Evidence of selection as a cause for racial disparities in fibroproliferative disease

Abstract

Fibroproliferative diseases are common complex traits featuring scarring and overgrowth of connective tissue which vary widely in presentation because they affect many organ systems. Most fibroproliferative diseases are more prevalent in African-derived populations than in European populations, leading to pronounced health disparities. It is hypothesized that the increased prevalence of these diseases in African-derived populations is due to selection for pro-fibrotic alleles that are protective against helminth infections. We constructed a genetic risk score (GRS) of fibroproliferative disease risk-increasing alleles using 147 linkage disequilibrium-pruned variants identified through genome-wide association studies of seven fibroproliferative diseases with large African-European prevalence disparities. A comparison of the fibroproliferative disease GRS between 1000 Genomes Phase 3 populations detected a higher mean GRS in AFR (mean = 148 risk alleles) than EUR (mean = 136 risk alleles; T-test p-value = 1.75x10-123). To test whether differences in GRS burden are systematic and may be due to selection, we employed the quantitative trait loci (QTL) sign test. The QTL sign test result indicates that population differences in risk-increasing allele burdens at these fibroproliferative disease variants are systematic and support a model featuring selective pressure (p-value = 0.011). These observations were replicated in an independent sample and were more statistically significant (T-test p-value = 7.26x10-237, sign test p-value = 0.015). This evidence supports the role of selective pressure acting to increase frequency of fibroproliferative alleles in populations of African relative to European ancestry populations.

A Trans-Ethnic Genome-Wide Association Study of Uterine Fibroids

“…The top variant in the WNT4/CDC42 had opposite directions of effect in African and European ancestry women, and associated variants in the TP53 locus were only polymorphic in European women. We have previously reported evidence for differential burdens of risk-increasing alleles for fibroproliferative traits across global populations that are consistent with prevalence disparities (Hellwege et al, 2017b). This finding was recently extended to evaluate only fibroid risk variants across populations, with an increased mean burden of risk alleles in black fibroid cases and controls from UKB compared to other racial/ethnic groups, with a similar result using frequencies from the gnomAD browser (Välimäki et al, 2018).…”

Evidence that geographic variation in genetic ancestry associates with uterine fibroids

“…Previous studies have shown that risk of broproliferative disease including keloids (Niessen et al, 1999), glaucoma (Morris et al, 1999, Racette et al, 2003, hypertension (Dustan, 1992, Suthanthiran et al, 2000, nephrosclerosis (August and Suthanthiran, 2003), scleroderma (Mayes et al, 2003), sarcoidosis (Rybicki et al, 1998), asthma (Barnes et al, 2007, Lester et al, 2001, Newth et al, 2012, Nickel et al, 1999, and broids (Flake et al, 2003), varies by race/ethnicity. Further supporting this are ndings from our group that demonstrated that the frequency of broproliferative risk alleles varies by geographic ancestry with a much higher burden among African-ancestry populations and lower among European-derived populations (Hellwege et al, 2017). Admixture mapping analysis of broid risk and multiple broid risk also demonstrates increased risk among Black women compared to White women (Bray et al, 2017, Giri et al, 2017.…”

“…However, there is large heterogeneity in symptomology, broid location, and broid growth, both within and between patients, demonstrating the complexity of mechanisms underlying the development and growth of broids (Ciavattini et al, 2013, Commandeur et al, 2015. We have published evidence that polygenic selection has occurred at risk loci for several broproliferative traits between African and non-African populations, which may contribute to racial disparities in risk and severity (Hellwege et al, 2017). In these studies we demonstrated that across published GWAS of broproliferative diseases there is strong evidence of increasing selection among those of African ancestry when compared to those of non-African ancestry.…”

“…Evidence suggests that adaptive variation conferring evolutionary advantages in tropical environments inhabited by ancestral African populations, such as connective tissue overgrowth in wound repair and hyperpigmentation as a response to ultraviolet radiation damage, may increase risk for multiple complex diseases in modern African-derived populations (Hellwege et al, 2017, Polednak, 1987. Russell et al postulated that variation protective for helminth infection may account for increased risk of broproliferative disease in African populations (Russell et al, 2015).…”

Fibroproliferative genes are preferentially expressed in central centrifugal cicatricial alopecia

“…Like CCCA, FPDs such as systemic sclerosis, keloids, atherosclerosis, and uterine fibroids (UFs) are all characterized by persistent low-grade inflammation and irritation that results in end-stage fibrosis. 7,8 The risk of certain FPDs is increased in people of African descent, and this increased risk is thought to be secondary to the protective effect that profibrotic alleles offer against helminths found in Sub-Saharan Africa. 8,9…”