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

Abstract

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 (r2 = 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.

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese

“…The result suggests that more than one functional variant in this gene locus may confer disease risk to SLE in our population, which is different from findings from Caucasians. Taylor et al 11 showed that four significantly associated SNPs in this locus are all highly linked. In their study, rs7601754 showed marginal significance when controlling the effect of rs7574865 (Table 4 in Taylor et al 11 ).…”

“…Taylor et al 11 showed that four significantly associated SNPs in this locus are all highly linked. In their study, rs7601754 showed marginal significance when controlling the effect of rs7574865 (Table 4 in Taylor et al 11 ).…”

“…Taylor et al 11 have shown that rs7574865 was more strongly associated with SLE with double-stranded DNA antibody production, lupus nephritis and age at diagnosis. We have seen the same trend in our cohort for lupus nephritis, anti-ds-DNA antibody production and immunologic disorders.…”

“…15 STAT4 has been shown to be Association of SLE in Hong Kong Chinese W Yang et al involved in several autoimmune diseases, such as inflammatory bowel disease and type I diabetes mellitus 16 as well as Sjogren's disease 17 in addition to SLE and RA. Association of rs7574865 with SLE in multiple populations and with disease severity 5,[9][10][11] indicates that the SNP may be a functional variant itself, but this cannot be proved unless there is detailed functional characterization of the SNP or extensive in-depth sequencing in the region excluding the existence of a true functional variant in LD with rs7574865.…”

“…[8][9][10] SNP rs7574865 was found to be associated with lupus nephritis, ds-DNA antibody production and age of onset. 11,12 In the GWA study by Hom et al, 7 rs7574865 in STAT4 showed highly significant association with SLE risk, with a P-value only second to variants in the human leukocyte antigen locus. In addition to rs7574865, both Harley et al 8 and Hom et al 7 showed that rs7601754 was also significantly associated with SLE.…”