Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases

<div><p>Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.</p></div

Pattern of differences between YRI and CEU HapMap populations, as determined by Fst between SNPs.

<p>(A) Th2 variants compared to background (18 genes and 256 SNPs); (B) Th1 variants compared to background (14 genes and 207 SNPs); (C) A comparison of Fst values for Th2 as compared to Th1 SNPs); (D) TGFβ and TGFβ-receptor variants, as compared to background (6 genes and 340 SNPs). Fst was calculated using the method of Weir and Cockerham [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005568#pgen.1005568.ref169" target="_blank">169</a>] and varies from zero (when two populations have identical allele frequencies of a given SNP) to one (when they are fixed for different alleles). Genes used for these analyses are listed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005568#pgen.1005568.s002" target="_blank">S1 Table</a>.</p

Helminth exposure selects for a protective Th2 immune response that simultaneously increases risk for fibrosis.

<p>The high prevalence of helminths in Africa has selected for genotypes favoring an enhanced Th2 immune response characterized by increased levels of interleukin 4 (IL4), interleukin 13 (IL13), and interleukin 4 receptor (IL4R), and other Th2 factors. This selection also decreases Th1 factors, such as interferon gamma (IFNG) and interferon gamma receptor (IFNGR), and Th2 regulatory factors, such as IL10 and interleukin 13 receptor alpha 2 (IL13RA2). These genotypes increase resistance to helminthic infection and contribute to a subset of fibroproliferative diseases that are more common and/or more severe in individuals of African ancestry. Global distribution of helminth species in upper part of figure adapted from Lustigman et al. [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005568#pgen.1005568.ref168" target="_blank">168</a>].</p

Relative frequencies of certain fibroproliferative diseases in black and white populations.

<p>Location of fibrosis</p><p>^a) airway</p><p>^b) eye</p><p>^c) kidney</p><p>^d) cardiovascular</p><p>^e) skin</p><p>^f) lung</p><p>^g) visceral organs</p><p>^h) uterus</p><p>Relative frequencies of certain fibroproliferative diseases in black and white populations.</p

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

<div><p>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.</p></div

Response to exposure by mouse strain.

<p>Response to exposure by mouse strain.</p

Population-specific allele frequencies (1,000 Genomes, 16 October 2014 release).

<p>^a) increased transcription</p><p>^b) decreased transcription</p><p>^c) increased IgE</p><p>^d) allergic disease/asthma</p><p>^e) resistance to helminthic infection</p><p>^f) fibrosis</p><p>^g) increased Th2 cytokines</p><p>^h) forward strand in 1,000 Genomes and HapMap, but apparently earlier literature reporting similar prevalence differences used complementary strand</p><p>ⁱ) sensitivity to helminthic infection</p><p>Population-specific allele frequencies (1,000 Genomes, 16 October 2014 release).</p

Distribution of fibroproliferative disease GRS in populations from 1000 Genomes.

<p>Results are sorted by median risk allele burden. Bars represent the 25^th and 75^th percentiles and are color coded by super-population (Green = EUR, Blue = AMR, Orange = SAS, Purple = EAS, Red = AFR).</p

Summary statistics for fibroproliferative GRS among AFR and EUR populations from 1000 Genomes, and among BioVU samples.

<p>Summary statistics for fibroproliferative GRS among AFR and EUR populations from 1000 Genomes, and among BioVU samples.</p

Cumulative distribution of GRS in 1000 Genomes AFR, EUR, ASW, and BioVU populations.

<p>*AFR includes only the continental African populations.</p