Genetic polymorphisms associated with rheumatoid arthritis susceptibility

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint inflammation and destruction of synovial tissues. Because RA is a multi-factorial disease, both genetic and environmental factors contribute to RA susceptibility and multi-genomic loci have been shown to be linked to RA susceptibility. HLA-DRB1 locus and several genes in non-HLA regions were reported to be associated with RA. However, these genes cannot totally explain genetic susceptibility of RA. In the present work, three types of case-control studies were performed to identify additional genetic polymorphisms associated with RA using genomic DNA from 1316 Korean RA patients and 1006 Korean controls. In the first candidate gene approach, 209 single nucleotide polymorphisms (SNPs) from 87 candidate genes in non-HLA region were investigated for identification of putative RA-associated SNPs by estimating allele frequency difference between genomic DNA pools of 1032 cases and those of 688 controls. Allele frequency differences of 7 SNPs in different 7 genes were higher than 0.045. Among these 7 SNPs, one SNP named as RA243 (rs1059703) located in X-chromosome showed significant allelic associations with RA when total RA and control subjects were individually genotyped and analyzed for RA associations. Two major haplotypes consisted of 6 SNPs containing the RA243 in a linkage disequilibrium (LD) block which ranges from 5’ downstream region IRAK1 to middle of MECP2 in X-chromosome were also associated with RA susceptibility in total subjects and subgroups stratified by genders. These two IRAK1/MECP2 haplotypes were also shown to be associated with rheumatoid factor positivity. No significant difference of mRNA expression levels of two IRAK1 isoforms and MECP2 was detected between two IRAK1/MECP2 haplotypes implying no existence of expression-regulatory SNPs. Because nonsynonymous SNPs do not exist on exonic regions of MECP2 in dbSNP list, two RA-associated nonsynonymous SNPs, ...