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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-I 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 −16 ). 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.

Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus