Journal article
Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus
PLoS genetics, v 4(5), e1000084
01 May 2008
PMID: 18516230
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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 (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.
Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one’s risk for lupus but do not fully determine the outcome. It is thought that the interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between subtypes of lupus and specific genes, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that the
STAT4
gene, very recently identified as a lupus risk gene, predisposes specifically to severe manifestations of lupus, including kidney disease.
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Details
- Title
- Specificity of the STAT4 Genetic Association for Severe Disease Manifestations of Systemic Lupus Erythematosus
- Creators
- Kimberly E. Taylor - University of California, San FranciscoElaine F. Remmers - National Institutes of HealthAnnette T. Lee - Northwell HealthWard A. Ortmann - GenentechRobert M. Plenge - Broad InstituteChao Tian - University of California, DavisSharon A. Chung - University of California, San FranciscoJoanne Nititham - University of California, San FranciscoGeoffrey Hom - GenentechAmy H. Kao - University of PittsburghF. Yesim Demirci - University of PittsburghM. Ilyas Kamboh - University of PittsburghMichelle Petri - Johns Hopkins MedicineSusan Manzi - University of PittsburghDaniel L. Kastner - National Institutes of HealthMichael F. Seldin - University of California, DavisPeter K. Gregersen - Northwell HealthTimothy W. Behrens - GenentechLindsey A. Criswell - University of California, San Francisco
- Publication Details
- PLoS genetics, v 4(5), e1000084
- Publisher
- Public Library of Science
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- General Internal Medicine
- Web of Science ID
- WOS:000256869100005
- Scopus ID
- 2-s2.0-44949149145
- Other Identifier
- 991021933909504721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Genetics & Heredity