RA and Lupus
More Clues to Genetic Roots of RA and SLE
Remmers EF, Plenge RM, Lee AT, et al. STAT4 and the risk of RA and systemic lupus erythematosus. N Engl J Med. 2007;357(10):977-986.
Background: RA 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 RA. We then performed fine mapping of the STAT1-STAT4 region in a total of 1,620 case patients with established RA and 2,635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1,529 patients with early RA and 881 controls, all from Sweden, and in a total of 1,039 case patients and 1,248 controls from three series of patients with systemic lupus erythematosus (SLE).
Results: A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both RA and SLE. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established RA, 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 versus those of controls, 1.32). The association was replicated in Swedish patients with recent-onset RA (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 versus 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 RA.
Conclusions: A haplotype of STAT4 is associated with increased risk for both RA and SLE, suggesting a shared pathway for these illnesses.
Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for RA—a genome-wide study. N Engl J Med. 2007;357(12):1199-1209.
Background: RA has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genome-wide association analysis to identify additional genetic loci associated with an increased risk of RA.
Methods: We genotyped 317,503 SNPs in a combined case-control study of 1,522 case subjects with RA and 1,850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American RA Consortium (NARAC) and the Swedish Epidemiological Investigation of RA (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (p<1×10-8) were genotyped in an independent set of case subjects with anti–CCP-positive RA (485 from NARAC and 512 from EIRA) and in control subjects (1,282 from NARAC and 495 from EIRA).