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The KIF6 719Arg allele is an interesting genomic variant widely screened in various populations and is reported to be associated with the risk of Coronary Artery Disease (CAD) and statin treatment outcome. Recent population based clinical studies and large-scale meta-analyses pondered over the role of 719Arg variant in CAD risk and treatment response. We screened the KIF6 Trp719Arg polymorphism (rs20455) in south Indian CAD patients in a case–control approach. A total of 1042 samples (510 CAD patients and 532 controls) were screened for the KIF6 Trp719Arg SNP by TaqMan SNP genotyping assay, followed by meta-analysis of the genotype data of non-Europeans reports. The 719Arg risk genotype (GG) was observed in 29.6% of CAD cases and in 30.1% of controls with an odds ratio (OR) of 1.07 (95% CI: 0.76–1.50), p value = 0.709. No significant difference in the genotype frequency was observed between CAD and controls in both dominant model (AG + GG vs AA) and allelic model (719Arg vs 719Trp) with an OR of 1.11 (p = 0.491) and 1.03 (p = 0.767), respectively. The covariate analysis indicated that smoking & alcohol consumption increased the risk for MI among CAD patients. Meta-analysis showed that the KIF6 719Arg allele is not associated with CAD risk in both fixed effect (p = 0.515, OR = 1.023, 95% CI = 0.956–1.094) and random effect (p = 0.547, OR = 1.022, 95% CI = 0.953–1.096). The symmetrical shape of the Egger's funnel plots revealed that there is no publication bias. These results suggest that there is no association of KIF6 719Arg allele with CAD risk in South Indian population and the meta-analysis confirms the same among non-European population., Highlights • First study to screen for KIF6Trp719Arg SNP in south Indian population • KIF6Arg variant is not a risk factor for south Indian CAD patients. • Meta-analysis showed no association of KIF6Arg allele in non-European CAD populations. • Smoking and alcoholic status were strong risk factors for MI; whereas KIF6 status is not.

OBJECTIVE:Cardiovascular disease (CVD) represents the most common and lethal chronic disease worldwide. Lipids levels are the strongest risk factors for CVD and this is demonstrated by the fact that lipid-lowering statin therapy is largely used to prevent CVD. The role of the KIF6 gene in response to the statin therapy is controversial, and the biological mechanism through which it may act is still unknown.We investigated the role of KIF6 locus variants alone and their interaction with the well-established lipid locus at HMGCR in the variability of metabolic traits and in response to statin therapy in an Italian sample. DESIGN AND METHOD:We genotyped two intronic rs20455, rs9462535 and a coding rs9471077 within the KIF6 gene, as well as two non-coding rs3761740 and rs3846662 at HMGCR. We tested the association of these SNPs with 19 cardiometabolic phenotypes and lipid-lowering therapy response in a sample of 1645 individuals from the Brisighella cohort (BC). RESULTS: Established rs3846662 (Willer et al, Nat Gen 2013) at HMGCR is associated (P = 8.5x10-4) with LDL cholesterol (LDL-C) in BC. We did not find any significant association of KIF6 variants with response to statin therapy. We observe a locus-wide significant association at KIF6 between rs9471077 and APOB levels and rs20455 and HDL-C (P less than 0.001). rs3761740 at HMGCR showed an effect on systolic and diastolic blood pressure (SBP/DBP, P less than 0.007), which however wasn't significant after multiple testing correction. CONCLUSIONS: This is the first genetic study reported for Brisighella cohort, which confirms association with LDL-C at HMGCR locus. We noticed an effect of KIF6 variants on APOB and HDL-C, while we don't observe any effect on statin therapy. The study sample is relatively small to discover a common variant effect and might still be due to chance; therefore, we are seeking for replication in additional cohorts. These findings, if confirmed, might contribute to development of approaches for stratified patient care.

Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins, coronary heart disease (CHD) at baseline, or CHD events on trial. We examined SNPs at the KIF6 (rs20455 or 719Arg), LPA (rs3798220), TAS2R50 (rs1376251) and VAMP8 (rs1010) in 5,411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No SNP was related to vascular disease at baseline. Only the KIF6 SNP was related to LDL-C lowering with homozygous Arg 719 subjects being significantly less responsive than other groups (p = 0.025, −34.2 vs. −36.1%). With regard to the primary CHD endpoint on trial (fatal or non-fatal myocardial infarction or stroke), we observed a significant relationship for KIF6 719Arg homozygotes (p = 0.03, hazards ratio 0.47, 12.8% of the population) in women on pravastatin only, and for TAS2R50 for the AA genotype (p = 0.03, hazards ratio 1.76, 8.9% of the population), also only in women on pravastatin. Our data indicate that the assessment of KIF6 rs20455 and TAS2R50 rs1376251 genotypes are not useful for predicting statin induced cardiovascular risk reduction in men, but do predict CHD risk reduction in women in this elderly population. However, these differences are no longer significant after correction for multiple comparisons, and we do not recommend the assessment of any of these SNPs in clinical practice.