003cem\u003eEGFR\u003c/em\u003e were not protective factors, as expected (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). No correlation was found between gastrointestinal reactions and SNPs.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFor GIST, it has been reported that the stomach (60\u0026ndash;65%) is the most frequent primary site, followed by the small intestine (20\u0026ndash;25%), and other sites are much less common [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In this study, the proportion of primary sites in the small intestine and other sites (52.6%) was greater than that in the stomach (37.8%), as all members of the population were surgically treated and categorized as having an intermediate or high risk of relapse, and the prognosis of non-gastric cancer is expected to be worse than that of gastric primary [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] with a higher risk of recurrence [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The etiology of the periorbital edema caused by IM remains unclear. The most accepted view currently involves platelet-derived growth factor receptor (PDGFR), which is one of the targets of IM. PDGFR is highly expressed in the skin around the eyes and maintains interstitial fluid homeostasis by regulating the tension between the extracellular matrix structures and cells [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. PDGFR inhibition leads to decreased interstitial pressure, increased capillary permeability, and fluid extravasation [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. There is also a complex network of connections between the lower eyelid skin and infraorbital wall, forming an enclosed space, which may allow for easier fluid collection and edema formation [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The incidence of IM-induced periorbital edema was similar to that reported in other studies; however, the ratio of more severe periorbital edema was much higher in this study [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This may be attributed to the fact that the population in this study was postoperative, showing an intermediate or high risk of recurrence, and physiological statuses differed from patients in other studies. Additionally, the present study focused on late toxicity instead of early toxicity, as it has been reported that approximately half of the patients developed grade\u0026thinsp;\u0026ge;\u0026thinsp;2 toxicities attributed to TKIs after the first cycle [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePeriorbital edema can be resolved by discontinuing IM, but this does not appear to be a reasonable option for most patients and is not recommended in situations where IM may markedly extend the recurrence-free survival of patients [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] and when therapeutic alternatives are limited. The risk of relapse increased after discontinuation, as shown in the BRF 14-trial, which highlighted that most patients relapsed or progressed after interruption of IM treatment [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In the event of a relapse, all previous efforts were lost. For mild edema, there is no need to take any steps, but to weigh and monitor regularly to detect any unusual weight gain or severe fluid retention [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In cases of grade 2 periorbital edema that poses difficulties in daily life, symptomatic treatment may be available, such as salt restriction and topical steroids. Diuretics or surgical intervention may be feasible approaches for grade 3 periorbital edema cases [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A researcher from Canada reported a patient with type 2 diabetes mellitus (T2DM) and GIST who developed grade 3 periorbital edema immediately after IM treatment. This greatly affected the patient\u0026rsquo;s life. However, it was only two days after replacing metformin with canagliflozin that the periorbital edema appeared markedly alleviated, and completely subsided after one week [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Canagliflozin is a new antihyperglycemic drug that inhibits glucose reabsorption in the proximal tubule by inhibiting sodium-glucose cotransporter-2 (SGLT-2). There are no prospective clinical trials of a certain scale to confirm this effect and clarify the mechanism, but an SGLT-2 inhibitor may be a good option for GIST patients with T2DM who are taking IM.\u003c/p\u003e \u003cp\u003eMore severe periorbital edema did not correlate with C\u003csub\u003e0\u003c/sub\u003e/D (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as described in a previous study [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The present study also indicates that genetic polymorphisms of \u003cem\u003eABCG2\u003c/em\u003e rs2231142 and \u003cem\u003eSLC22A1\u003c/em\u003e rs683369 may influence the trough plasma levels of IM. Genetic polymorphisms of \u003cem\u003eSLC22A1\u003c/em\u003e rs1867351, \u003cem\u003eEGFR\u003c/em\u003e rs2072454, and \u003cem\u003eCYP1A2\u003c/em\u003e rs11636419 have been found to play roles in IM-induced grade\u0026thinsp;\u0026ge;\u0026thinsp;2 periorbital edema. ABCG2 functions as a xenobiotic transporter and may play a major role in multi-drug resistance. ABCG2 plays a role in the transportation of many drugs, including IM [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and has attracted considerable interest. The present study found that polymorphisms in \u003cem\u003eABCG2\u003c/em\u003e rs2231142 significantly affected IM transport. \u003cem\u003eABCG2\u003c/em\u003e rs2231142 is a non-synonymous coding SNP that converts the originally encoded glutamine to another amino acid, and may have significantly affected ABCG2 activity, thereby affecting the plasma concentration of the drug. Many endogenous small organic cations, as well as a wide range of drugs and environmental toxins, are eliminated by organic cation transporters encoded by \u003cem\u003eSLC22A1\u003c/em\u003e. This was confirmed by the fact that polymorphisms in \u003cem\u003eSLC22A1\u003c/em\u003e were linked to grade\u0026thinsp;\u0026ge;\u0026thinsp;2 periorbital edema and IM trough plasma levels in this study. Gene polymorphisms can affect toxicity by influencing drug exposure or the ability of transporters to eliminate drug toxicity. Its impact on IM toxicity in this study was similar to that reported in a 2017 study [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cem\u003eEGFR\u003c/em\u003e, an oncogene, encodes a receptor for members of the epidermal growth factor family and plays an essential role in cell proliferation. This study describes the influence of \u003cem\u003eEGFR\u003c/em\u003e rs2072454 on adverse reactions of IM for the first time. In the present study, the rs2072454 CC genotype represented an adjusted OR of 2.85 (95% CI\u0026thinsp;=\u0026thinsp;1.10\u0026ndash;7.40, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032) for grade\u0026thinsp;\u0026ge;\u0026thinsp;2 periorbital edema compared to T carriers (CT\u0026thinsp;+\u0026thinsp;TT). The receptor, expressed in the ocular structure, is also a receptor for IM [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and toxicity may be a consequence of IM inhibition in this region. \u003cem\u003eCYP1A2\u003c/em\u003e encodes a member of the cytochrome P450 superfamily of enzymes localized to the endoplasmic reticulum. Polymorphisms in \u003cem\u003eCYP1A2\u003c/em\u003e were identified to be associated with more severe periorbital edema, and the gene was also found to be related to the need for dose reduction due to IM toxicity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This was thought to result from the inconsistent metabolic rates of IM between different genotypes. However, other genes may compensate for this.\u003c/p\u003e \u003cp\u003eThe sample size of this study was limited and the results may be biased. Additional research with larger samples size and prospective clinical trials are required to confirm the findings of this study. Additionally, the identification of haplotype-tagged SNP (htSNP) genotypes guarantees that all common variants can be captured in gene-drug response correlation studies, whereas single SNP-based correlation studies are difficult to achieve. Nonetheless, this study revealed several SNPs associated with individual treatments, which will facilitate research to identify better treatments and help to optimize individualized medical treatment.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u0026nbsp;\u003c/strong\u003eAll authors contributed to the manuscript. Xuehui Jiang designed this study and drafted the manuscript. Imatinib concentration quantification was done by Ying Kong and Hong Liu. Statistical analysis of data was conducted by Xuehui Jiang and Qun Fu. Kaisaner Rexiti reviewed data for this study. Xiaohua Wei, Pin Xiao and Hongwei Peng critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and funding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003eThe authors would like to thank the provision of financial support by Jiangxi Provincial Department of Science and Technology and technical support by Shanghai Bohao Biological Corporation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This study was supported by Jiangxi Provincial Department of Science and Technology (No. 20201BBG71008).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u0026nbsp;\u003c/strong\u003eAll the authors declare they have no conflict of interest in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the First Affiliated Hospital of Nanchang University ethics committee [(2021) Medical Research Ethics No. (12-001)] and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e Informed consent was obtained from all individuals included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Permission has been obtained from all named authors to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statements\u0026nbsp;\u003c/strong\u003eAll datasets used during the study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBlay JY, Kang YK, Nishida T, von Mehren M (2021) Gastrointestinal stromal tumours. 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Nat Med 2 (5):561\u0026ndash;566. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/nm0596-561\u003c/span\u003e\u003cspan address=\"10.1038/nm0596-561\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"IM, GIST, Genetic polymorphisms, Periorbital edema, Plasma levels","lastPublishedDoi":"10.21203/rs.3.rs-1994623/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1994623/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e Imatinib mesylate (IM) offers a significant survival benefit to patients with gastrointestinal stromal tumors (GIST). However, the clinical responses of IM vary drastically between individuals. Therefore, this study aimed to assess the role of genetic polymorphisms of metabolic enzymes, transporters and drug targets in IM plasma levels and adverse reactions in Chinese patients with GIST.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e The dose-adjusted trough plasma levels (C\u003csub\u003e0\u003c/sub\u003e/D) of IM in 95 patients were quantified using two-dimensional liquid chromatography. Nine SNPs in six genes were detected. The relationships between C\u003csub\u003e0\u003c/sub\u003e/D, single nucleotide polymorphisms (SNPs) and adverse reactions were tested. Logistic regression was used to test the risk factors for IM-related grade ≥ 2 periorbital edema.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e A range of C\u003csub\u003e0\u003c/sub\u003e/D from 1.33 to 7.04 ng/mL·mg\u003csup\u003e-1\u003c/sup\u003e for the 95 patients was found. G allele carriers (CG+GG) of \u003cem\u003eSLC22A1\u003c/em\u003e rs683369 and T allele carriers (GT+TT) of \u003cem\u003eABCG2\u003c/em\u003e rs2231142 had significantly higher C\u003csub\u003e0\u003c/sub\u003e/D. For all grades of periorbital edema, an increase in incidence with age was found, while this differed from more severe periorbital edema. Grade ≥ 2 periorbital edema was related to the carriership of two C-alleles in \u003cem\u003eEGFR\u003c/em\u003e rs2072454 with an adjusted OR of 2.85 (95% CI=1.10–7.40; \u003cem\u003eP\u003c/em\u003e=0.032), two T-alleles in \u003cem\u003eSLC22A1\u003c/em\u003e\u003cstrong\u003e\u003cem\u003e \u003c/em\u003e\u003c/strong\u003ers1867351 with an adjusted OR of 3.42 (95% CI=1.32–8.88; \u003cem\u003eP\u003c/em\u003e=0.010) and two A-alleles in \u003cem\u003eCYP1A2\u003c/em\u003e rs11636419 with an adjusted OR of 3.15 (95% CI=1.08–9.20; \u003cem\u003eP\u003c/em\u003e=0.036). None of the nine SNPs was found to be related to gastrointestinal reactions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e Rs683369 and rs2231142 have an impact on the metabolism of IM; rs2072454, rs1867351, and rs11636419 are linked to grade ≥ 2 periorbital edema. These SNPs may be biomarkers for IM dose adjustment and IM-related grade ≥ 2 periorbital edema.\u003c/p\u003e","manuscriptTitle":"Genetic polymorphisms are associated with imatinib plasma levels and periorbital edema in Chinese patients with gastrointestinal stromal tumors receiving adjuvant imatinib","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-26 18:17:44","doi":"10.21203/rs.3.rs-1994623/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":"a67268a9-2cf2-473f-b5e7-ea5b4b353976","owner":[],"postedDate":"August 26th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-09-02T10:59:25+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-26 18:17:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1994623","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1994623","identity":"rs-1994623","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}