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

• Published in: The American journal of cardiology 2008-06, Vol.101 (12), p.1683-1688
• Main Authors: Enquobahrie, Daniel A., MD, PhD, Smith, Nicholas L., MPH, PhD, Bis, Joshua C., MS, PhD, Carty, Cara L., MS, Rice, Kenneth M., PhD, Lumley, Thomas, PhD, Hindorff, Lucia A., MPH, PhD, Lemaitre, Rozenn N., MPH, PhD, Williams, Michelle A., DSc, Siscovick, David S., MD, MPH, Heckbert, Susan R., MD, PhD, Psaty, Bruce M., MD, PhD
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alleles; Biological and medical sciences; Biological variation; Brain Ischemia - blood; Brain Ischemia - epidemiology; Brain Ischemia - genetics; Cardiology. Vascular system; Cardiovascular; Cholesterol; Cholesterol Ester Transfer Proteins - blood; Cholesterol Ester Transfer Proteins - genetics; Confidence Intervals; Coronary heart disease; Cytokines; Dementia; DNA - genetics; Female; Follow-Up Studies; General aspects. Genetic counseling; Genes; Genetic Predisposition to Disease; Genetic Variation; Genetics; Haplotypes; Heart; Heart attacks; Humans; Incidence; Interleukin-8 - genetics; Male; Medical genetics; Medical sciences; Middle Aged; Myocardial Infarction - blood; Myocardial Infarction - epidemiology; Myocardial Infarction - genetics; Myocarditis. Cardiomyopathies; Neurology; Odds Ratio; Polymorphism, Single Nucleotide; PPAR alpha - blood; PPAR alpha - genetics; Prognosis; Retrospective Studies; Risk Factors; Stroke; Survival Rate; Toll-Like Receptor 4 - blood; Toll-Like Receptor 4 - genetics; Vascular diseases and vascular malformations of the nervous system; Washington - epidemiology
• ISSN: 0002-9149; 1879-1913
• DOI: 10.1016/j.amjcard.2008.02.052

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-α ( 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.