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.
| Original language | English (US) |
|---|---|
| Article number | e1000084 |
| Journal | PLoS Genetics |
| Volume | 4 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2008 |
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ASJC Scopus subject areas
- Genetics
- Molecular Biology
- Ecology, Evolution, Behavior and Systematics
- Cancer Research
- Genetics(clinical)
Cite this
Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. / Taylor, Kimberly E.; Remmers, Elaine F.; Lee, Annette T.; Ortmann, Ward A.; Plenge, Robert M.; 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.
In: PLoS Genetics, Vol. 4, No. 5, e1000084, 05.2008.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus
AU - Taylor, Kimberly E.
AU - Remmers, Elaine F.
AU - Lee, Annette T.
AU - Ortmann, Ward A.
AU - Plenge, Robert M.
AU - Tian, Chao
AU - Chung, Sharon A.
AU - Nititham, Joanne
AU - Hom, Geoffrey
AU - Kao, Amy H.
AU - Demirci, F. Yesim
AU - Kamboh, M. Ilyas
AU - Petri, Michelle
AU - Manzi, Susan
AU - Kastner, Daniel L.
AU - Seldin, Michael F
AU - Gregersen, Peter K.
AU - Behrens, Timothy W.
AU - Criswell, Lindsey A.
PY - 2008/5
Y1 - 2008/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=44949149145&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44949149145&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1000084
DO - 10.1371/journal.pgen.1000084
M3 - Article
VL - 4
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 5
M1 - e1000084
ER -