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, 86 (6), 970-7

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

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

Alexandra Zhernakova et al. Am J Hum Genet.

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.

Figures

Figure 1
Figure 1
Functional Consequences of IL18RAP and SH2B3 Genotypes (A) Individual gene expression correlation of IL18RAP with rs917997 from 1469 PAXgene samples (1240 hybridized to Illumina HT-12 arrays; 229 hybridized to Illumina Ref-8 v2 arrays). Spearman correlation coefficients are shown for HT-12 and Ref-8 v2 data, and meta-analysis p value results are shown (L.F., unpublished data). (B) Differences between the SH2B3 genotype after LPS stimulation show a moderately reduced IL-6 cytokine production in PBMCs isolated from individuals heterozygous for the celiac risk allele. (C and D) After MDP stimulation, a specific ligand of the NOD2 innate immune receptor, homozygous individuals carrying the risk allele showed an increased production of the IL-6 and IL1-β cytokines. (E) IL-8 production in these individuals also showed an elevated production of the cytokine. All data in panels (B)–(E) are presented as means and standard deviation (SD). The total number of individuals for each SH2B3 genotype is given under each bar and only the significant differences are included (Mann-Whitney U test).
Figure 2
Figure 2
Example of EHH Plot of SH2B3 rs3184504 SNP in European and Saharawi Populations (A) European (UK controls) population. (B) Saharawi population. Blue shows the derived haplotype; red shows the ancestral haplotype. Included are 1.4 Mb left and right from rs3184504. EHH plots for all the selected SNPs and all the studied populations are presented in Figure S1A–S1C.
Figure 3
Figure 3
Worldwide Allele Frequency Distribution of rs3184504 in SH2B3 The derived allele is the CD risk allele that shows a signature of recent selection in our European study populations. In this figure, the rs3184504 alleles are annotated on the reverse strand.

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