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March 1, 2010 - Thirteen new variants having genomewide significant association with risk for celiac disease were found in an international study headed by British and Dutch researchers. An additional 13 variants having suggestive association with disease risk were also found.

Consistent with previous genomewide association studies (GWASs) of celiac disease, which identified a risk locus in IL2-IL21, and follow-ups that found causal variants in HLA-DQA1 and HLA-DQB1, most of the newly discovered variants lie near genes with immune functions.

Celiac disease is an autoimmune disorder characterized by chronic inflammation of the small intestine resulting from exposure to gluten (a wheat protein) and similar proteins in barley and rye. Symptoms of the disease - also called celiac sprue, gluten enteropathy, or gluten intolerance - may include chronic diarrhea, fatigue, and failure to thrive. The chronic inflammation causes atrophy of the finger-like villi that line the small intestine, decreasing the surface area for nutrient absorption. The only treatment effective for celiac disease is a gluten-free diet.

The new GWAS, published online yesterday in Nature Genetics, drew on data from 5 European collections of patients with celiac disease (n = 4533) and control patients (n = 10,750). Of 417 single nucleotide polymorphisms (SNPs) with P GWAS < 10?4 that did not involve HLA sites, the SNPs chosen for replication included 18 that were previously known and 113 that were newly identified. The selected SNPs and their P values included:

  a.. 18 SNPs from 14 previously known risk loci for celiac disease
  b.. 13 from 7 newly identified regions having PGWAS < 5 × 10?7 
  c.. 86 from newly identified regions for which 5 × 10?7 < PGWAS < 5 × 10?5 
  d.. 14 from newly identified regions for which 5 × 10?5 < PGWAS < 10?4 
Follow-up was carried out in 7 independent cohorts with 4918 patients with celiac disease and 5684 control individuals. This reduced the field to the 14 previously reported SNPs, 13 new loci with P combined < 5 × 10?8, and 13 "suggestive" loci with P GWAS, P follow-up, or P combined values that approached (but did not fall within) GWAS threshold for significant association.

The pathways highlighted by the variants involve T-cell development in the thymus; immune detection of viral RNA; T- and B-cell costimulation or coinhibition; and cytokines, chemokines, and their receptors.

"We previously showed that there is considerable overlap between risk loci for celiac disease and type 1 diabetes, as well as between risk loci for celiac disease and rheumatoid arthritis," note the authors. The new findings provide "substantial evidence" that some risk loci are associated with more than one of the chronic immune-mediated diseases. Searching the literature and the Human Genome Epidemiology database, the investigators found that 18 of the 27 SNPs associated with risk for celiac disease at the genomewide level are associated with 1 or more other immune-mediated or inflammatory diseases.

Of particular interest was that genetic variation in ETS1 has an association with systemic lupus erythematosus (SLE) in people of Chinese origin but is not implicated in SLE in Europeans. However, the SNP most strongly associated with celiac disease in European populations (as in the present study) lies only 70 kb from the SNP most strongly associated with SLE in Chinese populations. This and other observations suggest that "distinct common variants within the same gene can predispose to different autoimmune diseases across different ethnic groups."

The present study not only examined disease risk associations but also analyzed blood samples (n = 1469) to determine expression of genes near loci with celiac risk variants. In 20 of the 38 loci tested, celiac risk variants correlated with expression of the gene on the same chromosome (P < .0028). The data "indicate that some risk variants might influence celiac disease susceptibility through a mechanism of altered gene expression."

Noting that more than half the variants associated with celiac disease risk correlate with changes in the expression of nearby genes, the investigators recommend that "[f]urther research is needed to definitively determine at each locus both the variants that can cause celiac disease and their functional mechanisms."

Nat Genet. Published online February 28, 2010.

Copied from Medscape

Susan First

Toledo, Ohio



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