Original Article: Genetics Independent predictive roles of eotaxin Ala23Thr, paraoxonase 2 Ser311Cys and b 3 -adrenergic receptor Trp64Arg polymorphisms on cardiac disease in Type 2 Diabetes—an 8-year prospective cohort analysis of 1297 patients Y. Wang, A. O. Y. Luk, R. C. W. Ma, W. Y. So, C. H. T. Tam, M. C. Y. Ng, X. Yang, L. Baum, V. Lam, P. C. Y. Tong*† and J. C. N. Chan*† Department of Medicine & Therapeutics, *Li Ka Shing Institute of Health Sciences and †Hong Kong Institute of Diabetes and Obesity, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China Accepted 23 January 2010 Abstract Aims To examine the independent and joint effects of multiple genetic variants on a cardiac end-point in an 8-year prospective study of a Chinese diabetic cohort. Methods Seventy-seven single nucleotide polymorphisms (SNPs) of 53 candidate genes for inflammation, thrombosis, vascular tone regulation and lipid metabolism were genotyped in 1297 Chinese patients with no prior history of coronary heart disease (CHD) or heart failure at baseline. Cardiac end-point was defined by the occurrence of CHD and ⁄ or heart failure. Results In Cox regression model, after adjustment for baseline confounding variables including age, sex, smoking status, duration of diabetes, glycaemic control, lipid levels, waist circumference, blood pressure, albuminuria and estimated glomerular filtration rate, genetic variants, including Ala ⁄ Ala of SCYA11 (eotaxin) Ala23Thr, Cys ⁄ Cys or Cys ⁄ Ser of PON2 (paraoxonase 2) Ser311Cys and Arg ⁄ Arg of ADRB3 (b 3 -adrenergic receptor) Trp64Arg, were independently associated with incident cardiac end-point, with respective hazard ratios (95% confidence interval) of 1.70 (1.10–2.61, P = 0.037), 1.42 (1.08–1.88, P = 0.013) and 3.84 (1.18–12.50, P = 0.025). Analysis of the joint effect of the risk alleles showed significant increased risk of the cardiac end-point with increasing number of risk alleles (P < 0.001). The adjusted risk for the cardiac end- point was 4.11 (P = 0.002) for patients carrying four risk alleles compared with those carrying one or no risk allele. Conclusions The independent risk conferred by genetic variants encoding pathways such as inflammation and lipid metabolism, not adequately reflected by conventional biomarkers, may identify high-risk individuals for intensified control of modifiable risk factors. Diabet. Med. 27, 376–383 (2010) Keywords coronary heart disease, genetic polymorphism, heart failure, Type 2 diabetes Abbreviations ACE, angiotensin-converting enzyme; ACR, albumin:creatinine ratio; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; eGFR, estimated glomerular filtration rate; HbA 1c , glycated haemoglobin; HDL, high-density lipoprotein; HR, hazard ratio; HWE, Hardy–Weinberg equilibrium; IQR, inter-quartile range; LDL, low-density lipoprotein; MAF, minor allele frequency; PAD, peripheral arterial disease; SNP, single nucleotide polymorphism Introduction Coronary heart disease (CHD) and heart failure are major causes of morbidity and mortality in Type 2 diabetes and are closely associated with hypertension, dyslipidaemia, obesity and renal Correspondence to: Professor Juliana C. N. Chan, Department of Medicine & Therapeutics, The Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. E-mail: jchan@cuhk.edu.hk DIABETICMedicine DOI: 10.1111/j.1464-5491.2010.02980.x ª 2010 The Authors. 376 Journal compilation ª 2010 Diabetes UK. Diabetic Medicine, 27, 376–383