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, $P=5.20{ imes}10^{-7}$). 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, $P=6.65{ imes}10^{-5}$). The association became more significant in the combined analysis of discovery and replication sets (OR = 1.56, $P=2.73{ imes}10^{-10}$). 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.