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Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.

ABSTRACT: OBJECTIVES:We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). BACKGROUND:Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. METHODS:The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. RESULTS:A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ?2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. CONCLUSIONS:The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

SUBMITTER: Assimes TL

PROVIDER: S-EPMC3084526 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.

Assimes Themistocles L TL Hólm Hilma H Kathiresan Sekar S Reilly Muredach P MP Thorleifsson Gudmar G Voight Benjamin F BF Erdmann Jeanette J Willenborg Christina C Vaidya Dhananjay D Xie Changchun C Patterson Chris C CC Morgan Thomas M TM Burnett Mary Susan MS Li Mingyao M Hlatky Mark A MA Knowles Joshua W JW Thompson John R JR Absher Devin D Iribarren Carlos C Go Alan A Fortmann Stephen P SP Sidney Stephen S Risch Neil N Tang Hua H Myers Richard M RM Berger Klaus K Stoll Monika M Shah Svati H SH Thorgeirsson Gudmundur G Andersen Karl K Havulinna Aki S AS Herrera J Enrique JE Faraday Nauder N Kim Yoonhee Y Kral Brian G BG Mathias Rasika A RA Ruczinski Ingo I Suktitipat Bhoom B Wilson Alexander F AF Yanek Lisa R LR Becker Lewis C LC Linsel-Nitschke Patrick P Lieb Wolfgang W König Inke R IR Hengstenberg Christian C Fischer Marcus M Stark Klaus K Reinhard Wibke W Winogradow Janina J Grassl Martina M Grosshennig Anika A Preuss Michael M Schreiber Stefan S Wichmann H-Erich HE Meisinger Christa C Yee Jean J Friedlander Yechiel Y Do Ron R Meigs James B JB Williams Gordon G Nathan David M DM MacRae Calum A CA Qu Liming L Wilensky Robert L RL Matthai William H WH Qasim Atif N AN Hakonarson Hakon H Pichard Augusto D AD Kent Kenneth M KM Satler Lowell L Lindsay Joseph M JM Waksman Ron R Knouff Christopher W CW Waterworth Dawn M DM Walker Max C MC Mooser Vincent E VE Marrugat Jaume J Lucas Gavin G Subirana Isaac I Sala Joan J Ramos Rafael R Martinelli Nicola N Olivieri Oliviero O Trabetti Elisabetta E Malerba Giovanni G Pignatti Pier Franco PF Guiducci Candace C Mirel Daniel D Parkin Melissa M Hirschhorn Joel N JN Asselta Rosanna R Duga Stefano S Musunuru Kiran K Daly Mark J MJ Purcell Shaun S Eifert Sandra S Braund Peter S PS Wright Benjamin J BJ Balmforth Anthony J AJ Ball Stephen G SG Ouwehand Willem H WH Deloukas Panos P Scholz Michael M Cambien Francois F Huge Andreas A Scheffold Thomas T Salomaa Veikko V Girelli Domenico D Granger Christopher B CB Peltonen Leena L McKeown Pascal P PP Altshuler David D Melander Olle O Devaney Joseph M JM Epstein Stephen E SE Rader Daniel J DJ Elosua Roberto R Engert James C JC Anand Sonia S SS Hall Alistair S AS Ziegler Andreas A O'Donnell Christopher J CJ Spertus John A JA Siscovick David D Schwartz Stephen M SM Becker Diane D Thorsteinsdottir Unnur U Stefansson Kari K Schunkert Heribert H Samani Nilesh J NJ Quertermous Thomas T

Journal of the American College of Cardiology 20101101 19

<h4>Objectives</h4>We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).<h4>Background</h4>Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.<h4>Methods</h4>The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association stu ...[more]

PMID: 20933357

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Project description:BackgroundCase-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival (34% one-year fatality following a coronary attack). A case in point is the KIF6 Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the KIF6 Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using KIF6 Trp719Arg as an example.ResultsTen replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among KIF6 Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between KIF6 genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD.In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the KIF6 719Arg variant, should also attenuate the KIF6 719Arg odds ratio in case-control studies.ConclusionsThese computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for KIF6 Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of KIF6 719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.

Dataset Information

Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.

Publications

Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.

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