Journal
PLOS GENETICS
Volume 4, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1000084
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Funding
- Intramural NIH HHS Funding Source: Medline
- NCRR NIH HHS [M01 RR000052, 5-M01-RR-00079, MOI-RR 00052, M01 RR000079] Funding Source: Medline
- NHLBI NIH HHS [R01 HL054900, HL74165, R01 HL074165, HL88648, R01 HL088648, HL54900] Funding Source: Medline
- NIAID NIH HHS [N01 AI95386, N01AI95386] Funding Source: Medline
- NIAMS NIH HHS [AR 43727, R01 AR043727, K24 AR02175, K23 AR051044, 2R01 AR046588 05A1, R01 AR050267, R01 AR052300, AR050267, R01 AR046588, R01 AR-44804, K23 AR51044-01, K24 AR002175] Funding Source: Medline
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Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-1 errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r(2) = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10 216). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p < 10(-19)), nephritis (MAF = 34.3%, OR = 1.80, p < 10(-11)), and age at diagnosis <30 years (MAF = 33.8%, OR = 1.77, p < 10(-13)). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p < 10(-4) in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.
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