Surprising genetic connections between diabetes, celiac disease and HIV susceptibility

An article in the latest issue of the New England Journal of Medicine takes a look at the sharing of genetic risk factors between type 1 diabetes and celiac disease, two reasonably common auto-immune disorders (affecting ~0.4 and ~0.1%, respectively, of individuals of northern European origin).

Celiac disease is more common in type 1 diabetes than in the general population, so there's some reason to expect some shared genetic risk factors between the two disease. And indeed in this study the degree of overlap in risk genes between the two diseases is striking - out of 25 genes with a well-replicated association in at least one disease, 14 show either a "convincing" or "suggestive" association in the other as well. However, there are also many loci with non-shared effects: for instance, the three type 1 diabetes risk variants with the largest effect sizes show nary a trace of a signal in celiac disease.

The picture emerging from this study and others (e.g. comparisons between Crohn's disease and ulcerative colitis) is of a complex web of shared genes linking together many disparate auto-immune diseases, but with each disease also being associated with its own set of unique risk variants.

Adding further complication to the story, two of the variants associated with increased risk for celiac disease actually show significant protective effects in type 1 diabetes. This is reminiscent of a protein-altering variant in the PTPN22 gene, which increases the risk of many auto-immune diseases (including type 1 diabetes) but protects against Crohn's disease. Similar opposing effects have also been described for more exotic pairs of diseases, such as the prostate cancer risk variant in the TCF2 gene that also protects against type 2 diabetes.

There's one other unexpected link that emerges from this study: the well-known HIV protection variant, the so-called delta32 (32-base deletion) variant in the CCR5 gene, is also associated with protection against both type 1 diabetes and celiac disease. Although the protective effect is modest (a 15-20% relative reduction in risk in both diseases), this provides an intriguing link between the genetics of pathogen resistance and the risk of auto-immunity. Assuming that the delta32 variant is causal in both cases, which seems plausible, it will be fascinating to unravel the molecular mechanisms underlying these shared associations.

Subscribe to Genetic Future.

D. J. Smyth, V. Plagnol, N. M. Walker, J. D. Cooper, K. Downes, J. H.M. Yang, J. M.M. Howson, H. Stevens, R. McManus, C. Wijmenga, G. A. Heap, P. C. Dubois, D. G. Clayton, K. A. Hunt, D. A. van Heel, J. A. Todd (2008). Shared and Distinct Genetic Variants in Type 1 Diabetes and Celiac Disease New England Journal of Medicine DOI: 10.1056/NEJMoa0807917