title: A genome-wide screen of gene-gene interactions for rheumatoid arthritis susceptibility.
abstract: The objective of the study was to identify interacting genes contributing to rheumatoid arthritis (RA) susceptibility and identify SNPs that discriminate between RA patients who were anti-cyclic citrullinated protein positive and healthy controls. We analyzed two independent cohorts from the North American Rheumatoid Arthritis Consortium. A cohort of 908 RA cases and 1,260 controls was used to discover pairwise interactions among SNPs and to identify a set of single nucleotide polymorphisms (SNPs) that predict RA status, and a second cohort of 952 cases and 1,760 controls was used to validate the findings. After adjusting for HLA-shared epitope alleles, we identified and replicated seven SNP pairs within the HLA class II locus with significant interaction effects. We failed to replicate significant pairwise interactions among non-HLA SNPs. The machine learning approach "random forest" applied to a set of SNPs selected from single-SNP and pairwise interaction tests identified 93 SNPs that distinguish RA cases from controls with 70% accuracy. HLA SNPs provide the most classification information, and inclusion of non-HLA SNPs improved classification. While specific gene-gene interactions are difficult to validate using genome-wide SNP data, a stepwise approach combining association and classification methods identifies candidate interacting SNPs that distinguish RA cases from healthy controls.
authors.affiliation: Center for Population Studies and the Framingham Heart Study, National Heart, Lung, and Blood Institute/NIH, 73 Mt. Wayte Avenue, Framingham, MA 01702, USA. liuchunyu2002@yahoo.com
authors.forename: Chunyu
authors.initials: C
authors.lastname: Liu
authors.forename: H Hoxie
authors.initials: HH
authors.lastname: Ackerman
authors.forename: John P
authors.initials: JP
authors.lastname: Carulli
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D006680:HLA Antigens