Genetic variants in the KIF6 region and coronary event reduction from statin therapy

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (Pinteraction < 0.1 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (Pinteraction < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from −4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy

Cost Effectiveness of Sequencing 34 Cancer-Associated Genes as an Aid for Treatment Selection in Patients with Metastatic Melanoma.

ObjectiveTo determine whether a next-generation sequencing (NGS) panel of 34 cancer-associated genes would cost-effectively aid in the treatment selection for patients with metastatic melanoma, compared with a single-site BRAF V600 mutation test.MethodsA decision model was developed to estimate the costs and health outcomes of the two test strategies. The cost effectiveness of these two strategies was analyzed from a payer perspective over a 2-year time horizon with model parameters taken from the literature.ResultsIn the base case, the gene sequencing panel strategy resulted in a cost of US$120,022 and 0.721 quality-adjusted life years (QALYs) per patient, whereas the single-site mutation test strategy resulted in a cost of US$128,965 and 0.704 QALYs. Thus, the gene sequencing panel strategy cost US$8943 less per patient and increased QALYs by 0.0174 per patient. Sensitivity analyses showed that, compared with the single-site mutation test strategy, the gene sequencing panel strategy had a 90.9$79.6 million and a gain of 155 QALYs

Cost Effectiveness of Sequencing 34 Cancer-Associated Genes as an Aid for Treatment Selection in Patients with Metastatic Melanoma.

ObjectiveTo determine whether a next-generation sequencing (NGS) panel of 34 cancer-associated genes would cost-effectively aid in the treatment selection for patients with metastatic melanoma, compared with a single-site BRAF V600 mutation test.MethodsA decision model was developed to estimate the costs and health outcomes of the two test strategies. The cost effectiveness of these two strategies was analyzed from a payer perspective over a 2-year time horizon with model parameters taken from the literature.ResultsIn the base case, the gene sequencing panel strategy resulted in a cost of US$120,022 and 0.721 quality-adjusted life years (QALYs) per patient, whereas the single-site mutation test strategy resulted in a cost of US$128,965 and 0.704 QALYs. Thus, the gene sequencing panel strategy cost US$8943 less per patient and increased QALYs by 0.0174 per patient. Sensitivity analyses showed that, compared with the single-site mutation test strategy, the gene sequencing panel strategy had a 90.9$79.6 million and a gain of 155 QALYs

Use of low density lipoprotein particle number levels as an aid in statin treatment decisions for intermediate risk patients: A cost-effectiveness analysis

BACKGROUND: The 2013 ACC/AHA guideline recommended either no statin therapy or moderate-intensity statin therapy (MST) for intermediate risk patients—those with 5–7.5% 10-year risk and without cardiovascular disease (CVD), hypercholesterolemia or diabetes. The guideline further suggested that the therapy choice be based on patient-clinician discussions of risks and benefits. Since low-density lipoprotein particle (LDL-P) levels were reported to be associated with CVD independently of traditional risk factors in intermediate and low risk patients, we investigated the cost-effectiveness of using LDL-P levels to identify intermediate risk patients likely to benefit from initiating or intensifying statin therapy. METHODS: We evaluated 5 care strategies for intermediate risk patients. These included the strategies suggested by the guideline: no-statin therapy and MST. We compared each of these strategies to a related strategy that incorporated LDL-P testing. No-statin therapy was compared with the strategy of MST for those with high LDL-P levels and no statin therapy for all other patients (test-and-MST). MST was compared with the strategy of high-intensity statin therapy (HST) for those with high LDL-P levels and MST for all other patients (test-and-HST). We also evaluated the strategy of HST for all. Costs (payer perspective) and utilities were assessed over a 5-year time horizon in a Markov model of 100,000 hypothetical intermediate risk patients. RESULTS: HST dominated all other strategies, costing less and—despite causing 739 more cases of diabetes than did MST—resulting in more quality adjusted life-years (QALYs). For patient-clinician discussions that would otherwise lead to the MST strategy, we found the test-and-HST strategy reduced costs by $4.67 MM and resulted in 134 fewer CVD events and 115 additional QALYs. For patient-clinician discussions that would otherwise lead to no statin therapy, we found that the test-and-MST strategy reduced costs by$3.25 MM, resulted in 97 fewer CVD events and 44 additional QALYs. CONCLUSIONS: The HST strategy was cost saving and improved outcomes in intermediate risk patients. For patient and clinicians concerned about the adverse events associated with HST, using LDL-P levels to target intensified statin therapy could improve outcomes and reduce costs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12872-016-0429-6) contains supplementary material, which is available to authorized users

Investigation of KIF6 Trp719Arg in a Case-Control Study of Myocardial Infarction: A Costa Rican Population

Background and Methodology The 719Arg allele of KIF6 (rs20455) was associated with coronary events in Caucasian participants of five prospective studies. We investigated whether this KIF6 variant was associated with non-fatal myocardial infarction (MI) in a case-control study of an admixed population from the Central Valley of Costa Rica. Genotypes of the KIF6 variant were determined for 4,134 men and women. Cases (1,987) had survived a first MI; controls (2,147) had no history of MI and were matched to cases by age, sex, and area of residence. We tested the association between the KIF6 719Arg allele and non-fatal MI by conditional logistic regression and adjusted for admixture of founder populations. Principal Findings Compared with the reference Trp/Trp homozygotes, KIF6 719Arg carriers were not at significantly higher risk for non-fatal MI in this study after adjustment for traditional risk factors or admixture (OR = 1.12; 95%CI, 0.98–1.28). Heterozygotes of the KIF6 Trp719Arg variant were at increased risk of non-fatal MI: the adjusted odds ratio was 1.16 (95% confidence interval, 1.01–1.34), but this association would not be significant after a multiple testing correction. Conclusions/Significance We found that carriers of the KIF6 719Arg allele were not at increased risk of non-fatal MI in a case-control study of Costa Ricans living in the Central Valley of Costa Rica. Introduction Kinesins are a superfamily of homodimeric motor proteins that transport cellular cargos (e.g., proteins, vesicles, or organelles) along microtubules in an ATP dependent process. A single nucleotide polymorphism (SNP) in the gene for the KIF6 protein—a member of the kinesin 9 family—has been reported to be associated with coronary heart disease (CHD) and event reduction during statin therapy[2]. In Caucasians, carriers of the 719Arg allele of this SNP (rs20455) were at increased risk for coronary events in 5 prospective studies: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS) , the Women's Health Study (WHS), and in the placebo groups of both the Cholesterol and Recurrent Events (CARE) study and the West of Scotland Coronary Prevention Study (WOSCOPS), In contrast to these prospective studies, KIF6 Trp719Arg was not associated with coronary artery disease (CAD) in two recently reported case-control studies: the Ottawa Heart Genomics study and the Welcome Trust Case-Control Consortium study Only limited data are available regarding whether the KIF6 719Arg allele is associated with CHD in other ethnic populations. For example, among African Americans in ARIC, each allele of KIF6 719Arg increased the risk for incident CHD by 1.23-fold (95%CI, 0.99–1.52), and among African Americans in CHS, carriers of the KIF6 719Arg allele had a hazard ratio for incident myocardial infarction (MI) of 4.14 (90%CI, 0.79–21.77), compared with noncarriers[4]. Thus, although the associations between the KIF6 719Arg allele and CHD were not statistically significant in the small African American study populations in ARIC and CHS, these results suggested that the KIF6 719Arg allele may be associated with CHD in ethnic populations other than Caucasians. Therefore, we asked whether the KIF6 719Arg allele is associated with MI in a Hispanic population from Costa Rica. Results The characteristics of cases with myocardial infarction and population-based controls from the Central Valley of Costa Rica used in this study are shown in Table 1. Age, sex, and residence (i.e., matched characteristics) did not differ significantly between cases and controls (Table 1). Other CHD risk factors (smoking, history of hypertension, family history of MI, and waist-to-hip ratio) were higher in cases than in controls (Table 1). The genotypes of the KIF6 SNP (rs20455) that cause a Trp719Arg variation did not deviate from the distribution expected under Hardy–Weinberg equilibrium (P = 0.38); the frequency of the minor allele (KIF6 719Arg) was 0.36 in the control subjects. Characteristics of Cases and Controls. We found that carriers of one or two copies of the KIF6 719Arg variant were not at increased risk of MI (OR = 1.12; 95%CI, 0.98–1.28; Table 2). Although the risk estimate for heterozygotes of the KIF6 variant (Trp/Arg), compared with major allele homozygotes (Trp/Trp), was 1.15 (95%CI 1.00–1.33; Table 2) after adjusting for potentially confounding risk factors and admixture in this Costa Rican population, this association would not be significant if corrected for the testing of multiple KIF6 719Arg carrier groups. Homozygotes of the KIF6 variant (Arg/Arg) were not at increased risk of MI, compared with major allele homozygotes (Trp/Trp)

Investigation of KIF6 Trp719Arg in a Case-Control Study of Myocardial Infarction: A Costa Rican Population

Background and Methodology: The 719Arg allele of KIF6 (rs20455) was associated with coronary events in Caucasian participants of five prospective studies. We investigated whether this KIF6 variant was associated with non-fatal myocardial infarction (MI) in a case-control study of an admixed population from the Central Valley of Costa Rica. Genotypes of the KIF6 variant were determined for 4,134 men and women. Cases (1,987) had survived a first MI; controls (2,147) had no history of MI and were matched to cases by age, sex, and area of residence. We tested the association between the KIF6 719Arg allele and non-fatal MI by conditional logistic regression and adjusted for admixture of founder populations. Principal Findings: Compared with the reference Trp/Trp homozygotes, KIF6 719Arg carriers were not at significantly higher risk for non-fatal MI in this study after adjustment for traditional risk factors or admixture (OR = 1.12; 95%CI, 0.98–1.28). Heterozygotes of the KIF6 Trp719Arg variant were at increased risk of non-fatal MI: the adjusted odds ratio was 1.16 (95% confidence interval, 1.01–1.34), but this association would not be significant after a multiple testing correction. Conclusions/Significance: We found that carriers of the KIF6 719Arg allele were not at increased risk of non-fatal MI in

Single Nucleotide Polymorphisms Associated with Coronary Heart Disease Predict Incident Ischemic Stroke in the Atherosclerosis Risk in Communities Study

Ischemic stroke and coronary heart disease (CHD) may share genetic factors contributing to a common etiology. This study investigates whether 51 single nucleotide polymorphisms (SNPs) associated with CHD in multiple antecedent studies are associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. From the multiethnic ARIC cohort of 14,215 individuals, 495 validated ischemic strokes were identified. Cox proportional hazards models, adjusted for age and gender, identified three SNPs in Whites and two SNPs in Blacks associated with incident stroke (p ≤ 0.05). The rs11628722 polymorphism in SERPINA9 was associated with incident stroke in Whites and Blacks, even after taking into account traditional risk factors. The idea that ischemic stroke and CHD may share some common genetic factors, such as variation in SERPINA9, should be investigated in other studies