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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.

Aims We investigated whether KIF6 Trp719Arg genotypes affect cardiovascular outcomes and efficacy of statin therapy in patients with type 2 diabetes mellitus undergoing hemodialysis. Methods and results We conducted a post hoc analysis of the 4D-study, a randomized trial including 1255 patients. Patients were randomly assigned to double-blind treatment with either 20mg of atorvastatin ( n =619) or placebo ( n =636) once daily and followed for 4 years (median). DNA was available for 1232 patients and we assessed KIF6 Trp719Arg genotypes by PCR and subsequent restriction digest. Carriers of the Arg719 allele showed no increased prevalence of cardiovascular disease. The incidence of cardiac death, MI, and stroke did not differ across KIF6 genotypes, irrespective of whether the patients were treated with atorvastatin or not. Conclusion In patients with type 2 diabetes mellitus on hemodialysis, KIF6 Trp719Arg genotypes were not associated with adverse cardiovascular outcomes during follow-up or with the efficacy of atorvastatin therapy.

Background Carotid intima-medial thickness (IMT) is a surrogate marker of subclinical atherosclerosis. This study aimed to investigate the impacts of genetic variants on IMT and future development of ischemic stroke in a cohort, followed by an independent replication study. Methods B-mode carotid ultrasound was performed among 3330 healthy adults in the CVDFACT cohort study, and the genetic effects of atherosclerosis-related genes including connexin37 ( GJA4 ), C-reactive protein ( CRP ), paraoxonase ( PON1 ), adiponectin ( ACDC ), angiotensin-converting enzyme ( ACE ), beta-adrenergic receptor ( ADRB1, ADRB2 ), antithrombin III ( SERPINC1 ), and kinesin family member 6 ( KIF6 ) were evaluated by a multivariate regression model, adjusting for traditional vascular risk factors. Study subjects were prospectively followed for the development of ischemic stroke to assess the prognostic impacts of these genetic variants. An independent case-control study was performed to replicate the genetic association from the cohort study. Results The T allele of connexin37 C1019T polymorphism significantly affected IMT ( β =0.014, p =0.013) after adjusting for traditional risk factors. During an average follow-up period of 10.7 years, 80 patients with ischemic stroke (2.4%) were identified. The connexin37 1019T allele was significantly associated with an increased rate of ischemic stroke under an additive model, with hazard ratios (HR) of 2.83 (95% confidence interval, 1.2–6.66) and 1.69 (95% confidence interval, 1.06–2.71), comparing TT and CT genotype with CC, respectively. After Cox analysis, age (HR, 1.78 every 10 years), diabetes mellitus (HR, 2.63), hypertension (HR, 2.08), and the T allele of C1019T polymorphism of GJA4 (HR, 1.69) were identified as independent predictors of ischemic stroke. The relationship between T allele of C1019T polymorphism of GJA4 gene and ischemic stroke was also confirmed by an independent association study. Conclusion Connexin 37 genetic variants significantly affect carotid IMT and contribute to future development of ischemic stroke.