The unfolding story of celiac disease risk factors.

What causes celiac disease (CD)? On the surface, the answer is straightforward: dietary gluten. In susceptible individuals, ingested gluten is deamidated by tissue transglutaminase in the lamina propria of the small intestine and then bound by antigen-presenting cells to the HLA DQ2 or DQ8. This sets off an immune cascade that results in infiltration of the epithelium with lymphocytes and tissue destruction, leading to villous atrophy that is characteristic of CD. The identification of dietary gluten as the environmental culprit was a major advance in the history of gastroenterology. Although diet was long considered to trigger or exacerbate CD, it was the Dutch pediatrician Willem Dicke who determined it was the protein fraction of wheat that made his patients ill. These observations were made before World War II, and Dicke’s hypothesis was borne out during a blockade-induced famine in 1944, when patients with CD improved markedly during the period of severe wheat shortage, only to relapse on the reintroduction of wheat at the end of the famine. The subsequent discovery that the HLA DQ2 or DQ8 haplotype was necessary for the development of CD led to the present understanding that CD arises when gluten is introduced to the genetically susceptible individual. Yet this simple explanation is belied by the fact that this gene–environment combination is far more common than the prevalence of CD; gluten is a ubiquitous dietary staple, and the at-risk HLA haplotypes are present in 30%-40% of Western populations. Genomewide association studies have identified dozens of additional genetic risk loci relating to the immune response, illustrating that CD is a complex, polygenic, immune-based disorder. But just as the genetic story of CD is more complicated than HLA inheritance, the environmental trigger of CD is about more than gluten. Ultimately, growing knowledge of the genetic determinants of CD will by itself not be adequate to understand why CD develops. Epidemics are triggered by environmental exposures, because genetic changes are too slow to drive these phenomena. We have now witnessed 2 epidemics of CD: one that was dramatic and limited, and another that, although less visible, is greater in scale and ongoing. The Swedish epidemic of CD of 1985–1994 has been extensively documented, and resulted in the development of hypotheses regarding environmental risk factors for this disorder. This epidemic was restricted to children younger than 2 years; in that age group, the incidence of diagnosed CD rose from 65 cases per 100,000 person-years to 198 cases per 100,000 person-years. In contrast, incidence data for older children were