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

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

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Title: Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus
Author: Taylor, Kimberly E.; Remmers, Elaine F.; Lee, Annette T.; Ortmann, Ward A.; Tian, Chao; Chung, Sharon A.; Nititham, Joanne; Hom, Geoffrey; Kao, Amy H.; Demirci, F. Yesim; Kamboh, M. Ilyas; Petri, Michelle; Manzi, Susan; Kastner, Daniel L.; Seldin, Michael F.; Gregersen, Peter K.; Behrens, Timothy W.; Criswell, Lindsey A.; Plenge, Robert M.

Note: Order does not necessarily reflect citation order of authors.

Citation: Taylor, Kimberly E., Elaine F. Remmers, Annette T. Lee, Ward A. Ortmann, Robert M. Plenge, Chao Tian, Sharon A. Chung, et al. 2008. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genetics 4(5): e1000084.
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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 = 10216). This SNP was more strongly associated
with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p,10219), nephritis (MAF = 34.3%,
OR = 1.80, p,10211), and age at diagnosis,30 years (MAF = 33.8%, OR = 1.77, p,10213). An association with severe
nephritis was even more striking (MAF = 39.2%, OR = 2.35, p,1024 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.
Published Version: doi:10.1371/journal.pgen.1000084
Other Sources: http://www.ncbi.nlm.nih.gov/pubmed/18516230
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4875871
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