Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies

Department of Medicine, Stanford University School of Medicine, Stanford, California 94304-1334, USA.
Journal of the American College of Cardiology (Impact Factor: 16.5). 10/2010; 56(19):1552-63. DOI: 10.1016/j.jacc.2010.06.022
Source: PubMed


We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.
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.
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.
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.

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Available from: Dawn M Waterworth, Oct 13, 2015
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    • "Chinese and Japanese also have been reported to have a high frequency (∼70%) of the risk allele [15]. Other investigators were unable to detect the association of the rs20455 allele with increased CHD risk [16] even with a large sample size [17]. Ference et al. [18] carried out a large meta-analysis with 88,535 subjects in 8 randomized statin trials examining the role of KIF6 Trp719Arg allele in CHD and concluded that the risk allele increases the vulnerability to elevated LDL-C cholesterol. "
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    ABSTRACT: The Trp719Arg allele of KIF6 rs20455, a putative risk factor for CHD especially in those with elevated low-density lipoprotein cholesterol (LDL-C), was investigated in Filipino-American women (FAW, n = 235) participating in health screenings in four cities. The rs20455 genotype of each subject was determined by a multiplex assay using a Luminex-OLA procedure. The risk allele Trp719Arg was present in 77% of the subjects. The genotype distribution was 23% Trp/Trp, 51% Arg/Trp, and 26% Arg/Arg. Genotype did not predict the presence of CHD risk factors. Moreover, LDL-C, HDL-C, and triglycerides mean values did not vary as a function of genotype. However, those with the Arg/Arg genotype on statin medication exhibited a significantly higher mean triglycerides level (P < 0.01). Approximately 60% of participants regardless of genotype exhibited LDL-C levels ≥100 mg/dL but were not taking medication. Approximately 43% of those with the Trp719Arg risk allele on statins exhibited elevated LDL-C levels. Our study suggests that the Trp719Arg allele of KIF 6 rs20455 is common among Filipino-American women; thus, even with borderline LDL-C levels would benefit from statin treatment. Secondly, many participants did not exhibit guideline recommended LDL-C levels including many who were on statin drugs.
    01/2014; 2014(25, supplement 1):328954. DOI:10.1155/2014/328954
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    • "Some of these studies also demonstrated a greater lipid lowering response from statin therapy among 719Arg carriers when compared to noncarriers [1] [2] [3] [4]. Others have found no association between 719Arg carrier status and cardiovascular outcomes [7] [8]. A recent study by Sabbagh et al. [9] found that positive 719Arg carrier status combined with statin use was associated with lower total cholesterol (TC) and lower low density lipoprotein (LDL) levels in a sample of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) patients. "
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    ABSTRACT: Recent research has demonstrated associations between statin use, KIF6 719Arg carrier status, and cholesterol levels and amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) patients. The association between 719Arg carrier status with homocysteine (tHcy) and c-reactive protein (CRP) levels in aMCI and AD has not been previously investigated. Data from 175 aMCI and AD patients were used for the analysis. 719Arg carriers had significantly lower levels of tHcy than noncarriers (P = 0.02). No significant difference in CRP levels between 719Arg carriers and noncarriers was present (P = 0.37). Logistic regression yielded no significant effect for 719Arg status on CRP [OR = 1.79 (0.85, 3.83), P = 0.13] but did demonstrate a significant effect for tHcy [OR = 0.44 (0.23, 0.83), P = 0.01] after adjusting for ApoE ε4 carrier status, age, gender, and statin use. This study is the first to explore the relationship between KIF6 719Arg carrier status with tHcy and CRP levels. 719Arg carriers were more likely to have normal tHcy levels after adjusting for ApoE ε4 status, age, gender, and statin use. These results suggest that the KIF6 gene might influence cardiovascular pathways associated with AD.
    International Journal of Alzheimer's Disease 12/2013; 2013:242303. DOI:10.1155/2013/242303
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    • "Initial reports using a candidate gene based approach in several atherosclerosis population cohorts observed an increase risk of adverse coronary events in carriers of the rs20455 C variant in the KIF6 gene which leads to a Trp719Arg substitution in the Kif6 protein [1], [2], [3], [4]. These findings were controversial and refuted by a large GWAS meta-analysis using 19 case-control studies [5] where cases were defined either by a history of prior myocardial infarction and/or the presence of coronary artery disease at angiography. Furthermore no association between the kif6 variant and coronary events was observed in the most recent large meta-analysis [6]. "
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    ABSTRACT: A KIF6 variant in man has been reported to be associated with adverse cardiovascular outcomes after myocardial infarction. No clear biological or physiological data exist for Kif6. We sought to investigate the impact of a deleterious KIF6 mutation on cardiac function in mice. Kif6 mutant mice were generated and verified. Cardiac function was assessed by serial echocardiography at baseline, after ageing and after exercise. Lipid levels were also measured. No discernable adverse lipid or cardiac phenotype was detected in Kif6 mutant mice. These data suggest that dysfunction of Kif6 is linked to other more complex biological/biochemical parameters or is unlikely to be of material consequence in cardiac function.
    PLoS ONE 01/2013; 8(1):e54636. DOI:10.1371/journal.pone.0054636 · 3.23 Impact Factor
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