Association of genetic polymorphisms with risk of renal injury after coronary bypass graft surgery.
BACKGROUND
Post-cardiac surgery renal dysfunction is a common, serious, multifactorial disorder, with interpatient variability predicted poorly by preoperative clinical, procedural, and biological markers. Therefore, we tested the hypothesis that selected gene variants are associated with acute renal injury, reflected by a serum creatinine level increase after cardiac surgery.


METHODS
One thousand six hundred seventy-one patients undergoing aortocoronary surgery were studied. Clinical covariates were recorded. DNA was isolated from preoperative blood; mass spectrometry was used for genotype analysis. A model was developed relating clinical and genetic factors to postoperative acute renal injury.


RESULTS
A race effect was found; therefore, Caucasians and African Americans were analyzed separately. Overall, clinical factors alone account poorly for postoperative renal injury, although more so in African Americans than Caucasians. When 12 candidate polymorphisms were assessed, 2 alleles (interleukin 6 -572C and angiotensinogen 842C) showed a strong association with renal injury in Caucasians (P < 0.0001; >50% decrease in renal filtration when they present together). Using less stringent criteria for significance (0.01 > P > 0.001), 4 additional polymorphisms are identified (apolipoproteinE 448C [4], angiotensin receptor1 1166C, and endothelial nitric oxide synthase [eNOS] 894T in Caucasians; eNOS 894T and angiotensin-converting enzyme deletion and insertion in African Americans). Adding genetic to clinical factors resulted in the best model, with overall ability to explain renal injury increasing approximately 4-fold in Caucasians and doubling in African Americans (P < 0.0005).


CONCLUSIONS
In this study, we identify genetic polymorphisms that collectively provide 2- to 4-fold improvement over preoperative clinical factors alone in explaining post-cardiac surgery renal dysfunction. From a mechanistic perspective, most identified genetic variants are associated with increased renal inflammatory and/or vasoconstrictor responses.
Stafford-Smith
Mark
M
Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA. staff002@mc.duke.edu
Podgoreanu
Mihai
M
Swaminathan
Madhav
M
Phillips-Bute
Barbara
B
Mathew
Joseph P
JP
Hauser
Elizabeth H
EH
Winn
Michelle P
MP
Milano
Carmelo
C
Nielsen
Dahlia M
DM
Smith
Mike
M
Morris
Richard
R
Newman
Mark F
MF
Schwinn
Debra A
DA
D058186:Acute Kidney Injury / Q000097:blood / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics; D001741:Black or African American / Q000235:genetics; D000368:Aged; D000483:Alleles; D000809:Angiotensins / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000601:surgery; D001026:Coronary Artery Bypass; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D009657:North Carolina / Q000453:epidemiology; D011110:Polymorphism, Genetic; D011183:Postoperative Complications / Q000453:epidemiology*; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012306:Risk; D044465:White People / Q000235:genetics
D000809:Angiotensins; D001057:Apolipoproteins E; D016207:Cytokines; D044140:Receptor, Angiotensin, Type 1; D003404:Creatinine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III