Objective

Recent studies have identified a number of novel rheumatoid arthritis (RA) loci in Caucasian populations. In this study, we sought to determine whether the genetic variants at 4q27, 6q23, CCL21, TRAF1/C5, and CD40 identified in Caucasians are also associated with RA in a Korean case-control collection. We also comprehensively evaluated the genetic variation within PTPN22, a well established autoimmune disease-associated gene.

Methods

We designed a Sequenom iPlex experiment to thoroughly evaluate the PTPN22 linkage disequilibrium region using tag SNPs and disease-associated SNPs at 5 other previously reported Caucasian RA-associated loci in 1123 RA Korean RA patients and 1008 ethnically matched controls. We also re-sequenced the PTPN22 gene to look for novel coding variants that might be contributing to disease in this population.

Results

None of the Caucasian RA susceptibility loci contributed significantly to disease in Koreans. Tag SNPs covering the PTPN22 linkage disequilibrium block, while polymorphic, did not reveal any disease association and re-sequencing did not identify any new common coding region variants in this population. The 6q23 and 4q27 SNPs assayed were non-polymorphic in this population and the TRAF1/C5, CD40, and CCL21 SNPs did not show any evidence for association.

Conclusions

Caucasian and Korean rheumatoid arthritis have different genetic risk factors. While patients of different ethnic groups share the HLA region as a major genetic risk locus, most other genes shown to be significantly associated with disease in Caucasians appear not to play a role in Korean RA.

Objective

The single nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported as a sexually dimorphic marker for rheumatoid arthritis susceptibility in a British population. We sought to replicate this finding and better characterize susceptibility alleles in the region in a North American population.

Methods

DNA from two North American collections of RA patients and controls (1605 cases and 2640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately contrasting male cases versus male controls and female cases versus female controls. Principal components analysis (EIGENSTRAT) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples (772 cases and 1213 controls) with whole genome SNP data.

Results

We failed to replicate association of the 7q region with rheumatoid arthritis. Initially, rs11761231 showed evidence for association with RA in the NARAC collection (p=0.0076) and rs11765576 showed association with RA in both the NARAC (p = 0.019) and RA replication (p = 0.0013) collections. These markers also exhibited sexual differentiation. However, in the whole genome subset, neither SNP showed significant association with RA after correction for population stratification.

Conclusion

While two SNPs on chromosome 7q appeared to be associated with RA in a North American cohort, the significance of this finding did not withstand correction for population substructure. Our results emphasize the need to carefully account for population structure to avoid false positive disease associations.

BACKGROUND

Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.

METHODS

We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus.

RESULTS

A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P = 2.81×10-7; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P = 0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P = 1.87×10-9; odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis.

CONCLUSIONS

A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.

A recent study in the North American White population has documented the association of a common STAT4 haplotype (tagged by rs7574865) with risk for rheumatoid arthritis (RA) and systemic lupus erythematosus. To replicate this finding in the Korean population, we performed a case-control association study. We genotyped 67 single nucleotide polymorphisms (SNPs) within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls. The most significant four risk SNPs (rs11889341, rs7574865, rs8179673, and rs10181656 located within the third intron of STAT4) among 67 SNPs are identical with those in the North American study. All four SNPs have modest risk for RA susceptibility (odds ratio 1.21–1.27). A common haplotype defined by these markers (TTCG) carries significant risk for RA in Koreans [34 percent versus 28 percent, P = 0.0027, OR (95 percent CI) = 1.33 (1.10–1.60)]. By logistic regression analysis, this haplotype is an independent risk factor in addition to the classical shared epitope alleles at the HLA-DRB1 locus. There were no significant associations with age of disease onset, radiographic progression, or serologic status using either allelic or haplotypic analysis. Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.