Association of single-nucleotide polymorphisms in JAK3, STAT4, and STAT6 with new cardiovascular events in incident dialysis patients.
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.


METHODS
Prospective cohort study.


METHODS
764 white (n = 518) and black (n = 246) participants from 79 dialysis centers.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Sperati
C John
CJ
Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. jsperati@jhmi.edu
Parekh
Rulan S
RS
Berthier-Schaad
Yvette
Y
Jaar
Bernard G
BG
Plantinga
Laura
L
Fink
Nancy
N
Powe
Neil R
NR
Smith
Michael W
MW
Coresh
Josef
J
Kao
W H Linda
WH
D000483:Alleles; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D006801:Humans; D015994:Incidence; D053616:Janus Kinase 3 / Q000235:genetics* / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000150:complications / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D006435:Renal Dialysis / Q000009:adverse effects* / Q000706:statistics & numerical data; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors; D014481:United States / Q000453:epidemiology
D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D004247:DNA; C507933:JAK3 protein, human; D053616:Janus Kinase 3