The contribution of natural selection to present-day susceptibility to chronic inflammatory and autoimmune disease

Abstract

Chronic inflammatory and autoimmune diseases have been the focus of many genome-wide association studies (GWAS) because they represent a significant cause of illness and morbidity, and many are heritable. Almost a decade of GWAS studies suggests that the pathological inflammation associated with these diseases is controlled by a limited number of networked immune system genes. Chronic inflammatory and autoimmune diseases are enigmatic from an evolutionary perspective because they exert a negative affect on reproductive fitness. The persistence of these conditions may be partially explained by the important roles the implicated immune genes play in pathogen defense and other functions thought to be under strong natural selection in humans. The evolutionary reasons for chronic inflammatory and autoimmune disease persistence and uneven distribution across populations are the focus of this review.

Figure 1

Recent positive selection targeting SNPs associated with susceptibility to chronic inflammatory, autoimmune and infectious diseases. (a) The proportion of GWAS SNPs that present evidence for recent positive selection, as attested by the Integrated Haplotype Score (iHS) statistic [21]. The complete list of GWAS-associated SNPs was obtained from the NIH Catalog of Published Genome-Wide Association Studies [105], which reports all SNP trait associations with a p-values <1.0 × 10⁻⁵. For the purpose of the current analyses we used all GWAS SNPs with an association at a significance threshold <1.0 × 10⁻⁶. We note, however, that the results are qualitatively similar if using more stringent cutoffs for the GWAS data. The y-axis represents the proportion of SNPs that present an absolute iHS values above the 99th percentile of the HapMap phase II genome-wide distribution for Europeans (left side — orange bars) and Africans (right side — green bars). Diseases were grouped into broader groups: the set of inflammatory disorders includes Crohn’s disease, ulcerative colitis and celiac disease. The set of autoimmune diseases includes rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, and psoriasis. The set of ‘Immune disorders’ encompasses both inflammatory and autoimmune diseases. The set of infectious diseases includes HIV/AIDS, Hepatitis B and C, Leprosy, Malaria and Tuberculosis. As a control we also looked at enrichment for signatures of selection among all cancer-related diseases. (b) iHS values for Europeans (orange) and Africans (green) for SNPs associated with several immune-related diseases by different GWAS studies. The genes reported by the GWAS as the most likely associated with the SNPs with absolute iHS values above the ninety-fifth percentile (orange dashed line) are reported. ‘NR’ stands for non-reported. # intergenic region. ## This is the same locus of SH2B3.

Figure 2

Levels of population differentiation at GWAS SNPs for immune-related diseases. (a) Boxplots of Fst values between European- (CEU) and African-descent individuals (YRI) based on the data from the 1000 Genomes Project. The Fst statistic examines variation in SNP allele frequencies between populations. Under neutrality, Fst is determined by genetic drift, which affects all loci across the genome similarly. Conversely, positive selection will cause an increase in Fst values in the population where selection occurs. Orange dots highlight highly differentiated GWAS SNPs with an Fst value above the 95th percentile of the genome-wide distribution. (b) Worldwide frequency distribution of two highly differentiated SNPs. The top panel shows the worldwide distribution of allele frequencies for rs2472649, an SNP associated with IBD located in a chemokine cluster on chromosome 4 (e.g., CXCL5,CXCL1,CXCL3,IL8,CXCL6,PF4,CXCL2,PF4V1) and the bottom panel shows the worldwide distribution of allele frequencies for rs653178 an SNP associated with celiac disease linking the SH2B3/ATXN2 locus with susceptibility to celiac disease.