Single nucleotide polymorphisms associated with rheumatoid arthritis susceptibility and etanercept response

Abstract

PART I. Genes and their single nucleotide polymorphisms associated with rheumatoid arthritis susceptibility Rheumatoid arthritis (RA) is a common autoimmune disease characterized by systemic inflammation. Genetically, RA has been highly associated with the HLA-DRB1 locus. In the present work we used a case-control study design to identify HLA-DRB1-independent loci associated with RA in a Korean population. Single nucleotide polymorphisms (SNPs) within 62 candidate genes were analyzed in 544 RA patients and 392 controls. Among 293 SNPs selected from a public database, 173 SNPs were polymorphic in a pooled case-control mixture. When these SNPs were assayed in separate case and control DNA pools, the difference in allele frequency between the two pools was larger than 0.045 (cut-off value) in 17 SNPs in 13 genes. The case and control samples were then individually genotyped for these 17 SNPs. We observed associations between RA and 11 SNPs in 8 genes located in the HLA region. Among them, one SNP (RA277) in HSPA1A was associated with RA susceptibility independent of the both HLA-DRB1 $^{*}0405$ and $^{*}0901$ alleles; the P values for the SNP was $8.3×10^{-8}$ (OR = 1.8, 95% CI = 1.4 - 2.2) in the total samples and 0.0068 (OR = 1.5, 95% CI = 1.1 - 2.0) after adjusting $^{*}0405$ and $^{*}0901$ alleles. The other 10 SNPs in 6 other genes (MICA, BAT1, ATP6V1G2, NFKBIL1, TNFA and TNXB) were not associated with RA in the $^{*}0405$ or $^{*}0901$ negative samples, implying that these SNPs were in linkage equilibrium with HLA-DRB1 $^{*}0405$ or $^{*}0901$ alleles. These findings suggest the hypothesis that RA susceptible gene or genes other than HLA-DRB1 may be located in HSPA1A locus. PART II. Pharmacogenetics of response to etanercept therapy in patients with rheumatoid arthritis Etanercept therapy is widely applied to treat RA, JRA, but it is expensive and one third of RA patients are not good responders. Therefore it would be valuable to predict etanercept efficac...