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KIF6 719Arg allele carriers are thought to have a greater lipid lowering response from statin therapy than non-carriers. Given the continued interest in the relationship between cholesterol, statin use, amnestic mild cognitive impairment (aMCI), and Alzheimer’s disease (AD) investigating the role of KIF6 719Arg carrier status in these relationships may be of importance. Data from 86 patients (36 aMCI, 50 AD) with an average age of 76.87±8.22 years were used for this study. Total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), and triglycerides were the outcome variables. 719Arg carriers taking statins had significantly lower TC (p < .001) and LDL (p < .001) levels than 719Arg carriers not taking statins. In addition, 719Arg carriers not taking statins had significantly higher TC (p = .004) and LDL (p < .001) than 719Arg non-carriers taking statins. Additional analyses indicated that ApoE e4 carrier status and statin use interaction is also associated with lower TC (p = .04), but not LDL (p = .06). The interaction between 719Arg and ApoE e4 carrier status on TC and LDL was not significant. This study is the first to demonstrate an association between lower cholesterol levels and statin use among KIF6 719Arg allele carriers with aMCI and AD. Accounting for 719Arg carrier status may be important in future studies investigating the link between cholesterol and AD and also for AD and aMCI clinical trials using statins as a treatment.

assistant. At the end of the day, club staff return participants to their respective units at individualized times to ease transition to existing milieu. There is a two-week trial period upon admission to the program followed by weekly monitoring to assure participants meet the criteria of the Club. For some residents, it is an interim solution to disruptive behaviors on their home unit; for others, it is long-term placement. In rare cases, it is respite for a resident that is a victim of aggressive behavior. Discharge criteria from the Club setting include behavior that is dangerous to other residents or staff, lack of participation or benefit from therapeutic structure, and/or medical needs that cannot be met in the Club setting. Results: Although data is preliminary, there are many documented benefits from this approach including reduced incidents of aggressive behavior and a decreased need for psychoactive medications. Other advantages include an increase in normal sleep patterns, reduced falls and hospitalizations, as well as, improvement in the overall quality of life through a more structured activities program. Conclusions: Not only do the residents themselves benefit from temporary or ongoing management in this setting, but the therapeutic milieu of the facility overall is enhanced.

Numerous strategies to improve statin adherence have been evaluated; however, none have utilized direct patient communication of genetic information as a motivator. This trial is the first to evaluate this novel technique. AKROBATS ([NCT01068834][1]) was a prospective, nonrandomized intervention

Study Hypothesis A common polymorphism in the kinesin-like protein 6 ( KIF6 ) gene, the Trp719Arg variant, was reported in multiple exploratory studies to be associated with both vascular risk and response to statin therapy. The clinical implication of these findings was that noncarriers of the Trp719Arg variant receive little benefit from statin therapy, suggesting clinical utility for a KIF6 pharmacogenetic test to predict the suitability of statin therapy for individual patients. More recent publications have disputed the reported associations. The authors of both studies described here (Hopewell et al1 and Ridker et al2) sought to definitively confirm or reject the hypothesis that the Trp719Arg variant affects the response to statin therapy with respect to incident vascular disease. ### How Was the Hypothesis Tested? Hopewell et al1 performed a retrospective analysis of data from the Heart Protection Study (HPS), in which more than 20 000 patients with established vascular disease or risk factors for vascular disease were randomly assigned to the use of 40 mg simvastatin daily versus placebo. Genotyping of the KIF6 Trp719Arg polymorphism (also designated rs20455) was successfully performed in 18 348 HPS participants of self-reported white ethnicity, with almost equal numbers from the simvastatin arm (n=9167) and the placebo arm (n=9181). The primary outcome was incident major vascular events (defined as …

A single-nucleotide polymorphism Trp719Arg (rs20455TC) in the kinesin-like protein 6 (KIF6), which is a protein involved in intracellular transport, has been shown to predict increased coronary artery disease (CAD) risk and event reduction during statin therapy.In the current study, we have evaluated the association of the variant Trp719Arg with CAD/non fatal myocardial infarction (MI) in Western Indians.Genotyping for Trp719Arg was done by an allele-specific real-time assay in 227 cases with confirmed CAD and 150 controls.We have found that the KIF6 719 Arg carriers were not at a significantly higher risk for CAD/non-fatal MI in this case-control study of an Indo-European population from Western India (Unadjusted odds ratio [OR] 0.767 95% confidence interval [CI] 0.573-1.027 for 719Arg carriers). When the genotypes were further tested to determine association with prevalent myocardial infarction as the event versus CAD, no association was seen in a univariate analysis (MI vs. CAD OR 0.804 95% CI 0.543-1.189; MI vs. Controls OR 0.702 95% CI 0.482-1.021).In summary, carriers of the KIF6 719Arg allele were not at increased risk of CAD/non-fatal MI in a case-control study of Indians (Indo-Europeans) living in Western India.

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.

Texto completo: acesso restrito. p. 659–662 Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2014-02-13T12:16:01Z No. of bitstreams: 1 Bernd Genser.pdf: 575667 bytes, checksum: 4a2156f9d29525fb7950b4da2703b248 (MD5) Made available in DSpace on 2014-02-13T12:16:01Z (GMT). No. of bitstreams: 1 Bernd Genser.pdf: 575667 bytes, checksum: 4a2156f9d29525fb7950b4da2703b248 (MD5) Previous issue date: 2011 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 20 mg 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.

For over two decades, substantial National efforts have been directed toward ­reducing blood cholesterol levels of the American population with the intent of reducing the burden of cardiovascular events. This initiative was initially prompted by the successful results of the Lipid Research Clinic-Coronary Primary Prevention Trial (LRC-CPPT) that first proved reducing LDL-C resulted in a statistically ­significant reduction in cardiovascular events [2]. Since then an abundance of monotherapy cholesterol-lowering drug trials have consistently reported an approximate 25% relative risk reduction (RRR) for cardiovascular events [3].

One of the promises of the Human Genome Project is individualization of patient care based on highly heterogeneous innate metabolic factors determined by DNA typing of gene polymorphisms. Translation of such gene polymorphisms into clinical decision support for personalized healthcare is the basis for DNA guided medicine. Pharmacogenetics serves as the foundation for the most clinically advanced application of DNA-guided medicine. Statin responsiveness is an area of high research interest given the success of the drug class in the treatment of hypercholesterolemia and in primary and secondary prevention of cardiovascular disease. Ongoing genetic inquiry into response variability indicates probable multigenic determinants for statin efficacy and safety. It is the vision that knowledge of the patient’s genetic status for a number of common variants will soon guide hyperlipidemic intervention.

Coronary artery disease (CAD) is a leading cause of death worldwide and in the United States it is responsible for more than 500,000 deaths each year. Genome-wide association studies (GWAS) have revealed connections between a number of common single nucleotide polymorphisms (SNPs) and CAD and other cardiovascular diseases. The p.Trp719Arg SNP in the kinesin-like family 6 (KIF6) gene has recently been reported as a potential risk factor for CAD as well as a predictor of response to statin therapy.

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.

Background Statin therapy has been found to substantially and significantly reduce coronary events in carriers of the KIF6 719Arg variant (rs20455) but not in noncarriers. We investigated whether, among the elderly, statin therapy also significantly reduced coronary events in carriers but not in noncarriers. Design and methods Among 5752 patients of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study, we assessed the effect of pravastatin, compared with placebo, on coronary events according to 719Arg carrier status using proportional hazards models. Results Since benefit from statin therapy in elderly patients has been primarily shown among those with prior vascular disease, we performed analyses in PROSPER patients with prior disease and found that pravastatin therapy significantly reduced events in 719Arg carriers [hazards ratio (HR): 0.66, 95% confidence interval (CI): 0.52-0.86] but not in noncarriers (HR: 0.94, 95% CI: 0.69-1.28), P = 0.09 for interaction between treatment and carrier status. Among those without prior disease, no significant benefit was observed in either carriers or noncarriers. Among those with prior vascular disease in the placebo arm, Trp719Arg heterozygotes were at significantly greater risk, compared with noncarriers (HR: 1.36, 95% CI: 1.03-1.81, P = 0.03); the HR of 719Arg carriers, compared with noncarriers, was 1.28 (95% CI: 0.98-1.69, P = 0.07). Conclusion Elderly carriers of the KIF6 719Arg variant with prior vascular disease received significant benefit from pravastatin therapy; no benefit was observed in noncarriers with prior disease or in those without prior disease (carriers or noncarriers). Eur J Cardiovasc Prev Rehabil 17:455-461 (C) 2010 The European Society of Cardiology

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.

Evidence from multiple large prospective studies suggests that a common polymorphism that encodes an arginine (Arg)-to-tryptophan substitution at position 719 in the KIF6 gene is associated with coronary heart disease (CHD) and reduction in coronary events from statin therapy. Carriers of the 719Arg allele were at greater risk for primary and secondary CHD events, and statin therapy significantly reduced coronary events in 719Arg carriers but not in noncarriers. The number needed to treat to prevent a single CHD event ranged from 10 to 20 for 719Arg carriers, compared to >80 for noncarriers in the Cholesterol and Recurrent Events (CARE) study, the West of Scotland Coronary Prevention Study (WOSCOPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) study. In conclusion, assessment of 719Arg carrier status holds promise for stratification of coronary event risk and for selection of optimal therapy in primary and secondary CHD prevention.

A previous genetic analysis of the Cholesterol and Recurrent Events (CARE) trial found that carriers of the 719Arg allele of the kinesin family member 6 gene (KIF6) (rs20455), but not noncarriers, received significant event reduction from pravastatin therapy. However, that previous analysis of CARE included only Caucasian patients and was limited to the myocardial infarction components of the primary end point. Therefore, the aim of this study was to investigate whether pravastatin therapy reduced primary end point events in KIF6 719Arg carriers and noncarriers, separately, in the combined ethnic groups of CARE. The effect of pravastatin therapy on primary end point events (fatal coronary event or nonfatal myocardial infarction) was investigated in Cox regression models that adjusted for population structure using either self-reported ethnicity or the principal components of genetic heterogeneity. After adjustment for age, gender, and self-reported ethnicity, pravastatin therapy reduced events in carriers of KIF6 719Arg (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.49 to 0.83) but not in noncarriers (HR 1.01, 95% CI 0.69 to 1.45) (p for interaction = 0.049). After adjustment for age, gender, traditional risk factors, and principal components, pravastatin therapy reduced events in carriers of 719Arg (HR 0.64, 95% CI 0.49 to 0.85) but not in noncarriers (HR 0.90, 95% CI 0.62 to 1.32) (p for interaction = 0.14). In conclusion, in an analysis that included CARE patients of all ethnic groups, pravastatin therapy significantly and substantially reduced primary end point events in carriers of the KIF6 719Arg allele but not in noncarriers.

Noncardioembolic stroke and coronary heart disease (CHD) may share genetic predispositions. We tested the hypothesis that genetic variants which are associated with risk of CHD would also be associated with risk of noncardioembolic stroke in 562 cases from the Vienna Stroke Registry and 815 controls. We selected 6 gene variants that had been consistently associated with risk of CHD in 3 studies, including the Atherosclerosis Risk in Communities study, and found that 4 of these gene variants were also associated with risk of noncardioembolic stroke. The odds ratios for noncardioembolic stroke were 1.31 (90% CI 1.07–1.60) for rs3900940 in MYH15, 1.24 (90% CI 1.01–1.5) for rs20455 in KIF6, 1.21 (90% CI 0.99–1.49) for rs1010 in VAMP8, and 1.20 (90% CI 0.95–1.50) for rs10757274 on chromosome 9p21.

Purpose: Because multiple genetic variants influence risk for coronary heart disease, we combined multiple variants that had been associated with coronary heart disease in several studies into a genetic risk score and asked whether a high genetic risk score would be significantly associated with coronary heart disease after accounting for traditional risk factors. Methods: We considered five variants that were associated with coronary heart disease in two studies and confirmed in the Atherosclerosis Risk in Communities study: rs20455 (KIF6), rs3900940 (MYH15), rs7439293 (PALLD), rs2298566 (SNX19), and rs1010 (VAMP8). We calculated a genetic risk score for each Atherosclerosis Risk in Communities study participant and estimated the hazard ratio for incident coronary heart disease of a high genetic risk score (compared with not-high) in Cox models that adjusted for traditional risk factors during a median of 13 years of follow-up. Results: For white participants with a high genetic risk score (4% of the 9129 whites), compared with those without a high genetic risk score, the hazard ratio for incident coronary heart disease was 1.57 (95% confidence interval 1.21–2.04; P = 0.001). Internal validation using bootstrap samples estimated that a hazard ratio of 1.43 could be expected in external populations. Conclusions: After adjusting for traditional risk factors, those with a high genetic risk score had a 57% increased risk of incident coronary heart disease in the Atherosclerosis Risk in Communities study.

Objective— We asked whether single nucleotide polymorphisms (SNPs) that had been nominally associated with cardiovascular disease in antecedent studies were also associated with cardiovascular disease in a population-based prospective study of 4522 individuals aged 65 or older. Methods and Results— Based on antecedent studies, we prespecified a risk allele and an inheritance model for each of 74 SNPs. We then tested the association of these SNPs with myocardial infarction (MI) in the Cardiovascular Health Study (CHS). The prespecified risk alleles of 8 SNPs were nominally associated (1-sided P KIF6 (CHS HR=1.29; 90%CI 1.1 to 1.52), VAMP8 (HR=1.2; 90%CI 1.02 to 1.41), TAS2R50 (HR=1.13; 90%CI 1 to 1.27), and LPA (HR=1.62; 90%CI 1.09 to 2.42). Conclusions— Although most of the SNPs investigated were not associated with MI in CHS, evidence from this investigation combined with previous studies suggests that 4 of these SNPs are likely associated with MI.

Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease.We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix).Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P1.3x10(-6)) and a high probability (80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212).We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

Recent studies have evaluated whether incorporating nontraditional risk factors improves coronary heart disease (CHD) prediction models. This 1986-2001 US study aggregated the contribution of multiple single nucleotide polymorphisms into a genetic risk score (GRS) and assessed whether the GRS plus traditional risk factors predict CHD better than traditional risk factors alone. The Atherosclerosis Risk in Communities (ARIC) cohort was followed for a median of 13 years for CHD events (n = 1,452). Individuals were genotyped for 116 single nucleotide polymorphisms associated with CHD in multiple case-control studies. Single nucleotide polymorphisms nominally predicting incident CHD in the ARIC study were included in the GRS. The GRS was significantly associated with incident CHD in Blacks (hazard rate ratio = 1.20, 95% confidence interval: 1.11, 1.29) and Whites (hazard rate ratio = 1.10, 95% confidence interval: 1.06, 1.14) as well as in each tertile defined by the traditional cardiovascular risk score (por = 0.02). When receiver operating characteristic curves based on traditional risk factors were recalculated after the GRS was added, the increase in the area under the receiver operating characteristic curve was statistically significant for Blacks and suggestive of improved CHD prediction for Whites. This study demonstrates the concept of aggregating information from multiple single nucleotide polymorphisms into a risk score and indicates that it can improve prediction of incident CHD in the ARIC study.

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][1]). Several recent reports identified a SNP (rs20455) that alters an amino acid in the KIF6 protein (Trp719Arg)

Clinical and pathomorphologic diversity in MDS is a reflection of heterogeneity of molecular lesions. Somatic mutations and chromosomal deletions/amplifications affect various pathways in a convergent and divergent fashion, generate phenocopy and can occur in a variety of combinations. Recent technological advances, including high density arrays and the new generation sequencing (NGS) led to the discovery of novel pathway mutations or gene families affected by somatic defects, e.g., cohesin or spliceosomal mutations. We have performed whole exome NGS of paired (tumor/germ line) samples in 222 patients with myeloid neoplasms from the Cleveland Clinic and University of Tokyo. Clinical parameters were studied including age, gender, overall survival (OS), bone marrow blast count, and metaphase cytogenetics. Additionally, we also used in our analysis data sets from 197 AML included in the Cancer Genome Atlas (TCGA). We found 1.4% (6/419) of non-canonical somatic mutations of KIF2Bwhich is a member of kinesin13 family located on the long arm of chromosome 17; 3 cases from our cohort (p.V32M (c.G94A), p.T113M (c.C338T), p.R163C (c.C487T)) and 3 cases from TCGA database (p.T47M (c.C140T), p.T310M (c.C929T), p.H551N (c.C1651A)). By analyzing clonal architecture and intra-tumor heterogeneity in 2 cases (RCMD and RAEB) by targeted deep sequencing, allelic frequencies of KIF2B mutations were more than 45% and larger than for any other concomitant mutations, suggesting that KIF2B mutations might consequently constitute ancestral events followed by subclonal acquisitions of the other mutations. Of note is that 6 non-sense mutations were also reported in lung cancer. Based on SNP-array mapping of chromosomal abnormalities, deletions of 17q involving the KIF2B locus (17q22) was present about 3% (6/215) of myeloid neoplasm. KIF2B defects were frequently detected in higher-risk MDS and AML phenotypes (9%). KIF2B performed an important role in regulation of kinetochore-microtubule attachment. Previous studies showed that the velocity of chromosomes’ movement in KIF2B-deficient cells is reduced 80% comparing to control and fail to perform cytokinesis. In our series, 56% of myeloid neoplasms with KI2B defects had complex cytogenetics and 67% cases of them were also UPD, suggesting that KIF2B defects might lead to inducing abnormal chromosomal movements and segregations. We then, expanded our study to the whole kinesin gene family: 17 somatic mutations and 57 deletions were identified in KIF1A (n=6), KIF23 (n=1), KIF26A (n=1), KIF27 (n=7), KIF1C (n=9), KIF21B (n=2), KIF13A (n=10), KIF14 (n=2), KIF17 (n=15), KIF25 (n=1), KIF3C (n=8), KIF6 (n=2) and CENPE (n=10). All mutations were heterozygous and mutually exclusive. By survival analysis of such mutated cases, a tendency towards worse prognosis was observed (HR; 1.72, 95%CI 0.86-3.37). Analysis of concomitant mutations associated with whole kinesin family mutations or deletions showed that most frequently affected genes are TET2 (n=14), DNMT3A (n=8), IDH1/2 (n=8) and MLL (n=5), all involved in epigenetic regulation. In conclusion, somatic mutations in kinesin family genes are found in myeloid malignancies and might be responsible for another pathogenesis of the disease. KIF2B is most frequently found in myeloid malignancies and associated with aggressive type of MDS. Since knockout mice of multiple kinesin family genes (KIF5A, KIF16B and EG5) were lethal in embryo and all the mutations occur in a heterozygous configuration, it is likely synthetic lethal approach might create therapeutic window between defective malignant cells and healthy controls. Kinesin family of motor proteins may be an emerging novel therapeutic target. In fact some kinesins have been already successfully targeted in solid tumors. Disclosures: Polprasert: MDS foundation: Research Funding. Makishima:AA & MDS international foundation: Research Funding; Scott Hamilton CARES grant: Research Funding. Maciejewski:NIH: Research Funding; Aplastic anemia&MDS International Foundation: Research Funding.

Aims The goal of our study is to assess the contribution of KIF6 Trp719Arg to both the risk of CHD and the efficacy of statin therapy in CHD patients. Methods and Results Meta-analysis of 8 prospective studies among 77,400 Caucasians provides evidence that 719Arg increases the risk of CHD (P

Background: We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol. Methods: We conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin. Results: In a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD (RR: 1.02, 95%CI: 0.98-1.07, p = 0.288). Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers (ratio of RR: 0.87, 95%CI: 0.80-0.94, p = 0.001) agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy (ratio of RR: 0.87, 95%CI: 0.77-0.99, p = 0.038). Conclusion: The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol. © 2011 Ference et al.

Objectives The aim of this study was to test the effects of the KIF6 Trp719Arg polymorphism (rs20455) on vascular risk and response to statin therapy in 18,348 participants from the Heart Protection Study. Background There have been claims that noncarriers of the KIF6 719Arg variant receive little benefit from statin therapy. Screening for this genetic variant is now being used to influence statin use. Methods Participants received 40 mg simvastatin daily for 4 to 6 weeks before being randomly allocated 40 mg simvastatin daily or placebo for 5 years. Major coronary event was pre-defined as coronary death or nonfatal myocardial infarction, and major vascular event was pre-defined as major coronary event plus revascularization or stroke. Results The KIF6 genotype was not significantly associated, among placebo-allocated participants, with the risks of incident major vascular events, major coronary events, revascularizations, or strokes. Overall, 40 mg simvastatin daily produced a 42% reduction in low-density lipoprotein cholesterol, which did not differ significantly by KIF6 719Arg carrier status (p = 0.51). Proportional reductions in the risk of major vascular events with statin therapy were similar (interaction p = 0.70) and highly significant across KIF6 genotypes: 23% (95% confidence interval: 16% to 29%; p = 5.3 × 10−10) in carriers (Arg/Arg or Trp/Arg), and 24% (95% confidence interval: 17% to 31%; p = 4.6 × 10−9) in noncarriers (Trp/Trp). A similar lack of interaction was observed for major coronary events, revascularizations, and strokes considered separately. Conclusions Statin therapy significantly reduces the incidence of coronary and other major vascular events to a similar extent, irrespective of KIF6 genotype. Consequently, the use of KIF6 genotyping to guide statin therapy is not warranted. (Heart Protection Study; ISRCTN48489393)

Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods 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. Results 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. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation

Introduction The therapeutic response to statins has a high interindividual variability with respect to reductions in plasma LDL-cholesterol (c-LDL) and increases in HDL cholesterol (c-HDL). Many studies suggest that there is a relationship between the rs20455 KIF6 gene variant (c.2155T> C, Trp719Arg) and a lower risk of cardiovascular disease in patients being treated with statins. Aim The aim of this study was to investigate whether or not the c.2155T> C KIF6 gene variant modulates the hypercholesteremic effects of treatment with simvastatin, atorvastatin, or rosuvastatin. Materials and methods This was a prospective, observational and multicenter study. Three hundred and forty-four patients who had not undergone prior lipid-lowering treatment were recruited. Simvastatin, atorvastatin or rosuvastatin were administered. Lipid profiles and multiple clinical and biochemical variables were assessed before and after treatment. Results The c.2155T> C variant of the KIF6 gene was shown to influence physiological responses to treatment with simvastatin and atorvastatin. Patients who were homozygous for the c.2155T> C variant (CC genotype, ArgArg) had a 7.0% smaller reduction of LDL cholesterol levels (p = 0.015) in response to hypolipidemic treatment compared to patients with the TT (TrpTrp) or CT (TrpArg) genotype. After pharmacological treatment with rosuvastatin, patients carrying the genetic variant had an increase in c-HDL that was 21.9% lower compared to patients who did not carry the variant (p = 0.008). Conclusion Being a carrier of the c.2155T> C variant of the KIF6 gene negatively impacts patient responses to simvastatin, atorvastatin or rosuvastatin in terms of lipid lowering effect. Increasing the intensity of hypolipidemic therapy may be advisable for patients who are positive for the c.2155T> C variant.

Background Case-control studies typically exclude fatal endpoints from the case set, which we hypothesize will substantially underestimate risk if survival is genotype-dependent. The loss of fatal cases is particularly nontrivial for studies of coronary heart disease (CHD) because of significantly reduced survival (34% one-year fatality following a coronary attack). A case in point is the KIF6 Trp719Arg polymorphism (rs20455). Whereas six prospective studies have shown that carriers of the KIF6 Trp719Arg risk allele have 20% to 50% greater CHD risk than non-carriers, several cross-sectional case-control studies failed to show that carrier status is related to CHD. Computer simulations were therefore employed to assess the impact of the loss of fatal events on gene associations in cross-sectional case-control studies, using KIF6 Trp719Arg as an example. Results Ten replicates of 1,000,000 observations each were generated reflecting Canadian demographics. Cardiovascular disease (CVD) risks were assigned by the Framingham equation and events distributed among KIF6 Trp719Arg genotypes according to published prospective studies. Logistic regression analysis was used to estimate odds ratios between KIF6 genotypes. Results were examined for 33%, 41.5%, and 50% fatality rates for incident CVD. In the absence of any difference in percent fatalities between genotypes, the odds ratios (carriers vs. noncarriers) were unaffected by survival bias, otherwise the odds ratios were increasingly attenuated as the disparity between fatality rates increased between genotypes. Additional simulations demonstrated that statin usage, shown in four clinical trials to substantially reduce the excess CHD risk in the KIF6 719Arg variant, should also attenuate the KIF6 719Arg odds ratio in case-control studies. Conclusions These computer simulations show that exclusions of prior CHD fatalities attenuate odds ratios of case-control studies in proportion to the difference in the percent fatalities between genotypes. Disproportionate CHD survival for KIF6 Trip719Arg carriers is suggested by their 50% greater risk for recurrent myocardial infarction. This, and the attenuation of KIF6 719Arg carrier risk with statin use, may explain the genotype's weak association with CHD in cross-sectional case-control studies. The results may be relevant to the underestimation of risk in cross-sectional case-control studies of other genetic CHD-risk factors affecting survival.

Background Genetic risk factors might improve prediction of coronary events. Several variants at chromosome 9p21.3 have been widely reported to be associated with coronary heart disease (CHD) in prospective and case-control studies. A variant of KIF6 (719Arg) has also been reported to be associated with increased risk of CHD in large prospective studies, but not in case-control studies. We asked whether the addition of genetic information (the 9p21.3 or KIF6 variants) or a well-established non-genetic risk factor (C-reactive protein [CRP]) can improve risk prediction by the Framingham Risk Score (FRS) in the Cardiovascular Health Study (CHS)--a prospective observational study of risk factors for cardiovascular disease among > 5,000 participants aged 65 or older. Methods Improvement of risk prediction was assessed by change in the area under the receiver-operator characteristic curve (AUC) and by net reclassification improvement (NRI). Results Among white participants the FRS was improved by addition of KIF6 719Arg carrier status among men as assessed by the AUC (from 0.581 to 0.596, P = 0.03) but not by NRI (NRI = 0.027, P = 0.32). Adding both CRP and 719Arg carrier status to the FRS improved risk prediction by the AUC (0.608, P = 0.02) and NRI (0.093, P = 0.008) in men, but not women (P ≥ 0.24). Conclusions While none of these risk markers individually or in combination improved risk prediction among women, a combination of KIF6 719Arg carrier status and CRP levels modestly improved risk prediction among white men; although this improvement is not significant after multiple-testing correction. These observations should be investigated in other prospective studies.

We read with interest the editorial comment ([1][1]) accompanying 3 reports that described the association of the 719Arg allele of KIF6 with both increased risk of coronary heart disease and with response to statin treatment ([2–4][2]). However, we would like to comment on 2 assertions made in

BackgroundMuch attention is focused on genetic polymorphisms associated with coronary artery disease. A candidate gene controversially associated with risk of coronary events is the kinesin-like protein 6 (KIF6), which is correlated with Trp719Arg polymorphism. In acute myocardial infarction (AMI), endothelial progenitor cells, particularly endothelial colony forming cells (ECFC) are mobilized from bone marrow and correlated with infarct size reduction. We investigated whether there was a relationship between presence of ECFC in AMI at admission and genetic status with regard to the KIF6 Trp719Arg polymorphism (rs20455).MethodsForty five patients aged