Cholesterol ester transfer protein, interleukin-8, peroxisome proliferator activator receptor alpha, and Toll-like receptor 4 genetic variations and risk of incident nonfatal myocardial infarction and ischemic stroke.
Variations in candidate genes participating in oxidative stress, inflammation, and their interactions are potentially associated with diseases of atherosclerotic origin. We investigated independent and joint associations of variations in cholesterol ester transfer protein (CETP), interleukin-8 (IL8), peroxisome proliferator activator receptor-alpha (PPARA), and Toll-like receptor 4 (TLR4) genes with incident nonfatal myocardial infarction (MI) or ischemic stroke. In a population-based case-control study, patients (848 with MI and 368 with ischemic stroke) and controls (2,682) were recruited from postmenopausal women and hypertensive men/women who were members of Group Health in western Washington State. Common tag single-nucleotide polymorphisms (SNPs; n=34) representing gene-wide variations were selected from gene sequencing data using pairwise linkage disequilibrium. Haplotypes were inferred using a modified expectation maximization algorithm. Multivariate logistic regression evaluated individual haplotype and SNP-disease associations in log-additive models. Global haplotype tests assessed overall gene-disease associations. Logic regression was used to evaluate gene-gene interactions. False discovery rates and permutation tests were used for multiple testing adjustment in evaluating independent associations and interactions, respectively. Overall, gene-wide variations in PPARA and TLR4 genes were associated with MI. The minor allele of the PPARA SNP, rs4253623, was associated with a higher risk of MI (odds ratio 1.25, 95% confidence interval 1.08 to 1.46), whereas the minor allele of the TLR4 SNP, rs1927911, was associated with a lower risk of MI (odds ratio 0.88, 95% confidence interval 0.77 to 0.99). No within-gene or gene-gene interaction was associated with MI or ischemic stroke risk. In conclusion, potential SNP-disease associations identified in the present study are novel and need further investigation.
Enquobahrie
Daniel A
DA
Cardiovascular Health Research Unit, University of Washington, Seattle, Washington, USA. denquoba@hsph.harvard.edu
Smith
Nicholas L
NL
Bis
Joshua C
JC
Carty
Cara L
CL
Rice
Kenneth M
KM
Lumley
Thomas
T
Hindorff
Lucia A
LA
Lemaitre
Rozenn N
RN
Williams
Michelle A
MA
Siscovick
David S
DS
Heckbert
Susan R
SR
Psaty
Bruce M
BM
D000328:Adult; D000368:Aged; D000483:Alleles; D002545:Brain Ischemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics*; D016001:Confidence Intervals; D004247:DNA / Q000235:genetics; D003704:Dementia; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015994:Incidence; D016209:Interleukin-8 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D047493:PPAR alpha / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000235:genetics*; D014861:Washington / Q000453:epidemiology
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D016209:Interleukin-8; D047493:PPAR alpha; D051197:Toll-Like Receptor 4; D004247:DNA