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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 G. Jaar^*,,||, Nancy Fink^*,,||, Neil Powe^*,,||, Michael J. Klag^*,,||, Michael W. Smith^,¶ and Josef Coresh^*,

^* Department of Epidemiology and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; Laboratory of Genomic Diversity and ^¶ Basic Research Program, SAIC-Frederick, National Cancer Institute–Frederick, Frederick, Maryland; School of Medicine, Wake Forest University, Winston-Salem, North Carolina; and ^|| Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

Address correspondence to: Dr. Josef Coresh, Department of Epidemiology, Biostatistics and Medicine Johns Hopkins University, 2024 E. Monument St., Suite 2-600, Baltimore, MD 21205. Phone: 410-955-0495; Fax: 410-955-0476; E-mail: coresh{at}jhu.edu

Received for publication September 21, 2005. Accepted for publication May 16, 2006.

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.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673