Association of Single-Nucleotide Polymorphisms in JAK3, STAT4, and STAT6 With New Cardiovascular Events in Incident Dialysis Patients

Abstract

Background: Increasing evidence supports a role for cell-mediated immunity in the pathogenesis of cardiovascular disease. Single-nucleotide polymorphisms (SNPs) in JAK3, STAT4, and STAT6 of the Janus kinase-signal transducer and activator of transcription (Jak-Stat) signal transduction pathway were examined for association with time to new cardiovascular events in incident dialysis patients from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study. Study Design: Prospective cohort study. Setting & Participants: 764 white (n = 518) and black (n = 246) participants from 79 dialysis centers. Predictor: SNPs in JAK3, STAT4, and STAT6 selected using a pairwise approach to identify a maximally informative set of tag SNPs for populations of European and African descent. Outcomes & Measurements: Cox proportional hazards models were used to estimate unadjusted and multivariable-adjusted hazard ratios (HRs) for incident cardiovascular disease events after dialysis therapy initiation associated with each race-specific SNP. Results: 2 European tag SNPs (rs3212780 and rs3213409) in JAK3 were associated with new cardiovascular disease events in white patients with unadjusted HRs of 1.92 (P < 0.001) and 1.82 (P = 0.07), respectively. One dual-tag SNP (rs3212752) in JAK3 was associated with new cardiovascular events in white patients with an unadjusted HR of 2.09 (P < 0.001) and in black patients with an HR of 2.07 (P = 0.007). SNP rs3213409 codes for a valine to isoleucine change at amino acid 722, a potentially functional mutation. SNPs in STAT4 and STAT6 were not associated with cardiovascular events after the initiation of dialysis therapy. Limitations: This study does not provide direct evidence for the mechanism of increased risk. Replication in independent cohorts is necessary. Conclusions: Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients. © 2009 National Kidney Foundation, Inc.