Uterine leiomyomata and keloids fibrosis origins: a mini-review of fibroproliferative diseases.

benign growth, disparities, fibroproliferative, fibrosis, gynecologic

Diseases such as uterine leiomyomata (fibroids and benign tumors of the uterus) and keloids (raised scars) may share common etiology. Fibroids and keloids can co-occur in individuals, and both are highly heritable, suggesting they may share common genetic risk factors. Fibroproliferative diseases are common and characterized by scarring and overgrowth of connective tissue, impacting multiple organ systems. These conditions both have racial disparities in prevalence, with the highest prevalence observed among individuals of African ancestry. Several fibroproliferative diseases are more severe and common in populations of sub-Saharan Africa. This mini-review aims to provide a broad overview of the current knowledge of the evolutionary origins and causes of fibroproliferative diseases. We also discuss current hypotheses proposing that the increased prevalence of these diseases in African-derived populations is due to the selection for profibrotic alleles that are protective against helminth infections and provide examples from knowledge of uterine fibroid and keloid research.

Fibrosis causes morbidity and mortality, affecting millions worldwide. Despite many studies assessing the mechanisms of fibrosis and potential therapeutic strategies, no satisfactory treatments directly target the fibrosis process (1). Uterine leiomyomata (fibroids) and keloids are fibrotic diseases with evidence of shared etiology and racial disparities in prevalence. Both disproportionately impact Black women and have significant public health impacts on this population (2, 3). It has been hypothesized that the two diseases may share etiology because both conditions result from an abnormal response to tissue damage, resulting from disordered healing and changes to the formation of the extracellular matrix. This review will discuss the potential causes of uterine fibroids and keloids in the broader context of fibrosis and fibroproliferative disease. FIBROPROLIFERATIVE DISEASE Fibroproliferative diseases are common complex diseases that vary widely in presentation, as scarring and overgrowth of connective tissue can affect many organ systems. Fibroproliferative diseases share pathological features and may share a common genetic background (4). Many fibroproliferative diseases are more prevalent in African ancestry populations relative to those of European ancestry (Table 1), leading to pronounced health disparities. For example, keloids are more common in individuals with darker skin pigmentation (10), much like systemic scleroderma, nephrosclerosis, and sarcoidosis, which are more prevalent in African ancestry individuals (4). Table 1. | Disease | Fold Increase in Blacks vs. Whites | Mortality/Severity | Selected References | |---|---|---|---| | Sarcoidosis | 1–17 | 12–14 | (5) | | Lupus | 2–8 | 3.9 | (6) | | Asthma | 1.5 | 3–5 | (7) | | Keloids | 20 | 0 | (8) | | Hypertension | 1.5–2 | 1.3–1.5 | (9) | | Fibroidsa | 2–3 | 3.5–6.8 | (3) | Severity was determined via the need for hospitalization, myomectomies, and/or hysterectomies, as well as self-reported severe symptoms ascertained from surveys. Diseases were selected based on previous works identifying each of the above fibroproliferative diseases to have similar immune components as well as known racial disparities. NATURAL SELECTION AND FIBROSIS Fibrosis is a normal part of wound healing, and profibrotic immune processes are essential for health. Many human populations experience fibrotic diseases, demonstrating the evolutionary challenge of balancing the benefits of fibrosis in wound healing and defense from parasites with potential harms. One hypothesis suggests that individuals of African descent have a more robust, profibrotic immune response due to selection in response to helminth infections in Africa, which leads to an increased prevalence of fibroproliferative diseases (4). When infected with a helminth parasite, the host body elicits a T-helper cell type-2 (Th2) response to the parasite to help eliminate it (Fig. 1). Helminths actively downregulate the Th2 host response with secreted factors. As generations of individuals were exposed to these infections, those with more effective immune responses would survive, which increased the frequency of profibrotic, anti-helminthic alleles in the population (4, 11). This process then potentially resulted in an evolutionary equilibrium between pathogens and host immune responses, where the prevalence and severity of fibrotic conditions were mitigated by helminths, and hosts were protected from severe helminth infections by upregulated Th2-mediated immune responses to overcome helminth defenses. In the absence of helminth parasites, the propensity for chronic fibrosis in various tissue and organ systems could increase (4, 11). Similar scenarios of diseases arising due to selective response to infection in African ancestry populations have been seen in sickle cell disease conferring resistance to malaria (12), and the increased frequency of chronic kidney disease in carriers of APOL1 variants, which offer enhanced ability to resist trypanosome infection (the cause of African sleeping sickness) (13). GENETICS OF FIBROPROLIFERATIVE DISEASES Multiple studies have established the heritability of fibroproliferative conditions (14, 15). Genome-wide association studies (GWAS) have identified many common susceptibility variants for several fibroproliferative diseases (16). Our group has studied the genetics of uterine fibroids and discovered several novel genetic associations in both predominantly African and European populations (17–19). Across published GWAS loci associated with fibroproliferative diseases, there is evidence of polygenic selection among persons of African ancestry compared with non-African ancestry, potentially contributing to the observed disparities in risk across many conditions. In a study by Hellwege et al. (20), independent sentinel genetic predictors of seven fibroproliferative diseases were compared with regard to allele frequency across global populations. That study observed that risk-increasing alleles for fibroproliferative traits were significantly more likely to be at higher frequency in predominantly African ancestry populations than other global populations (20), which is consistent with a signature of polygenic selection (21). Genes listed in Table 2, such as interleukin 6 (IL-6), IL-7, SMAD family member 2 (SMAD2), and tumor protein p53 (TP53), are critical regulators of the Th2 fibrotic pathway and are associated with various fibroproliferative diseases. IL-6 (interleukin 6) and IL-7 (interleukin 7) modulate the wound inflammatory and reparative process in response to tissue injury. SMAD2 helps in this process by triggering TGF-β, which promotes fibrosis by increasing macrophage presence and enhancing the expression of profibrotic cytokines (22, 25, 28). While TP53 is primarily known as a tumor suppressor gene, it activates the initial immune response via chemokines, cytokines, and extracellular matrix modulator activation (32). If any of these immune system modulators become dysregulated, the result will increase inflammations and the subsequent continuous fibrosis experienced in fibroproliferative diseases. Table 2. | Sarcoidosis | Lupus | Asthma | Keloids | Hypertension | Fibroids | References | | |---|---|---|---|---|---|---|---| | IL-6 | No | No | Yes | Yes | Yes | No | (19, 22–24) | | IL7R | Yes | Yes | Yes | No | Yes | No | (25–27) | | SMAD2 | Yes | Yes | Yes | Yes | No | No | (8, 27, 28) | | SMAD3 | Yes | No | Yes | No | Yes | Yes | (8, 18, 27–29) | | TNF-α 308a | No | No | No | No | Yes | Yes | (30, 31) | | TP53 | No | Yes | Yes | Yes | Yes | Yes | (8, 17, 32–34) | Diseases were selected based on previous works identifying each of the above fibroproliferative diseases to have similar immune components as well as known racial disparities. UTERINE FIBROIDS AND KELOIDS Uterine Fibroids Uterine fibroids are the most common female pelvic tumor, yet their etiology is unknown. Fibroids are benign, elliptical growths of smooth muscle and connective tissue anchored within the muscular wall of the uterus. Fibroids are hormone-dependent neoplasms of monoclonal origin (17, 19). Dysregulation of estrogen receptor density and function has been postulated to be necessary for fibroid formation (35). Fibroids have been found to have increased numbers of estrogen receptors, progesterone overexpression, reduced capacity for metabolizing estradiol, and enhanced transcriptional response to estrogen exposure (36, 37). Studies have shown altered expression in fibroid tumors in genes involved in insulin and estrogen pathways, HMGA2 and small coding RNAs, and microRNAs (38). Studies have also shown an overrepresentation of inflammatory cells in fibroids compared with normal tissue, which may cause excess extracellular membrane protein production (39). Fibroid prevalence ranges from 20% to 77% and increases with age until menopause, with significant clinical impact observed among Black women with a twofold greater risk than White women (3). Black women also develop fibroids at younger ages, have higher clinical diagnosis rates, and are more likely to undergo hysterectomy (3, 36). Unlike White women, fibroids among Black women generally do not regress after menopause (32). Common clinical risk factors for fibroids include high body mass index (BMI), hypertension, lower age at menarche, keloids (specifically among individuals of African ancestry), and advancing age (19, 36, 40–42). Lifestyle and environmental factors associated with fibroid development include using hair relaxers (predominantly among Black women), vitamin D deficiency, stress, diet, smoking, and low physical activity (1–3, 36, 39). The impact of clinical risk factors can differ among ancestry groups. High BMI is a risk factor for fibroids in various ancestries, including Black women (36). Hypertension may have a stronger association with fibroids in Black women compared with other ethnic groups (36). A personal history of keloids is a clinical risk factor, specifically among individuals of African ancestry (41). Advancing age is generally a risk factor for fibroid development in all ancestry groups, but the age of manifestation and progression may differ (42). Parity has a protective effect, potentially influenced by pregnancy-related hormonal factors, which may vary across ancestries (42). Genetic factors influence fibroid risk. Fibroids are highly heritable based on twin-pair and familial aggregation studies. Heritability studies of fibroids in European populations have observed that between 26% and 69% of fibroid risk is due to genetic factors (43). Racial disparities described earlier further support a genetic etiology (42). Several large-scale genetic studies of uterine fibroids in and across specific populations have collectively reported 52 independent candidate loci for the risk of fibroids (19, 44). One GWAS has also evaluated fibroid size and number (45). Candidate gene association studies have focused on steroid hormones (39), growth factors (46), reproductive factors (3, 36), dysregulation of microRNAs (36), telomerase shortening (47), excessive production of disorganized extracellular matrix (46), and acquired chromosomal aberrations (38). There are specific fibroid driver somatic mutations, including mediator complex subunit 12 (MED12), high-mobility group AT-hook 2 (HMGA2), fumarate hydratase (FH), and collagen type IV alpha chain five and six (COL4A5, COL4A6). MED12 is on the X chromosome and encodes a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex, and mutations in MED12 are also present in adenomyosis and mammary adenomyoma cells. However, the process that leads from germline sequences to the development of driver mutations and subsequent pathogenesis is poorly understood. In a study from the UK and Finland, Välimäki et al. (44) identified a locus upstream of MED12 with subtle effects on uterine fibroid risk and stronger effects on MED12 mutation positivity (MED12mut+) in uterine fibroid tumors. That study also reported a positive association between the uterine fibroid genetic risk score and the number of MED12mut+ tumors per patient. However, they did not investigate other somatic subtypes or report on other SNPs and their relationship with MED12mut+ status. HMGA2 encodes a nonhistone chromatin protein that binds to DNA to regulate transcription processes. FH encodes an enzyme in the tricarboxylic acid cycle and is a tumor suppressor gene. Keloids Keloids are a form of dermal fibrosis that occurs during prolonged wound healing, extending beyond the boundaries of the original injury. They are more prevalent in individuals of African, Asian, and Hispanic descent, with highest risk in Black individuals compared with White individuals in the United States (10). Keloids can develop following any deep dermal injury, such as ear piercings, acne, trauma, or burns, and can continue to grow for up to and beyond 1-yr postinjury (10). Despite being a disfiguring and sometimes disabling disorder that significantly impairs the quality of life, keloids remain understudied compared with other chronic skin disorders. Treatment options for keloids have shown limited effectiveness in most cases (2). In addition to the known racial and ethnic differences in keloid prevalence, several additional clinical risk factors and characteristics have been associated with keloids, potentially exhibiting ancestral differences. Studies conducted in various African and Asian countries, including Cameroon (1), Kenya (2), Japan (3), and Taiwan (4), have reported varying male-to-female ratios of keloids, ranging from 0.64 to 0.71, suggesting that biological sex may play a role in keloid development and exhibit variability across ancestral groups. Keloids primarily appear during adolescence and young adulthood, but they can also occur in individuals as young as less than a year old, indicating potential differences in onset across ancestries. In addition, certain syndromes, such as Rubinstein–Taybi syndrome, have been associated with keloids, with a study in the Netherlands identifying keloids in 24% of patients with this syndrome (10). While some cases of keloid formation may be due to somatic mutation (48), multiple keloids in the same individual and evidence for a multicellular origin of keloids suggest somatic mutation is not the primary driving event in most cases (49). Differences in the expression of genes that play a role in fibrosis have been observed between keloid and normal fibroblasts. Keloid-derived fibroblasts in culture have shown altered expression of many genes and provided evidence for an epigenetically altered wound healing program (23). However, no unifying hypothesis to explain keloid formation has been proposed. Identifying genes associated with keloid risk may help to elucidate actionable biological mechanisms and candidate treatments. Several lines of evidence support a genetic basis for keloids, including the occurrence of familial forms and racial and ethnic differences in prevalence. Keloid formation has been linked to chromosome region 2q23 in Japanese, 7p11 and 15q21.3 in African ancestry and Chinese individuals, and 10q23.31, 15q22.31, and 18q21.1 in genetic linkage studies. GWAS have identified various single nucleotide polymorphisms (SNPs) (rs873549, rs1442440, rs1511412, and rs940187) associated with keloid risk in Japanese or Chinese Han populations. Pleiotropy across Fibroids and Keloids Studies have shown that individuals with keloids have an increased risk of developing fibroids and vice versa. Women with fibroids in Taiwan had a 2.25-fold increased risk of keloids. In UK Biobank, Black participants with keloids and hypertrophic scars were suggested to have an increased risk of leiomyoma (41). Assessments of leiomyomas and keloid tissues have shown they have comparable molecular features, including collagen fibril orientation. Gene expression studies have also revealed consistencies, including similarities in the extracellular matrix, TGF-β signaling, dermatopontin, and the proteoglycans versican and decorin levels relative to their respective normal tissue counterparts. There are some differences in tissue-specific regulatory control, as might be expected given the different tissue origins of keloids and fibroids (50). EVIDENCE OF AFRICAN ANCESTRY ASSOCIATING WITH FIBROID AND KELOID RISK Consistent with the observed disparity by race, studies have observed associations between fibroids (51, 52) and keloids (53) and increasing proportions of African ancestry. One study observed that West African ancestry was associated with fibroid risk [odds ratio (OR) 1.54 per 10% increase in ancestry proportion], but there was no association with East African ancestry (OR 1.00) with fibroids in Black women (51). Another study also showed a strong association between increasing African ancestry and having multiple fibroids (52). These results suggest that a proportion of fibroid and perhaps keloid risk disparities are due to genetic differences between geographic groups. Admixture mapping (associating small tracts of ancestry in the genome with disease risk) has been successful in studies of several disorders that occur more frequently in individuals of African ancestry, including asthma (54), hypertension (55), and nondiabetic end-stage kidney disease (13). Admixture mapping is ideally suited for genetic traits with strong evidence for a racial disparity in disease prevalence, such as keloids and fibroids. Published admixture mapping studies of fibroid risk have collectively identified numerous regions of interest (52, 56). We have also performed an admixture mapping analysis that identified several suggestive regions for several fibroids and one for fibroid volume (52). In a separate study by our group, we detected an interaction between African ancestry and BMI on fibroid risk (56). The strongest admixture mapping signal was observed in the obese (BMI >30 kg/m2) category. An admixture mapping study was also conducted for keloids in 478 Black individuals. This study identified an admixture mapping peak on chr15q21.2-22.3 (53). The results suggest that either increasing dosage of European ancestry alleles provides protection from keloids or that keloid risk-increasing alleles are more common in African than European ancestry individuals. This study reported an association with neural precursor cell expressed, developmentally downregulated 4, E3 ubiquitin protein ligase [NEDD4; implicated in prior GWAS of keloids (57)], but conditional analyses supported an association with nearby gene myosin 1 e (MYO1E). In chr15q21.2-22.3, several genes have been associated with other fibroproliferative disorders: aldehyde dehydrogenase 1 family member A2 (ALDH1A2), NEDD4, RAR-related orphan receptor A (RORA), MYO1E, G2/mitotic-specific cyclin B2 (CCNB2), ring finger protein 111 (RNF111), and aquaporin 9 (AQP9) (9, 12–14).

This review describes the shared etiology and genetic foundations of the fibroproliferative diseases, uterine fibroids and keloids. Admixture mapping studies demonstrate the substantial impact of genetic ancestry, particularly among individuals of African descent, on disease development. The involvement of the Th2 immune response and potential selective pressures are examples of the genetic underpinnings of fibrosis. Understanding the common molecular features and gene expression patterns in fibroids and keloids may provide opportunities for diagnostic and therapeutic strategies. Personalized interventions based on genetic and clinical risk factors hold great potential to transform disease management and enhance patient outcomes. The complex physiology of fibroproliferative diseases and the putative evolutionary origins of disparities and opportunities for precision medicine require further study. These endeavors may contribute to the development of novel therapeutic strategies and the identification of potential interventions. By advancing precision medicine in fibroproliferative diseases, we can ultimately improve the lives of individuals affected by these conditions, mitigating disparities, and offering enhanced outcomes and better quality of life. GRANTS This work was funded by National Institutes of Health Grants K12HD043483 (to J.H.) and R01HD093671 (to D.R.V.E. and T.E.). DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors. AUTHOR CONTRIBUTIONS G.H., J.K., T.E., J.H., and D.R.V.E. conceived and designed research; G.H. prepared figures; G.H., J.K., T.E., J.H., and D.R.V.E. drafted manuscript; G.H., J.K., T.E., J.H., and D.R.V.E. edited and revised manuscript; G.H., J.K., T.E., J.H., and D.R.V.E. approved final version of manuscript. ACKNOWLEDGMENTS The graphical abstract was created with BioRender.com and used with permission.

- 1. Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature 587: 555–566, 2020. doi: 10.1038/s41586-020-2938-9. [DOI] [PMC free article] [PubMed] [Google Scholar] - 2. Delaleu J, Charvet E, Petit A. Keloid disease: review with clinical atlas. Part I: definitions, history, epidemiology, clinics and diagnosis. Ann Dermatol Venereol 150: 3–15, 2023. doi: 10.1016/j.annder.2022.08.010. [DOI] [PubMed] [Google Scholar] - 3. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 188: 100–107, 2003. doi: 10.1067/mob.2003.99. [DOI] [PubMed] [Google Scholar] - 4. Russell SB, Smith JC, Huang M, Trupin JS, Williams SM. Pleiotropic effects of immune responses explain variation in the prevalence of fibroproliferative diseases. PLoS Genet 11: e1005568, 2015. doi: 10.1371/journal.pgen.1005568. [DOI] [PMC free article] [PubMed] [Google Scholar] - 5. Rybicki B, Maliarik M, Major M, Popovich J Jr, Iannuzzi M. Epidemiology, demographics, and genetics of sarcoidosis. Seminars Respir Infect 13: 166–173, 1998. [PubMed] [Google Scholar] - 6. Krishnan E, Hubert HB. Ethnicity and mortality from systemic lupus erythematosus in the US. Ann Rheum Dis 65: 1500–1505, 2006. doi: 10.1136/ard.2005.040907. [DOI] [PMC free article] [PubMed] [Google Scholar] - 7. Lebak N, Schwartz L. Population density and race as factors in asthma mortality. J Allergy Clin Immunol 119: S76, 2007. doi: 10.1016/j.jaci.2006.11.321. [DOI] [Google Scholar] - 8. Glass DA 2nd. Current understanding of the genetic causes of keloid formation. J Investig Dermatol Symp Proc 18: S50–S53, 2017. doi: 10.1016/j.jisp.2016.10.024. [DOI] [PubMed] [Google Scholar] - 9. Ostchega Y, Fryar CD, Nwankwo T, Nguyen DT. Hypertension prevalence among adults aged 18 and over: United States, 2017–2018. NCHS Data Brief 364: 1–8, 2020. [PubMed] [Google Scholar] - 10. Ud-Din S, Bayat A. Strategic management of keloid disease in ethnic skin: a structured approach supported by the emerging literature. Br J Dermatol 169, Suppl 3: 71–81, 2013. doi: 10.1111/bjd.12588. [DOI] [PubMed] [Google Scholar] - 11. Babu S, Nutman TB. Immune responses to helminth infection. In: Clinical Immunology, edited by Rich RR, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM.. Amsterdam: Elsevier, 2019, p. 437–447. [Google Scholar] - 12. Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S, Kortok M, Snow RW, Marsh K. An immune basis for malaria protection by the sickle cell trait. PLoS Med 2: e128, 2005. doi: 10.1371/journal.pmed.0020128. [DOI] [PMC free article] [PubMed] [Google Scholar] - 13. Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329: 841–845, 2010. doi: 10.1126/science.1193032. [DOI] [PMC free article] [PubMed] [Google Scholar] - 14. Marneros AG, Norris JE, Olsen BR, Reichenberger E. Clinical genetics of familial keloids. Arch Dermatol 137: 1429–1434, 2001. doi: 10.1001/archderm.137.11.1429. [DOI] [PubMed] [Google Scholar] - 15. Allanore Y, Wipff J, Kahan A, Boileau C. Genetic basis for systemic sclerosis. Joint Bone Spine 74: 577–583, 2007. doi: 10.1016/j.jbspin.2007.04.005. [DOI] [PubMed] [Google Scholar] - 16. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, Klemm A, Flicek P, Manolio T, Hindorff L, Parkinson H. The NHGRI GWAS catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42: D1001–D1006, 2014. doi: 10.1093/nar/gkt1229. [DOI] [PMC free article] [PubMed] [Google Scholar] - 17. Edwards TL, Giri A, Hellwege JN, Hartmann KE, Stewart EA, Jeff JM, Bray MJ, Pendergrass SA, Torstenson ES, Keaton JM, Jones SH, Gogoi RP, Kuivaniemi H, Jackson KL, Kho AN, Kullo IJ, McCarty CA, Im HK, Pacheco JA, Pathak J, Williams MS, Tromp G, Kenny EE, Peissig PL, Denny JC, Roden DM, Velez Edwards DR. A trans-ethnic genome-wide association study of uterine fibroids. Front Genet 10: 511, 2019. doi: 10.3389/fgene.2019.00511. [DOI] [PMC free article] [PubMed] [Google Scholar] - 18. Di X, Andrews DM, Tucker CJ, Yu L, Moore AB, Zheng X, Castro L, Hermon T, Xiao H, Dixon D. A high concentration of genistein down-regulates activin A, Smad3 and other TGF-β pathway genes in human uterine leiomyoma cells. Exp Mol Med 44: 281–292, 2012. doi: 10.3858/emm.2012.44.4.024. [DOI] [PMC free article] [PubMed] [Google Scholar] - 19. Hellwege JN, Jeff JM, Wise LA, Gallagher CS, Wellons M, Hartmann KE, Jones SF, Torstenson ES, Dickinson S, Ruiz-Narváez EA, Rohland N, Allen A, Reich D, Tandon A, Pasaniuc B, Mancuso N, Im HK, Hinds DA, Palmer JR, Rosenberg L, Denny JC, Roden DM, Stewart EA, Morton CC, Kenny EE, Edwards TL, Velez Edwards DR. A multi-stage genome-wide association study of uterine fibroids in African Americans. Hum Genet 136: 1497–1498, 2017. doi: 10.1007/s00439-017-1846-z. [DOI] [PMC free article] [PubMed] [Google Scholar] - 20. Hellwege JN, Torstenson ES, Russell SB, Edwards TL, Velez Edwards DR. Evidence of selection as a cause for racial disparities in fibroproliferative disease. PLoS One 12: e0182791, 2017. doi: 10.1371/journal.pone.0182791. [DOI] [PMC free article] [PubMed] [Google Scholar] - 21. Orr HA. Testing natural selection vs. genetic drift in phenotypic evolution using quantitative trait locus data. Genetics 149: 2099–2104, 1998. doi: 10.1093/genetics/149.4.2099. [DOI] [PMC free article] [PubMed] [Google Scholar] - 22. Lajunen T, Jaakkola J, Jaakkola M. Interleukin 6 SNP rs1800797 associates with the risk of adult-onset asthma. Genes Immun 17: 193–198, 2016. doi: 10.1038/gene.2016.8. [DOI] [PubMed] [Google Scholar] - 23. Ghazizadeh M. Essential role of IL-6 signaling pathway in keloid pathogenesis. J Nippon Med Sch 74: 11–22, 2007. doi: 10.1272/jnms.74.11. [DOI] [PubMed] [Google Scholar] - 24. Senchenkova EY, Russell J, Yildirim A, Granger DN, Gavins FN. Novel role of T cells and IL-6 (interleukin-6) in angiotensin II-induced microvascular dysfunction. Hypertension 73: 829–838, 2019. doi: 10.1161/HYPERTENSIONAHA.118.12286. [DOI] [PMC free article] [PubMed] [Google Scholar] - 25. Diekmann F, Legchenko E, Chouvarine P, Lichtinghagen R, Bertram H, Happel CM, Hansmann G. Circulating interleukin-7 in human pulmonary arterial hypertension. Front Cardiovasc Med 8: 794549, 2021. doi: 10.3389/fcvm.2021.794549. [DOI] [PMC free article] [PubMed] [Google Scholar] - 26. Hahn W-H, Suh J-S, Park H-J, Cho B-S. Interleukin 7 receptor gene polymorphisms and haplotypes are associated with susceptibility to IgA nephropathy in Korean children. Exp Ther Med 2: 1121–1126, 2011. doi: 10.3892/etm.2011.322. [DOI] [PMC free article] [PubMed] [Google Scholar] - 27. Tsuo K, Zhou W, Wang Y, Kanai M, Namba S, Gupta R, Majara L, Nkambule LL, Morisaki T, Okada Y, Neale BM; Global Biobank Meta-analysis Initiative; Daly MJ, Martin AR. Multi-ancestry meta-analysis of asthma identifies novel associations and highlights the value of increased power and diversity. Cell Genom 2: 100212, 2022. doi: 10.1016/j.xgen.2022.100212. [DOI] [PMC free article] [PubMed] [Google Scholar] - 28. Piotrowski W, Kiszałkiewicz J, Pastuszak-Lewandoska D, Antczak A, Górski P, Migdalska-Sęk M, Górski W, Czarnecka K, Nawrot E, Domańska D, Brzeziańska-Lasota E. TGF-β and SMADs mRNA expression in pulmonary sarcoidosis. In: Respiratory Carcinogenesis, edited by Pokorski M. Cham, Switzerland: Springer, 2015, p. 59–69. [DOI] [PubMed] [Google Scholar] - 29. Wang W, Huang XR, Canlas E, Oka K, Truong LD, Deng C, Bhowmick NA, Ju W, Bottinger EP, Lan HY. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ Res 98: 1032–1039, 2006. doi: 10.1161/01.RES.0000218782.52610.dc. [DOI] [PMC free article] [PubMed] [Google Scholar] - 30. Li Y-y. Tumor necrosis factor-alpha g308α gene polymorphism and essential hypertension: a meta-analysis involving 2244 participants. PLoS One 7: e35408, 2012. doi: 10.1371/journal.pone.0035408. [DOI] [PMC free article] [PubMed] [Google Scholar] - 31. Passan S, Goyal S, Bhat MA, Singh D, Vanita V. Association of TNF-α gene alterations (c.-238G>A, c.-308G>A, c.-857C>T, c.-863C>A) with primary glaucoma in north Indian cohort. Gene 709: 25–35, 2019. doi: 10.1016/j.gene.2019.05.035. [DOI] [PubMed] [Google Scholar] - 32. Yuan L, Wang L, Du X, Qin L, Yang M, Zhou K, Wu M, Yang Y, Zheng Z, Xiang Y, Qu X, Liu H, Qin X, Liu C. The DNA methylation of FOXO3 and TP53 as a blood biomarker of late-onset asthma. J Transl Med 18: 467, 2020. [Erratum in J Transl Med 19: 107, 2021]. doi: 10.1186/s12967-020-02643-y. [DOI] [PMC free article] [PubMed] [Google Scholar] - 33. Yang J, Zhu J-M, Wu S, Li J, Wang M-R, Wang T-T, Lu Y-W. Association study between the TP53 Rs1042522G/C polymorphism and susceptibility to systemic lupus erythematosus in a Chinese Han population. Rheumatol Int 37: 523–529, 2017. doi: 10.1007/s00296-017-3662-0. [DOI] [PubMed] [Google Scholar] - 34. Reiling E, Lyssenko V, Boer J, Imholz S, Verschuren WMM, Isomaa B, Tuomi T, Groop L, Dollé ME. Codon 72 polymorphism (rs1042522) of TP53 is associated with changes in diastolic blood pressure over time. Eur J Hum Genet 20: 696–700, 2012. doi: 10.1038/ejhg.2011.240. [DOI] [PMC free article] [PubMed] [Google Scholar] - 35. Andersen J. Factors in fibroid growth. Baillieres Clin Obstet Gynaecol 12: 225–243, 1998. [PubMed] [Google Scholar] - 36. Salehi AM, Jenabi E, Farashi S, Aghababaei S, Salimi Z. The environmental risk factors related to uterine leiomyoma: an umbrella review. J Gynecol Obstet Hum Reprod 52: 102517, 2023. doi: 10.1016/j.jogoh.2022.102517. [DOI] [PubMed] [Google Scholar] - 37. Yamamoto T, Tamura T, Kitawaki J, Osawa Y, Okada H. Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5α-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes. Eur J Endocrinol 130: 634–640, 1994. doi: 10.1530/eje.0.1300634. [DOI] [PubMed] [Google Scholar] - 38. Mehine M, Kaasinen E, Mäkinen N, Katainen R, Kämpjärvi K, Pitkänen E, Heinonen HR, Bützow R, Kilpivaara O, Kuosmanen A, Ristolainen H, Gentile M, Sjöberg J, Vahteristo P, Aaltonen LA. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med 369: 43–53, 2013. doi: 10.1056/NEJMoa1302736. [DOI] [PubMed] [Google Scholar] - 39. Flake GP, Andersen J, Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 111: 1037–1054, 2003. doi: 10.1289/ehp.5787. [DOI] [PMC free article] [PubMed] [Google Scholar] - 40. Takeda T, Sakata M, Isobe A, Miyake A, Nishimoto F, Ota Y, Kamiura S, Kimura T. Relationship between metabolic syndrome and uterine leiomyomas: a case-control study. Gynecol Obstet Invest 66: 14–17, 2008. doi: 10.1159/000114250. [DOI] [PubMed] [Google Scholar] - 41. Sun LM, Wang KH, Lee YC. Keloid incidence in Asian people and its comorbidity with other fibrosis-related diseases: a nationwide population-based study. Arch Dermatol Res 306: 803–808, 2014. doi: 10.1007/s00403-014-1491-5. [DOI] [PubMed] [Google Scholar] - 42. Baird DD, Dunson DB. Why is parity protective for uterine fibroids? Epidemiology 14: 247–250, 2003. doi: 10.1097/01.EDE.0000054360.61254.27. [DOI] [PubMed] [Google Scholar] - 43. Luoto R, Kaprio J, Rutanen EM, Taipale P, Perola M, Koskenvuo M. Heritability and risk factors of uterine fibroids—the Finnish Twin Cohort study. Maturitas 37: 15–26, 2000. doi: 10.1016/s0378-5122(00)00160-2. [DOI] [PubMed] [Google Scholar] - 44. Välimäki N, Kuisma H, Pasanen A, Heikinheimo O, Sjöberg J, Bützow R, Sarvilinna N, Heinonen HR, Tolvanen J, Bramante S, Tanskanen T, Auvinen J, Uimari O, Alkodsi A, Lehtonen R, Kaasinen E, Palin K, Aaltonen LA. Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability. eLife 7: e37110, 2018. doi: 10.7554/eLife.37110. [DOI] [PMC free article] [PubMed] [Google Scholar] - 45. Bray MJ, Wellons MF, Jones SH, Torstenson ES, Edwards TL, Velez Edwards DR. Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women. Fertil Steril 110: 737–745.e34, 2018. doi: 10.1016/j.fertnstert.2018.04.035. [DOI] [PMC free article] [PubMed] [Google Scholar] - 46. Sozen I, Arici A. Interactions of cytokines, growth factors, and the extracellular matrix in the cellular biology of uterine leiomyomata. Fertil Steril 78: 1–12, 2002. doi: 10.1016/s0015-0282(02)03154-0. [DOI] [PubMed] [Google Scholar] - 47. Bonatz G, Frahm SO, Andreas S, Heidorn K, Jonat W, Parwaresch R. Telomere shortening in uterine leiomyomas. Am J Obstet Gynecol 179: 591–596, 1998. doi: 10.1016/s0002-9378(98)70050-x. [DOI] [PubMed] [Google Scholar] - 48. Saed GM, Ladin D, Olson J, Han X, Hou Z, Fivenson D. Analysis of p53 gene mutations in keloids using polymerase chain reaction-based single-strand conformational polymorphism and DNA sequencing. Arch Dermatol 134: 963–967, 1998. doi: 10.1001/archderm.134.8.963. [DOI] [PubMed] [Google Scholar] - 49. Moulton-Levy P, Jackson CE, Levy HG, Fialkow PJ. Multiple cell origin of traumatically induced keloids. J Am Acad Dermatol 10: 986–988, 1984. doi: 10.1016/s0190-9622(84)80319-9. [DOI] [PubMed] [Google Scholar] - 50. Carrino DA, Mesiano S, Barker NM, Hurd WW, Caplan AI. Proteoglycans of uterine fibroids and keloid scars: similarity in their proteoglycan composition. Biochem J 443: 361–368, 2012. doi: 10.1042/BJ20111996. [DOI] [PubMed] [Google Scholar] - 51. Keaton JM, Jasper EA, Hellwege JN, Jones SH, Torstenson ES, Edwards TL, Velez Edwards DR. Evidence that geographic variation in genetic ancestry associates with uterine fibroids. Hum Genet 140: 1433–1440, 2021. doi: 10.1007/s00439-021-02322-y. [DOI] [PMC free article] [PubMed] [Google Scholar] - 52. Bray MJ, Edwards TL, Wellons MF, Jones SH, Hartmann KE, Velez Edwards DR. Admixture mapping of uterine fibroid size and number in African American women. Fertil Steril 108: 1034–1042.e26, 2017. doi: 10.1016/j.fertnstert.2017.09.018. [DOI] [PMC free article] [PubMed] [Google Scholar] - 53. Velez Edwards DR, Tsosie KS, Williams SM, Edwards TL, Russell SB. Admixture mapping identifies a locus at 15q21.2-22.3 associated with keloid formation in African Americans. Hum Genet 133: 1513–1523, 2014. doi: 10.1007/s00439-014-1490-9. [DOI] [PMC free article] [PubMed] [Google Scholar] - 54. Flores C, Ma SF, Pino-Yanes M, Wade MS, Pérez-Méndez L, Kittles RA, Wang D, Papaiahgari S, Ford JG, Kumar R, Garcia JG. African ancestry is associated with asthma risk in African Americans. PLoS One 7: e26807, 2012. doi: 10.1371/journal.pone.0026807. [DOI] [PMC free article] [PubMed] [Google Scholar] - 55. Zhu X, Luke A, Cooper RS, Quertermous T, Hanis C, Mosley T, Gu CC, Tang H, Rao DC, Risch N, Weder A. Admixture mapping for hypertension loci with genome-scan markers. Nat Genet 37: 177–181, 2005. doi: 10.1038/ng1510. [DOI] [PubMed] [Google Scholar] - 56. Giri A, Edwards TL, Hartmann KE, Torstenson ES, Wellons M, Schreiner PJ, Velez Edwards DR. African genetic ancestry interacts with body mass index to modify risk for uterine fibroids. PLoS Genet 13: e1006871, 2017. doi: 10.1371/journal.pgen.1006871. [DOI] [PMC free article] [PubMed] [Google Scholar] - 57. Nakashima M, Chung S, Takahashi A, Kamatani N, Kawaguchi T, Tsunoda T, Hosono N, Kubo M, Nakamura Y, Zembutsu H. A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population. Nat Genet 42: 768–771, 2010. doi: 10.1038/ng.645. [DOI] [PubMed] [Google Scholar]