Celiac Disease: The Evolutionary Paradox

Celiac disease (CD), an autoimmune disorder triggered by gluten ingestion, negatively affects individuals' health if left untreated. In individuals with the requisite genes, CD destroys the intestinal lining because specific peptide fragments of gluten (protein found in wheat and related grains) bind to the receptor proteins coded for by HLA-DQ2 and DQ8 genes, thereby causing an autoimmune response that damages intestinal cells and results in malnutrition. Because the disease has a genetic basis and can lead to impaired reproductive functioning and death, natural selection should lead to a decrease in CD prevalence over time. However, evidence suggesting CD increases in some populations contradicts this hypothesis, resulting in the ‘Celiac Disease Evolutionary Paradox.' The worldwide average prevalence rate is around 1%, although rates of up to 5% have been observed in certain populations. Maintenance or increase in the frequency of CD-predisposing genes in certain populations suggests potential evolutionary benefits for those genes, which may exhibit antagonistic pleiotropy, such as being beneficial for infectious disease but detrimental for chronic disease such as CD. Recent dietary and environmental changes (including dietary gluten exposure, breastfeeding duration and the intestinal microbiome, and immune function) may have led to discordance with the Environment of Evolutionary Adaptedness, thus contributing to increases in CD. Consideration of potential benefits of CD-risk gene alleles, in conjunction with a deeper understanding of environmental factors exerting positive and negative selection on those alleles, may help to explain population variation in CD prevalence rates, and shed light on the complex gene-environment interactions influencing this devastating disease.