IDENTIFICATION OF GENES ASSOCIATED WITH QT INTERVAL USING THE 50K CARDIO-METABOLIC SNP CHIP: RESULTS FROM THE WHITEHALL II STUDY

Abstracts / Atherosclerosis 207 (2009) e1–e13

IDENTIFICATION OF GENES ASSOCIATED WITH QT INTERVAL USING THE 50K CARDIO-METABOLIC SNP CHIP: RESULTS FROM THE WHITEHALL II STUDY S. Shah 1,∗ , F. Drenos 2 , T. Shah 3 , J. Palmen 2 , C. Vezzili 4 , R. Sofat 3 , M. Kumari 5 , M. Kivamaki 5 , J. Pallas 6 , P. MacFarlane 7 , J. Whittaker 4 , P.J. Talmud 2 , S.E. Humphries 2 , A.D. Hingorani 3,5 1

UCL Genetics Institute, Department of Genetics, Environment and Evolution, Gower St, London, UK 2 Division of Cardiovascular Genetics, Department of Medicine, Royal Free and University College Medical School, 5 University St, London, UK 3 Centre for Clinical Pharmacology, British Heart Foundation Laboratories at UCL, London, UK 4 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK 5 Department of Epidemiology and Public Health, UCL, London, UK 6 WIBR, UCL London, UK 7 Division of Cardiovascular & Medical Sciences, Gardiner Institute, Western Infirmary, Glasgow, UK Background: The QT interval on an electrocardiogram is a measure of the total time from ventricular depolarization to repolarization. QT interval, a heritable quantitative trait, and its prolongation by drugs, cardiac disease and electrolyte abnormalities are associated with the risk of developing ventricular arrhythmias and sudden cardiac death. Methods and aims: Using a dense gene-centric SNP array (50,000 SNPs in 2100 genes implicated across a range of cardiovascular, metabolic and inflammatory traits) we analysed data from 5059 Caucasian individuals from a large prospective observational study of middle aged civil servants (Whitehall II) in which ECG QT interval was available from digitised ECG data. Results: We observed multiple associations at P < 1 × 10−4 of SNPs in NOS1AP, KCNH2 and PLN. NOS1AP codes for an adaptor protein known to be involved in myocardial repolarisation. KCNH2 codes for a potassium ion channel protein and mutations in the gene alter the activity of the channel leading to the abnormal heart rhythm characteristic of short QT syndrome. PLN encodes cardiac phosphlamban which has been linked to dilated cardiomyopathy and heart failure in mouse models. Additional novel loci identified will require replication in separate population studies and further analysis will be done to refine the genetic associations to identify independent signals of association. Conclusions: Common variants in the genes NOS1AP, KCNH2 and PLN influence QT interval in men and women, confirming results from recent whole genome analyses. doi:10.1016/j.atherosclerosis.2009.09.058 CONSIDERATION OF ETHNICITY IN CORONARY RISK PREDICTION USING CRP T. Shah 1,∗ , P. Newcombe 2 , J. Addo 2 , J.P. Casas 2 , L. Smeeth 2 , J. Whittaker 2 , A.D. Hingorani 1

1 2

Departments of Medicine and Epidemiology, UCL, UK LSHTM, UK

Rationale: CRP cut-points for the evaluation of CHD risk are mainly based on studies in Europeans. We evaluated CRP concentration in populations of differing geographical and ancestral background to consider the implications for risk prediction in non-European populations. Methods: We conducted a systematic review of population-based studies examining CRP in any ethnic group. CRP values in populations of the same ancestral background were pooled to obtain

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summary estimates and compared. Further analyses were performed to examine whether differences in CRP by ethnic group were accounted for by systematic differences in assay, study design or age. Results: 66 studies (N = 162530) examining European, AfricanAmerican, Hispanic, South Asian and East Asian populations were included. An unadjusted meta-regression of geometric mean CRP on ethnicity inferred 2.12 mg/L (95%CI: 1.84–2.82) in African-Americans (N = 11307), 2.16 mg/L (95%CI: 1.88–2.49) in Hispanics (N = 5313), 2.11 mg/L (95%CI: 1.78–2.49) in South Asians (N = 1109), 1.78 mg/L (95%CI: 1.54–2.05) in Europeans (N = 80145) and 0.89 mg/L (95%CI: 0.76–1.04) in East Asians (N = 2501). No systematic differences were found by study design or assay type. In age-adjusted analyses, differences in CRP were attenuated but still present across ethnic groups. Conclusion: The current work shows substantial differences in CRP concentration between groups of differing ancestry are large enough to affect estimation of risk. More work is needed to incorporate an individual’s ethnic background into CRP cut-points if it is to be used as a tool for coronary risk prediction. doi:10.1016/j.atherosclerosis.2009.09.059 THE KIF6 719ARG ALLELE IS ASSOCIATED WITH INCREASED RISK OF CORONARY HEART DISEASE AMONG MALES IN THE WELCOME TRUST CASE CONTROL CONSORTIUM STUDY OF CORONARY HEART DISEASE D. Shiffman 1,∗ , C.M. Rowland 1 , J. Thompson 2 , A.S. Hall 3 , J.J. Devlin 1 , N.J. Samani 2 1

Celera, Alameda, CA 94502, USA Department of Cardiovascular Sciences, University of Leicester, Leicester, UK 3 Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, LS1 3EX, UK 2

Carriers of the KIF6 719Arg allele, compared with noncarriers, have a higher risk of coronary heart disease (CHD) in several prospective studies and in the placebo groups of two randomized trials of pravastatin. In these trials, pravastatin treatment ameliorated the risk associated with 719Arg allele. In the Welcome Trust Case-Control Consortium (WTCCC) CHD study, although no association was observed between the 719Arg allele and CHD, a significant association between the 719Arg allele and CHD was observed in a sex-differentiated test. In order to investigate this sexdifferentiated association, we analyzed the association between the KIF6 polymorphism and CHD by comparing carriers of the 719Arg allele with noncarriers separately among males and females of the WTCCC CHD study. Among females, the 719Arg allele was not associated with increased risk of CHD (OR = 0.91, 95% CI: 0.72–1.14). Among males, the 719Arg allele was associated with increased risk of CHD (OR = 1.18, 95% CI: 1.02–1.36). We also estimated the risk that would be expected among males for 719Arg carriers, compared with noncarriers, if the cases had been drawn from a population that was not under statin therapy. Thus, if 20% of the population from which the WTCCC cases were drawn was under statin therapy prior to their CHD event, the estimated risk of CHD among untreated cases for 719Arg carriers compared with noncarriers, would have been modestly higher (OR = 1.23, 95% CI: 1.02–1.42). Thus, the KIF6 719Arg allele is associated with increased risk of CHD among males of the WTCCC CHD but not among females. doi:10.1016/j.atherosclerosis.2009.09.060