STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus

Abstract

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=2.81x10(-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=1.87x10(-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.

Figure 1. Linkage Peak for Rheumatoid Arthritis on Chromosome 2q and Initial Screen of Candidate Genes for Disease-Associated SNPs in the North American Rheumatoid Arthritis Consortium Case-Control Series

Panel A shows previously determined linkage data for SNPs on chromosome 2. The black bar represents the 2-LOD support interval, containing candidate genes selected for analysis. Panel B shows the significance of the association data (presented as 1 divided by the P value) for 68 tag SNPs (solid diamonds) and 14 imputed SNPs (open diamonds) in 525 case patients and 1165 controls. The black bars represent the 13 candidate genes evaluated. The candidate-gene SNPs are shown in their physical order across the region, evenly spaced rather than according to their chromosomal position. The imputed SNP in STAT4 found to be associated with rheumatoid arthritis was confirmed by direct genotyping.

Figure 2. Linkage Disequilibrium Surrounding the STAT4 SNP Found to be Associated with Rheumatoid Arthritis

Linkage disequilibrium between pairs of SNPs across the STAT1-STAT4 region is shown within the HapMap CEU population data (from persons of northern and western European ancestry). Blocks connecting pairs of SNPs are shaded according to the strength of the linkage disequilibrium between the SNPs, from 0.0 (white) to 1.0 (bright red), as measured by the disequilibrium coefficient D′. The lavender blocks indicate pairs of markers for which D′ is equal to 1.0 but the LOD score is less than 2.0. The imputed STAT4 SNP, rs7574865, associated with rheumatoid arthritis is shown within the rectangle outlined in black. This SNP and three others (asterisks) were associated with disease susceptibility in both North American rheumatoid arthritis case-control series. The locations of the STAT1 and STAT4 genes are indicated by the blue arrows (pointing in the direction of transcription). The region selected for fine mapping is located between the black arrowheads.

Figure 3. Associations of STAT1-STAT4 SNPs with Disease Susceptibility in Two North American Rheumatoid Arthritis Case-Control Series

The significance of the associations (presented as 1 divided by the P value) is shown for 63 SNPs in the STAT1-STAT4 region, shown according to chromosomal position (from the Human March 2006 assembly of the University of California at Santa Cruz Genome Browser [hg18], National Center for Biotechnology Information build 36). The five SNPs with P values of less than 1×10^-5 are labeled. The locations of the STAT1 and STAT4 genes are indicated by the blue arrows (pointing in the direction of transcription). Vertical black bars on the arrows represent the locations of exons. The association data are from the 1620 case patients and the 2635 controls in the North American Rheumatoid Arthritis Consortium series and the rheumatoid arthritis replication series.