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    Association Analysis of the Extended MHC Region in Celiac Disease Implicates Multiple Gene Sites


    Jefferson Adams
    Association Analysis of the Extended MHC Region in Celiac Disease Implicates Multiple Gene Sites
    Image Caption: Photo: CC--The Pale Side of Insomnia

    Celiac.com 12/26/2012 - Currently, researchers have found forty separate gene sites that they associate with celiac disease. They classify all of these sies as "low-penetrance," with the exception of the high-risk genotypes in the HLA-DQA1 and HLA-DQB1 genes, which are necessary, but not sufficient to cause the disease.

    Photo: CC--The Pale Side of InsomniaSo far, their efforts to find more such sites have been prevented by the strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC).

    A research team wanted to test the hypothesis that additional celiac disease gene sites exist within the extended major histocompatibility complex (xMHC).

    The research team included Richard Ahn, Yuan Chun Ding, Joseph Murray, Alessio Fasano, Peter H. R. Green, Susan L. Neuhausen, and Chad Garner. They are variously affiliated with the Department of Epidemiology, University of California Irvine, Irvine, California, the Department of Population Sciences at eh Beckman Research Institute of City of Hope in Duarte, California, the Department of Medicine and Immunology at The Mayo Clinic in Rochester, Minnesota, the Center for Celiac Research at the University of Maryland School of Medicine in Baltimore, Maryland, and the Celiac Disease Center at Columbia University in New York, New York.

    To follow up on the hypothesis, they looked at a collection of single nucleotide polymorphisms, frequently called SNPs (pronounced “snips”), which are the most common type of genetic variation among people.

    For their study, the research team analyzed a set of 1898 SNPs for association across the 7.6 Mb xMHC region in 1668 patients with confirmed celiac disease, and 517 non-celiac control subjects.

    The researchers used what is called conditional recursive partitioning to create a marker of known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects.

    After accounting for the known effects, they used a linkage disequilibrium-based grouping procedure to estimate the number of independent celiac disease loci present in the xMHC. They found strong statistical evidence for four new independent celiac disease loci within the classic MHC region.

    This was the first time researchers have conducted a comprehensive association analysis of the xMHC in celiac disease that specifically accounts for the known HLA disease genotypes and the genetic complexity of the region.

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    Guest sufferer

    Posted

    Lots of big words and acronyms, but no content for sufferers. We need real news concerning celiac disease: how deep frying or sugar may lessen the effects, etc.

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    Guest gluten free forever

    Posted

    This research is very valuable for those of us who did not test DQ2 or DQ8, but have definite symptoms and suffer just as great. The medical community presently does not recognize other genomes as suspect and will not give the proper diagnosis. This helps with more extensive genome possibilities which will hopefully give the medical community more info that celiac disease is not limited to just HLA DQ2 or 8.

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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, and science. He previously served as Health News Examiner for Examiner.com, and provided health and medical content for Sharecare.com.

    Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book Dangerous Grains by James Braly, MD and Ron Hoggan, MA.

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    Jefferson Adams
    Celiac.com 03/11/2010 - As part of an effort to investigate the possibility of multiple common variants for celiac disease influencing immune gene expression, a team of more than sixty scientists recently worked together to conduct a second-generation genome-wide association study (GWAS) of 4,533 individuals with clinically proven celiac disease, along with 10,750 control subjects.
    They genotyped a total of 113 selected SNPs with PGWAS < 10−4 and 18 SNPs from 14 known loci in another 4,918 confirmed celiac disease patients and 5,684 control subjects. The research team included dozens of scientists associated with a variety of major research institutions, hospitals and clinics.
    The GWAS included five European sample collections of celiac disease and control cases, including the celiac disease dataset reported previously. The team's stringent data quality control measures included calling genotypes using a custom algorithm on both large sample sets and, where possible, cases and controls together. The team tested 292,387 non-HLA SNPs from the Illumina Hap300 marker pool for association in 4,533 individuals with celiac disease and 10,750 control subjects of European descent. They also tested another 231,362 additional non-HLA markers from the Illumina Hap550 marker set for association in a subset of 3,796 individuals with celiac disease and 8,154 controls. All markers came from autosomes or the X chromosome. For both datasets, Genotype call rates were >99.9%.
    The study showed over-dispersion factor of association test statistics comparable to that observed in other GWASs of this sample size. Factoring in missing genotypes for 737 cases with celiac disease genotyped on the Hap300 BeadChip and corresponding controls did not change the findings in any meaningful way.Variants from 13 new regions reached genome-wide significance (Pcombined < 5 × 10−8); most contain geneswith immune functions, such as BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1, while ETS1, RUNX3, THEMIS and TNFRSF14 play key roles in thymic T-cell selection.
    The data suggested associations for 13 additional regions. Expression quantitative trait meta-analysis of 1,469 whole blood samples showed that 52.6% of tested loci (20 of 38 loci) had celiac risk variants corresponding with cis gene expression (P < 0.0028, FDR 5%).
    Source:

    Nature Genetics (28 February 2010) | doi:10.1038/ng.543

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