Genetic and anthropologic factors in gluten‐sensitive enteropathy

Gluten‐sensitive enteropathy (GSE), a disease characterized by intestinal villous atrophy and malabsorption, is due to a sensitivity to wheat protein, gliadin, and probably has its basis in an underlying immunologic defect. GSE has a genetic basis in that some 70–80% of north American and northern European patients bear the HLA‐B8 histocompatibility type and about 90% bear the HLA‐DRw3 histocompatibility type. These histocompatibility types are both increased because they are in linkage disequilibrium in normal populations. This suggests that HLA‐B8 and HLA‐DRw3 genes are in linkage disequilibrium with a GSE disease gene, accounting for the association of the disease with certain histocompatibility antigens. A gene coding for a lymphoid surface antigen has been identified which is not HLA‐linked. This gene is distributed at a low frequency in the general population; it has been proposed that both the HLA and non‐HLA genes important to GSE code for different domains of the single surface receptor molecule that somehow predisposes to a heightened immune reaction to gliadin, thus causing the disease. GSE is most prevalent where HLA‐B8 occurs at the highest frequency in the general population and is not seen in populations where HLA‐B8 is not found. One explanation for this is that the gene complex containing HLA‐B8 (and HLA‐DRw3) evolved in response to infectious agents: Individuals bearing this complex were capable of more vigorous antibody response. However, such individuals were also more likely to be hypersensitive to wheat protein; as wheat became domesticated these individuals may have been at a disadvantage. It is only in regions such as northern Europe where wheat domestication occurred relatively late that one finds both a high frequency of HLA‐B8 and a high incidence of GSE.