Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus

Taylor, KE and Remmers, EF and Lee, AT and Ortmann, WA and Plenge, RM and Tian, C and Chung, SA and Nititham, J and Hom, G and Kao, AH and Demirci, FY and Kamboh, MI and Petri, M and Manzi, S and Kastner, DL and Seldin, MF and Gregersen, PK and Behrens, TW and Criswell, LA (2008) Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genetics, 4 (5). ISSN 1553-7390

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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 = 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.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Taylor, KE Remmers, EF Lee, AT Ortmann, WA Plenge, RM Tian, C Chung, SA Nititham, J Hom, G Kao, AH Demirci, FY fyd1@pitt.edu FYD1 Kamboh, MI kamboh@pitt.edu KAMBOH Petri, M Manzi, S Kastner, DL Seldin, MF Gregersen, PK Behrens, TW Criswell, LA
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Abecasis, Gonçalo UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	1 May 2008
Date Type:	Publication
Journal or Publication Title:	PLoS Genetics
Volume:	4
Number:	5
DOI or Unique Handle:	10.1371/journal.pgen.1000084
Schools and Programs:	School of Public Health > Human Genetics
Refereed:	Yes
ISSN:	1553-7390
PubMed ID:	18516230
Date Deposited:	18 Jul 2012 20:31
Last Modified:	22 Jun 2021 11:55
URI:	http://d-scholarship.pitt.edu/id/eprint/12978

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