Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection

Abstract

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

Celiac disease: a model disease for gene–environment interaction

“…9 It has been proposed that some immunologically relevant CD-associated alleles-including the SH2B3 rs3184504*A allele, which plays a protective role against bacterial infection-may have undergone positive selection rather recently. 8 This finding, along with those in other recent studies of the role of infections 10 and intestinal indigenous microflora composition 11,12 in CD, show that immune reactions to gluten are strongly influenced by changes in the intestinal microbiome.…”

“…Genome-wide association studies have revealed about 40 non-HLA loci, from which one may infer that nearly 50% of genetic susceptibility to CD is known. 8 Many of these genes encode immunologically relevant proteins with important influence on innate and/or adaptive immunity pathways in CD. 9 It has been proposed that some immunologically relevant CD-associated alleles-including the SH2B3 rs3184504*A allele, which plays a protective role against bacterial infection-may have undergone positive selection rather recently.…”

Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics

“…A few clear examples exist, however, for selection acting on individual variants. For example, the T1D-and celiac disease-associated risk allele of the SH2B3 locus shows evidence of selection Zhernakova et al 2010), perhaps due its greater response to bacterial infection (Zhernakova et al 2010), and at the IFIH1 locus, associated with T1D risk and response to viral infection, selection appears to act on the haplotypes associated with infectious disease (Fumagalli et al 2010). Thus, compelling anecdotal evidence of selection on diseaseassociated loci also suggests that pleiotropic effects, especially those relating to infectious disease, may be important determinants of selection.…”

Shared genetics in coeliac disease and other immune-mediated diseases

“…Moreover, it has been suggested that SH2B3 may play a role in protection from bacterial infections, because carriers of this risk variant may have a strong activation of nucleotide-binding oligomerization domain containing 2 (NOD2)recognition. Further support for SH2B3 being involved in bacterial protection comes from studies showing that the risk allele has undergone positive selection during evolution [60].…”