Abstract
BackgroundNon-celiac wheat sensitivity is an emerging wheat-related syndrome showing peak prevalence in Western populations. Recent studies hypothesize that new gliadin alleles introduced in the human diet by replacement of ancient wheat with modern varieties can prompt immune responses mediated by the CXCR3-chemokine axis potentially underlying such pathogenic inflammation. This cultural shift may also explain disease epidemiology, having turned European-specific adaptive alleles previously targeted by natural selection into disadvantageous ones.MethodsTo explore this evolutionary scenario, we performed ultra-deep sequencing of genes pivotal in the CXCR3-inflammatory pathway on individuals diagnosed for non-celiac wheat sensitivity and we applied anthropological evolutionary genetics methods to sequence data from worldwide populations to investigate the genetic legacy of natural selection on these loci.ResultsOur results indicate that balancing selection has maintained two divergent CXCL10/CXCL11 haplotypes in Europeans, one responsible for boosting inflammatory reactions and another for encoding moderate chemokine expression.ConclusionsThis led to considerably higher occurrence of the former haplotype in Western people than in Africans and East Asians, suggesting that they might be more prone to side effects related to the consumption of modern wheat varieties. Accordingly, this study contributed to shed new light on some of the mechanisms potentially involved in the disease etiology and on the evolutionary bases of its present-day epidemiological patterns. Moreover, overrepresentation of disease homozygotes for the dis-adaptive haplotype plausibly accounts for their even more enhanced CXCR3-axis expression and for their further increase in disease risk, representing a promising finding to be validated by larger follow-up studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12263-016-0532-4) contains supplementary material, which is available to authorized users.
Highlights
Non-celiac wheat sensitivity is an emerging wheat-related syndrome showing peak prevalence in Western populations
Sequence variability of the non-celiac wheat sensitivity (NCWS) sample Two amplicon-based massive parallel sequencing runs were performed on an Ion PGMTM platform to characterize profiles of 18 NCWS subjects at a 14.8-kb genomic interval including CXCR3, CXCL9, CXCL10, and CXCL11 genes, as well as their promoter and untranslated regions
A total of 48 different sequence variants were identified in the whole sample, 94 % of which were single nucleotide polymorphisms (SNPs) already annotated on the dbSNP database, while only 3 were small INDELs
Summary
Non-celiac wheat sensitivity is an emerging wheat-related syndrome showing peak prevalence in Western populations. Recent studies hypothesize that new gliadin alleles introduced in the human diet by replacement of ancient wheat with modern varieties can prompt immune responses mediated by the CXCR3-chemokine axis potentially underlying such pathogenic inflammation. Other wheat proteins in addition to gluten have been proposed to play a role in the development of such pathogenic condition so that it has been suggested to reclassify it as non-celiac wheat sensitivity (NCWS) [5] It remains to be elucidated whether the substantial rise of disease prevalence in Western populations [3, 6] is the result of increased awareness and reporting/diagnosis or is due to its increasing diffusion in such human groups. Since CXCR3 has been proposed to bind gliadins [20], it could be hypothesized that gluten itself may trigger an initial innate challenge able to further induce secretion of CXCR3 chemokine ligands and to establish a vicious cycle that results in amplified Th1-type inflammation
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