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

Abstract

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. Prospective cohort study. 764 white (n = 518) and black (n = 246) participants from 79 dialysis centers. 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. 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. 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. This study does not provide direct evidence for the mechanism of increased risk. Replication in independent cohorts is necessary. Genetic polymorphisms in the Jak-Stat signaling pathway are associated with an increased risk of new cardiovascular events in incident dialysis patients.