title: Association analysis of the extended MHC region in celiac disease implicates multiple independent susceptibility loci.
abstract: Celiac disease is a common autoimmune disease caused by sensitivity to the dietary protein gluten. Forty loci have been implicated in the disease. All disease loci have been characterized 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. The very strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC) have precluded a thorough investigation of the region. The purpose of this study was to test the hypothesis that additional celiac disease loci exist within the extended MHC (xMHC). A set of 1898 SNPs was analyzed for association across the 7.6 Mb xMHC region in 1668 confirmed celiac disease cases and 517 unaffected controls. Conditional recursive partitioning was used to create an informative indicator of the known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects. A linkage disequilibrium-based grouping procedure was utilized to estimate the number of independent celiac disease loci present in the xMHC after accounting for the known effects. There was significant statistical evidence for four new independent celiac disease loci within the classic MHC region. This study is the first 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.
authors.affiliation: Department of Epidemiology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Ahn
authors.forename: Yuan Chun
authors.initials: YC
authors.lastname: Ding
authors.forename: Joseph
authors.initials: J
authors.lastname: Murray
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
authors.forename: Peter H R
authors.initials: PH
authors.lastname: Green
authors.forename: Susan L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: Chad
authors.initials: C
authors.lastname: Garner
mesh_terms: D002446:Celiac Disease / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide
chemical_list: D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen