Haplotype of signal transducer and activator of transcription 3 gene predicts cardiovascular disease in dialysis patients

Lin Zhang, W. H Linda Kao, Yvette Berthier-Schaad, Yongmei Liu, Laura Plantinga, Bernard Jaar, Nancy Fink, Neil Powe, Michael John Klag, Michael W. Smith, Josef Coresh

Research output: Contribution to journalArticle

Abstract

Signal transducer and activator of transcription 3 (STAT3) protein has been linked to cardiovascular disease (CVD) through multiple pathways in experimental and animal studies. STAT3 gene variation was examined as a predictor of incident CVD in a subcohort of 529 incident white dialysis patients. Fifteen single-nucleotide polymorphisms of the STAT3 gene were genotyped. Haplotypes were estimated using software PHASE 2.1, and associations with first CVD event were tested using Cox proportional hazards analysis. Adjusted global tests of haplotype association with incident CVD and inflammation markers were performed using permutated P value in R-package Haplo.score. An a priori specified additive genetic model was assumed for haplotype analysis. Both genotypes (four single nucleotide polymorphisms with P <0.001) and haplotypes (P = 0.002 overall) were associated with incident CVD. Two major haplotype blocks, blocks A and C, were identified. Compared with common haplotype A-1, A-3 was associated with a hazard ratio (HR) of 0.70 (95% confidence interval [CI] 0.51 to 0.94) for CVD events after adjustment for covariates including C-reactive protein (CRP) and interleukin 6. Compared with common haplotype C-1, C-3 was associated with an adjusted HR of 2.12 (95% CI 1.25 to 3.57) for CVD events. Associations were independent of inflammation markers, but IL-6 levels were 14% lower (geometric mean ratio 0.86; 95% CI 0.77 to 0.96) per copy of haplotype A-3 compared with haplotype A-1 in block A after adjustment for CRP and other risk factors (P = 0.008). Variation in the STAT3 gene is associated with the risk for CVD among white dialysis patients independent of serum IL-6 and CRP levels.

Original languageEnglish (US)
Pages (from-to)2285-2292
Number of pages8
JournalJournal of the American Society of Nephrology
Volume17
Issue number8
DOIs
StatePublished - Aug 2006

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STAT3 Transcription Factor
Haplotypes
Dialysis
Cardiovascular Diseases
Genes
C-Reactive Protein
Interleukin-6
Confidence Intervals
Single Nucleotide Polymorphism
STAT Transcription Factors
Inflammation
Genetic Models
Software
Genotype

ASJC Scopus subject areas

  • Nephrology

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Haplotype of signal transducer and activator of transcription 3 gene predicts cardiovascular disease in dialysis patients. / Zhang, Lin; Kao, W. H Linda; Berthier-Schaad, Yvette; Liu, Yongmei; Plantinga, Laura; Jaar, Bernard; Fink, Nancy; Powe, Neil; Klag, Michael John; Smith, Michael W.; Coresh, Josef.

In: Journal of the American Society of Nephrology, Vol. 17, No. 8, 08.2006, p. 2285-2292.

Research output: Contribution to journalArticle

Zhang, Lin ; Kao, W. H Linda ; Berthier-Schaad, Yvette ; Liu, Yongmei ; Plantinga, Laura ; Jaar, Bernard ; Fink, Nancy ; Powe, Neil ; Klag, Michael John ; Smith, Michael W. ; Coresh, Josef. / Haplotype of signal transducer and activator of transcription 3 gene predicts cardiovascular disease in dialysis patients. In: Journal of the American Society of Nephrology. 2006 ; Vol. 17, No. 8. pp. 2285-2292.
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abstract = "Signal transducer and activator of transcription 3 (STAT3) protein has been linked to cardiovascular disease (CVD) through multiple pathways in experimental and animal studies. STAT3 gene variation was examined as a predictor of incident CVD in a subcohort of 529 incident white dialysis patients. Fifteen single-nucleotide polymorphisms of the STAT3 gene were genotyped. Haplotypes were estimated using software PHASE 2.1, and associations with first CVD event were tested using Cox proportional hazards analysis. Adjusted global tests of haplotype association with incident CVD and inflammation markers were performed using permutated P value in R-package Haplo.score. An a priori specified additive genetic model was assumed for haplotype analysis. Both genotypes (four single nucleotide polymorphisms with P <0.001) and haplotypes (P = 0.002 overall) were associated with incident CVD. Two major haplotype blocks, blocks A and C, were identified. Compared with common haplotype A-1, A-3 was associated with a hazard ratio (HR) of 0.70 (95{\%} confidence interval [CI] 0.51 to 0.94) for CVD events after adjustment for covariates including C-reactive protein (CRP) and interleukin 6. Compared with common haplotype C-1, C-3 was associated with an adjusted HR of 2.12 (95{\%} CI 1.25 to 3.57) for CVD events. Associations were independent of inflammation markers, but IL-6 levels were 14{\%} lower (geometric mean ratio 0.86; 95{\%} CI 0.77 to 0.96) per copy of haplotype A-3 compared with haplotype A-1 in block A after adjustment for CRP and other risk factors (P = 0.008). Variation in the STAT3 gene is associated with the risk for CVD among white dialysis patients independent of serum IL-6 and CRP levels.",
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AU - Jaar, Bernard

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