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

Abstract

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.

Fig 1. Helminth exposure selects for a protective Th2 immune response that simultaneously increases risk for fibrosis.

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. [168].

Fig 2. Pattern of differences between YRI and CEU HapMap populations, as determined by Fst between SNPs.

(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 [169] 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 S1 Table.