CORRESPONDENCE: RESEARCH CORRESPONDENCE
Kinesin Family Member 6 Variant Trp719Arg Does Not Associate With Angiographically Defined Coronary Artery Disease in the Ottawa Heart Genomics Study
Alexandre F.R. Stewart, PhD*,
Sonny Dandona, MD,
Li Chen, MSc,
Olivia Assogba, BSc,
Melanie Belanger, BSc,
Gwen Ewart, RN,
Rosemary LaRose, RN,
Heather Doelle, RN,
Kathryn Williams, MSc,
George A. Wells, PhD,
Ruth McPherson, MD, PhD and
Robert Roberts, MD
* University of Ottawa Heart Institute, 40 Ruskin Street, H3100, Ottawa, Ontario K1Y 4W7, Canada (Email: astewart{at}ottawaheart.ca).
To the Editor:
To date, the only common genetic variant to consistently associate with risk of coronary artery disease (CAD) or myocardial infarction (MI) is the 9p21.3 variant (1,2). Several recent reports identified a SNP (rs20455) that alters an amino acid in the KIF6 protein (Trp719Arg) and associates with acute coronary events and the response to statin therapy (3–5). However, recent genome-wide association studies for CAD (1) or MI (71% MI in the WTCCC [Wellcome Trust Case Control Consortium] study and 100% MI in the GMIF [German Myocardial Infarction in Families] study) (2) did not report this association. Since the rs20455 SNP is present on the Affymetrix (Santa Clara, California) 500K and the 6.0 single nucleotide polymorphism (SNP) microarrays, we used data from the ongoing OHGS (Ottawa Heart Genomics Study) and the WTCCC study to test whether rs20455 associates with CAD.
Written informed consent was obtained from all study participants according to a protocol approved by the Research Ethics Board of the University of Ottawa Heart Institute. A sample size of 1,500 cases and 1,500 controls was estimated to detect alleles associated with CAD in an additive model based on an odds ratio of  1.3, a minor allele frequency 10%, with a level of significance of 0.001 and a power of 90%. Cases with onset before the age of 55 years in males and 65 years in females were eligible. Cases were recruited through the coronary catheterization laboratory and the lipid clinic of the University of Ottawa Heart Institute. Subjects with diabetes mellitus and overt hyperlipidemia were excluded. Asymptomatic elderly persons without cardiovascular disease history were selected as controls (65 years of age for males, 70 years of age for females) and recruited by an advertising campaign in the Ottawa community.
The rs20455 SNP was genotyped for 1,606 cases and 1,472 controls using the Affymetrix 500K or 6.0 SNP arrays. In a subset of samples, genomic deoxyribonucleic acid was amplified by polymerase chain reaction (PCR [primers: rs20455 forward 5'-ACA CTG TGA AAC TCC TTC TGG-3' and rs20455 reverse 5'-GCC ACT GTC TTG AGT ATC TAC G-3']) and genotyped by high-resolution melting curve analysis according to the Roche LightCycler 480 protocol. Population stratification was ascertained using the software Eigenstrat (Reich Lab, Harvard University), and 64 case and 17 control outliers were identified and removed. The Cochran-Armitage trend and dominant tests were used to evaluate the association of rs20455 with CAD or MI using a threshold of p < 0.001.
The 9p21.3 SNP rs1333049 showed a very strong association with CAD in our cohort (p = 3.55 x 10–13), serving as a positive control to detect a CAD risk variant. In contrast, no association was detected for the rs20455 SNP with CAD, nor did rs20455 associate with MI among CAD cases (Table 1). We also genotyped 957 cases and 1,004 controls by PCR using the Lightcycler (Roche Applied Science, Laval, Quebec, Canada) protocol and found no association between rs20455 and CAD or MI. Of the 1,518 case and control samples genotyped both by microarrays and by PCR, a 98% concordance of the genotypes was observed, and the difference did not account for the lack of association.
Our data do not support the hypothesis that Caucasian carriers of the 719Arg allele of KIF6 have increased risk of CAD or MI in the OHGS. Moreover, data from the WTCCC also showed no association of rs20455 with CAD (trend p = 0.897). Because 71% of cases in the WTCCC had an MI, it is also doubtful whether rs20455 SNP associates with MI in this cohort.
In the Women's Health Study, the KIF6 variant was associated with coronary heart disease broadly defined as revascularization, MI, and cardiovascular death (4). If we perform the analysis excluding MI, the KIF6 variant shows no association with revascularization or cardiovascular death. Thus, the association with the composite end point is apparently driven by MI. In a second report from the CARE (Cholesterol and Recurrent Events) trial and the WOSCOPS (West of Scotland Coronary Prevention Study) cohorts, an association of the KIF6 variant with coronary heart disease was observed. However, all cases were MI or cardiovascular death, supporting the idea that the KIF6 variant associates with MI rather than with CAD (3).
The OHGS is a cross-sectional case-control study designed to identify genes that predispose to angiographically defined CAD, not MI. A potential association between KIF6 and MI may be confounded by a higher CAD disease burden in our population. Genes that predispose specifically to MI rather than CAD would most readily be identified in MI patients with minimal CAD burden.
Our study was not designed to test whether KIF6 is associated with a beneficial response to statin therapy, as reported (5). Although including statin use as a covariate did not make KIF6 associate with CAD or MI, it is possible that MI is under-represented among KIF6 carriers who are on a regimen of statin therapy.
The 719Arg variant of KIF6 did not associate with risk of CAD in either the OHGS or the WTCCC. Whether the KIF6 variant is associated with MI or improves the benefit from statin therapy awaits confirmation in other studies.
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Footnotes
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Please note: Drs. Stewart, Wells, McPherson, and Roberts are supported by grants from the Canadian Institutes of Health Research. Infrastructure support is provided by the Canada Foundation for Innovation and the Ontario Research Foundation. The authors are grateful to the WTCCC for access to their data, and thank Patricia Gerard for data management.
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References
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1. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease Science 2007;316:1488-1491.[Abstract/Free Full Text]2. Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease N Engl J Med 2007;357:443-453.[CrossRef][Medline] 3. Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials J Am Coll Cardiol 2008;51:435-443.[Abstract/Free Full Text] 4. Shiffman D, Chasman DI, Zee RY, et al. A kinesin family member 6 variant is associated with coronary heart disease in the Women's Health Study J Am Coll Cardiol 2008;51:444-448.[Abstract/Free Full Text] 5. Iakoubova OA, Sabatine MS, Rowland CM, et al. Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study J Am Coll Cardiol 2008;51:449-455.[Abstract/Free Full Text]
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