Abstract
Although the genetic component in the etiology of rheumatoid arthritis (RA) has been consistently suggested, many novel genetic loci remain to uncover. To identify RA risk loci, we performed a genome-wide association study (GWAS) with 100 RA cases and 600 controls using Affymetrix SNP array 5.0. The candidate risk locus (APOM gene) was re-sequenced to discover novel promoter and coding variants in a group of the subjects. Replication was performed with the independent case-control set comprising of 578 RAs and 711 controls. Through GWAS, we identified a novel SNP associated with RA at the APOM gene in the MHC class III region on 6p21.33 (rs805297, odds ratio (OR) = 2.28, P = 5.20 × 10-7). Three more polymorphisms were identified at the promoter region of the APOM by the re-sequencing. For the replication, we genotyped the four SNP loci in the independent case-control set. The association of rs805297 identified by GWAS was successfully replicated (OR = 1.40, P = 6.65 × 10-5). The association became more significant in the combined analysis of discovery and replication sets (OR = 1.56, P = 2.73 × 10-10). The individuals with the rs805297 risk allele (A) at the promoter region showed a significantly lower level of APOM expression compared with those with the protective allele (C) homozygote. In the logistic regressions by the phenotype status, the homozygote risk genotype (A/A) consistently showed higher ORs than the heterozygote one (A/C) for the phenotype-positive RAs. These results indicate that APOM promoter polymorphisms are significantly associated with the susceptibility to RA.
Highlights
Rheumatoid arthritis (RA) is a common systemic autoimmune disease that is characterized by chronic inflammation of the synovium, which can lead to progressive joint destruction
Apolipoprotein M is high density lipoprotein (HDL)-associated apoprotein mainly expressed in the liver and kidney (Xu and Dahlback, 1999)
Recent evidence has indicated that Apolipoprotein M (apoM) may contribute to the anti-inflammatory function of HDL (Burger and Dayer, 2002; Feingold et al, 2008) and apoM inhibited by siRNA resulted in decreased HDL level (Wolfrum et al, 2005)
Summary
Rheumatoid arthritis (RA) is a common systemic autoimmune disease that is characterized by chronic inflammation of the synovium, which can lead to progressive joint destruction. It is a complex disease that is caused by multiple factors such as genetic, environmental, and hormonal contributions (Firestein, 2003). While the exact pathogenesis of RA is still unknown, multiple lines of evidence such as a higher concordance rate in monozygotic twins than in dizygotic twins and the higher risk in siblings of patients compared with that in a general population (MacGregor et al, 2000; Goronzy and Weyand, 2009), suggest the genetic component in the etiology of this disease. As for the efforts to understand the genetic etiology of RA, various genome-wide association studies (GWAS) and meta-analyses have identified a number of risk loci including HLA-DRB1, PTPN22, CD40, STAT4, OLIG3, TNFAIP3, TNFRSF14, CTLA4, CCL2, PADI4 and TRAF1/C5
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