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Celiac.com 08/25/2010 - The revolution in genetic studies continues to drive discoveries about the genetic triggers for celiac disease. In recent developments, a genome-wide association study (GWAS) has nearly doubled the number of single-nucleotide polymorphisms (SNPs) associated with celiac disease from 14 to 27, most of which contain genes related to immune functions. Doctors have known for some time now that people with genetic markers DQ2 and DQ8 are more susceptible to celiac disease than those without those gene markers. This fact points to the importance of histocompatibility complex presentation of gluten antigens to immune cells. In 2007, a landmark study established 14 celiac-associated SNPs. Recently, a team of researchers conducted a comprehensive follow-up to that study. The study team included P. C. Dubois, G. Trynka, and L. Franke. The resulting GWAS used six times more genetic samples than the 2007 study, including five European case-control data sets comprised of 4,533 celiac disease patients and 10,750 controls. In all, the team tested nearly 300,000 genes. Based on low P values (P < 5 Ã— 10-8) and biological likelihood of candidate SNPs being related to immune function, the team selected a total of 131 single-nucleotide polymorphisms (SNPs) for replication in an independent cohort of 4918 cases and 5684 controls. Their data identify 13 additional regions associated with celiac disease. To determine the trigger gene for each potential locus, the team used three complementary, objective methods. They first used a computerized algorithm, known as GRAIL, that searches PubMed for specific terms related to various gene features. They next employed what is called expression quantitative trait locus mapping, which isolates variations that may influence the expression of the gene, rather than its protein structure and function. Lastly, they looked for co-expression of gene clusters in suspect candidate genes relative to known susceptibility loci. Each of these methods shed additional light on the association between suspect SNPs and celiac disease susceptibility. However, the authors of the study go out of their way to note that, ultimately, the authors categorized loci and predicted causal genes using their "own knowledge of celiac disease pathogenesis.” This fact, they point out, emphasizes the crucial role played by knowledgable scientists exercising their insights to reap the most benefit from ‘objective’ advanced genomic data mining technologies. 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. Their findings also identify several new pathways of celiac disease pathogenesis that merit further investigation. The study team also notes that these findings only account for 20% of the variance in celiac disease heritability. This, they say, points to a need for additional studies regarding genetic triggers for celiac disease. Source: Nature Genetics 42, 295 - 302 (2010). doi:10.1038/ng.543
Celiac.com 07/29/2010 - The underlying causes of psoriasis are not well understood. Many patients with psoriasis also have a sensitivity to gluten. In an effort to better understand any connection between psoriasis, celiac disease, and the HLA Cw6 genotype, a research team examined the expression of celiac-associated antibodies gliadin IgA, gliadin IgG, and tissue transglutaminase IgA, and possible associations the antibodies may have with the HLA Cw6 gene in people with psoriasis. The team included Sangeeta Singh, Gyanendra Kumar Sonkar, Usha, and Sanjay Singh. They are variously affiliated with the Division of Immunopathology in the Department of Pathology at the Institute of Medical Sciences, the Department of Dermatology and Venereology, and the Academic Staff College at Banaras Hindu University in Varanasi, India. Antigens are substances that are recognized by the immune system and trigger an immune reaction. Class I human histocompatibility (HLA) antigens are coded into a small cluster of structural genes at the C locus on chromosome 6. They show substantially lower immune-triggering action than the HLA-A and -B determinants, and so are not a major factor in medical donations. Researchers find them useful because of their high-risk association with certain diseases, such as spondylarthritis, psoriasis, multiple myeloma. About 50 percent of all psoriasis patients carry HLC-Cw6. For the study the team evaluated 56 patients with psoriasis, along with 60 healthy control subjects. The team used ELISA to measure antibody levels, and the microcytotoxicity method to type HLA Cw6. Blood samples of psoriasis patients showed significant HLA Cw6 expression compared with control subjects (P Psoriasis patients showed substantially higher celiac-associated antibodies for gliadin IgA/IgG and tissue transglutaminase IgA compared with control subjects (P Women showed substantially higher serum anti-tissue transglutaminase IgA (anti tTG IgA) than did men. Older patients showed higher expressions than did their younger counterparts. Antibodies showed significant positive correlation (anti-gliadin IgA with anti-gliadin IgG: r=0.67, P. From their results, the team concludes that patients with psoriasis commonly show latent celiac disease or celiac-associated antibodies, but that HLA Cw6 is not connected with expression of these antibodies in patients with psoriasis. Source: Journal of Clinical Laboratory Analysis, Volume 24 Issue 4, Pages 269 - 272