At least 13 new gene regions tied to celiac

[Zizzle]

This article on MedScape explains that researchers identified 13 new gene regions that predispose to celiac disease, most of them related to immune function. This raises the total to 27 beyond HLADQ2 and 8.

The Genetics of Celiac Disease: Moving Beyond DQ2 and DQ8
Gil Y. Melmed, MD; Dermot P.B. McGovern, MD, PhD

Posted: 07/26/2010

http://www.medscape.com/viewarticle/725 ... uac=9310BX

Summary
Celiac disease is a chronic inflammatory disease of the small intestine. It is characterized by an aberrant immune response to gluten that results in destruction of the small bowel epithelium, usually manifesting as intestinal symptoms and nutrient malabsorption. Clinically, celiac disease can be diagnosed by detection of antibodies to gluten and the enzyme tissue transglutaminase.

It has previously been known that susceptibility to celiac disease is increased among those with DQ2 and DQ8, highlighting the role of the major histocompatibility complex presentation of gluten antigens to immune cells. In 2007, a genome-wide association study (GWAS) identified 14 genes related to innate and adaptive immunity important to susceptibility to celiac disease.[1] In the current study, a GWAS was performed on 6 times as many samples, using 5 European case-control data sets that consisted of 4533 cases of celiac disease and 10,750 controls, and tested nearly 300,000 genes. A total of 131 single-nucleotide polymorphisms (SNPs) were selected for replication in an independent cohort of 4918 cases and 5684 controls on the basis of low P values (P < 5 ×
10-8) and biologic plausibility on the basis of candidate SNPs being related to immune function. In addition to the previously established 14 loci, an additional 13 regions were identified, most of which contain genes related to immune functions.

Viewpoint
The authors used 3 complementary, objective methods to help determine the underlying causal gene at each of the candidate loci. The first is a computerized algorithm called GRAIL that searches PubMed for like terms used to describe different genes. The second approach used expression quantitative trait locus mapping, which highlights the contribution of alterations that may influence gene expression rather than protein structure and function. The third approach looked for co-expression of clusters of genes by assessing suspected candidate genes relative to known susceptibility loci.

All 3 of these approaches helped to further clarify the candidate SNP for association with celiac disease susceptibility. However, as noted in the editorial accompanying the manuscript,[2] “in the end the authors used the old-fashioned approach of placing loci (and predicted causal genes) into... categories on the basis of their own knowledge of celiac disease pathogenesis.” Thus, the role of the thoughtful scientist remains paramount even in the current era of advanced genomic technologies designed for ‘objective’ data mining.

This study involved genetic assessment in a very large cohort, replication in a similarly large cohort, and multiple independent approaches at refining candidate SNPs. As a result, the number of known loci of celiac disease susceptibility genes has increased from 14 to 27. On the basis of these findings, several new pathways of disease pathogenesis are identified and warrant further exploration. However, despite these findings, only 20% of the variance in celiac disease heritability is explained, reflecting the need for further research into the genetic underpinnings of this relatively common disorder.