A role for CETP TaqIB polymorphism in determining susceptibility to atrial fibrillation: a nested case control study

BackgroundStudies investigating the genetic and environmental characteristics of atrial fibrillation (AF) may provide new insights in the complex development of AF. We aimed to investigate the association between several environmental factors and loci of candidate genes, which might be related to the presence of AF.MethodsA nested case-control study within the PREVEND cohort was conducted. Standard 12 lead electrocardiograms were recorded and AF was defined according to Minnesota codes. For every case, an age and gender matched control was selected from the same population (n = 194). In addition to logistic regression analyses, the multifactor-dimensionality reduction (MDR) method and interaction entropy graphs were used for the evaluation of gene-gene and gene-environment interactions. Polymorphisms in genes from the Renin-angiotensin, Bradykinin and CETP systems were included.ResultsSubjects with AF had a higher prevalence of electrocardiographic left ventricular hypertrophy, ischemic heart disease, hypertension, renal dysfunction, elevated levels of C-reactive protein (CRP) and increased urinary albumin excretion as compared to controls. The polymorphisms of the Renin-angiotensin system and Bradykinin gene did not show a significant association with AF (p > 0.05). The TaqIB polymorphism of the CETP gene was significantly associated with the presence of AF (p < 0.05). Using the MDR method, the best genotype-phenotype models included the combination of micro- or macroalbuminuria and CETP TaqIB polymorphism, CRP >3 mg/L and CETP TaqIB polymorphism, renal dysfunction and the CETP TaqIB polymorphism, and ischemic heart disease and CETP TaqIB polymorphism (1000 fold permutation testing, P < 0.05). Interaction entropy graph showed that the combination of albuminuria and CETP TaqIB polymorphism removed the most entropy.ConclusionCETP TaqIB polymorphism is significantly associated with the presence of AF in the context of micro- or macroalbuminuria, elevated C-reactive protein, renal dysfunction, and ischemic heart disease.

[1]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.

[2]  S. Lévy,et al.  Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. The College of French Cardiologists. , 1999, Circulation.

[3]  R. D. de Boer,et al.  Liver X receptors alpha and beta regulate renin expression in vivo. , 2005, The Journal of clinical investigation.

[4]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[5]  S. Nattel,et al.  Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing–Induced Congestive Heart Failure , 2001, Circulation.

[6]  A. Chakravarti,et al.  Linkage disequilibrium and haplotype diversity in the genes of the renin-angiotensin system: findings from the family blood pressure program. , 2003, Genome research.

[7]  Harlan M Krumholz,et al.  Reporting of model validation procedures in human studies of genetic interactions. , 2004, Nutrition.

[8]  J. Stengård,et al.  Genes, Environment, and Cardiovascular Disease , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[9]  R. Peters,et al.  Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The Prospective EPIC (European Prospective Investigation into Cancer and nutrition)–Norfolk Population Study , 2004, Circulation.

[10]  J A Kors,et al.  Methodology of the Modular ECG Analysis System MEANS , 1990, Methods of Information in Medicine.

[11]  A. Goette,et al.  Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation. , 2000, Journal of the American College of Cardiology.

[12]  J. Kors,et al.  Mild renal dysfunction is associated with electrocardiographic left ventricular hypertrophy. , 2005, American journal of hypertension.

[13]  B. Mittal,et al.  Association of CETP TaqI and APOE polymorphisms with type II diabetes mellitus in North Indians: a case control study , 2005, BMC endocrine disorders.

[14]  Marylyn D Ritchie,et al.  Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation , 2004, Circulation.

[15]  R. Brugada.  Is Atrial Fibrillation a Genetic Disease? , 2005, Journal of cardiovascular electrophysiology.

[16]  Jason H Moore,et al.  Computational analysis of gene-gene interactions using multifactor dimensionality reduction , 2004, Expert review of molecular diagnostics.

[17]  Jason H. Moore,et al.  Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions , 2003, Bioinform..

[18]  Jason H. Moore,et al.  Power of multifactor dimensionality reduction for detecting gene‐gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity , 2003, Genetic epidemiology.

[19]  Jianfeng Xu,et al.  Positive results in association studies are associated with departure from Hardy-Weinberg equilibrium: hint for genotyping error? , 2002, Human Genetics.

[20]  J. Goudevenos,et al.  Atrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stress. , 2003, Medical science monitor : international medical journal of experimental and clinical research.

[21]  B. Wolffenbuttel,et al.  The effect of cholesteryl ester transfer protein -629C->A promoter polymorphism on high-density lipoprotein cholesterol is dependent on serum triglycerides. , 2005, The Journal of clinical endocrinology and metabolism.

[22]  P A Wolf,et al.  Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. , 1998, The American journal of cardiology.

[23]  P J Talmud,et al.  Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment: Individual Patient Meta-Analysis of 13 677 Subjects , 2005, Circulation.

[24]  Todd Holden,et al.  A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. , 2006, Journal of theoretical biology.

[25]  M. P. van den Berg,et al.  C-reactive protein and microalbuminuria are associated with atrial fibrillation. , 2005, International journal of cardiology.

[26]  A. Goette,et al.  Expression and activity of ectopeptidases in fibrillating human atria. , 2001, Journal of molecular and cellular cardiology.

[27]  L. Råstam,et al.  Atrial fibrillation and its association with type 2 diabetes and hypertension in a Swedish community , 2004, Diabetes, obesity & metabolism.

[28]  Jonathan L Haines,et al.  Genetics, statistics and human disease: analytical retooling for complexity. , 2004, Trends in genetics : TIG.

[29]  Gil Atzmon,et al.  Unique lipoprotein phenotype and genotype associated with exceptional longevity. , 2003, JAMA.

[30]  Francesco Burzotta,et al.  The −174G/C Interleukin-6 Polymorphism Influences Postoperative Interleukin-6 Levels and Postoperative Atrial Fibrillation. Is Atrial Fibrillation an Inflammatory Complication? , 2003, Circulation.

[31]  Ivan Bratko,et al.  Microarray data mining with visual programming , 2005, Bioinform..

[32]  P. Barter,et al.  Antiinflammatory Properties of HDL , 2004 .

[33]  B. Paulweber,et al.  Cholesteryl ester transfer protein TaqIB polymorphism and its relation to parameters of the insulin resistance syndrome in an Austrian cohort. , 2004, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[34]  J. Gustafsson,et al.  Liver X receptors α and β regulate renin expression in vivo , 2005 .

[35]  A. Tall,et al.  Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. , 2000, The Journal of clinical investigation.

[36]  J. H. Moore,et al.  Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. , 2001, American journal of human genetics.