期刊
GENES AND IMMUNITY
卷 12, 期 7, 页码 568-574出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2011.30
关键词
rheumatoid arthritis; immunogenetics; North American Native; genetic risk
资金
- Assembly of Manitoba Chiefs
- Chiefs and Band Council of the Norway House community
- Chiefs and Band Council of the St Theresa Point community
- Canadian Institutes of Health Research [MOP 7770, MOP 79321, IIN-84042]
- Ontario Research Fund [RE01061]
- Sherman Family Chair in Genomic Medicine
- Canada Research Chair
Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n = 333) and controls (n = 490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio = 2.2, 95% confidence interval 1.6-3.1, P < 0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles. Genes and Immunity (2011) 12, 568-574; doi:10.1038/gene.2011.30; published online 26 May 2011
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