Summary Background Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of ...both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. Methods A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48 421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. Findings When individuals were divided into low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22–1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55–1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. Interpretation A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. Funding National Institutes of Health.
Background Carriers of the rs4363657C and rs4149056C alleles in SLCO1B1 have increased myopathic complaints when taking simvastatin. Whether rosuvastatin has a similar effect is uncertain. This study ...assesses whether SLCO1B1 polymorphisms relate to clinical myalgia after rosuvastatin therapy. Methods In the JUPITER trial, participants without prior cardiovascular disease or diabetes who had low-density lipoprotein cholesterol <130 mg/dL and C-reactive protein ≥2 mg/L were randomly allocated to rosuvastatin 20 mg or placebo and followed for the first cardiovascular disease events and adverse effects. We evaluated the effect of rs4363657 and rs4149056 in SLCO1B1 , which encodes organic anion–transporting polypeptide OATP1B1, a regulator of hepatic statin uptake, on clinically reported myalgia. Results Among 4,404 participants allocated to rosuvastatin, clinical myalgia occurred with a rate of 4.1 events per 100 person-years as compared with 3.7 events per 100 person-years among 4,378 participants allocated to placebo (hazard ratio HR 1.13, 95% CI 0.98-1.30). Among those on rosuvastatin, there were no differences in the rate of myalgia among those with the rs4363657C (HR 0.95, 95% CI 0.79-1.14 per allele) or the rs4149056C allele (HR 0.95, 95% CI 0.79-1.15 per allele) compared with those without the C allele. Similar null data were observed when the myalgia definition was broadened to include muscle weakness, stiffness, or pain. None of the 3 participants on rosuvastatin or the 3 participants on placebo with frank myopathy had the minor allele at either polymorphism. Conclusion There appears to be no increased risk of myalgia among users of rosuvastatin who carry the rs4363657C or the rs4149056C allele in SLCO1B1.
Abstract Background The role of lose dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared ...LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. Design CIRT will randomize up to 7,000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose 15–20 mg/week) or placebo for an average follow-up period of 3–5 years; subjects in both treatment arms receive folic acid 1 mg daily for six days each week. The primary endpoints of CIRT include recurrent vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. Summary CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.
A Kinesin Family Member 6 Variant Is Associated With Coronary Heart Disease in the Women’s Health Study Dov Shiffman, Daniel I. Chasman, Robert Y. L. Zee, Olga A. Iakoubova, Judy Z. Louie, James J. ...Devlin, Paul M. Ridker The 719Arg allele of KIF6 was previously found to be associated with risk of coronary heart disease (CHD) in the ARIC (Atherosclerosis Risk In Communities), CARE (Cholesterol And Recurrent Events), and WOSCOPS (West of Scotland Coronary Prevention Study) trials. In Caucasian participants of the WHS (Women’s Health Study), carriers of the 719Arg allele had increased risk of CHD (adjusted hazard ratio HR = 1.24 95% confidence interval (CI) 1.04 to 1.46, p = 0.013) and myocardial infarction (adjusted HR = 1.34 95% CI 1.02 to 1.75, p = 0.034) but not ischemic stroke.
Background Variation in the Fat-Mass and Obesity-Associated ( FTO ) gene has been associated with obesity, diabetes, and hypertension. However, its association with cardiovascular disease (CVD) in ...healthy populations and any interaction with physical activity remain unclear. Methods The FTO rs8050136 allele was determined in a prospective cohort study of 21,674 apparently healthy White US women in the Women's Genome Health Study. Results During a mean follow-up of 12.7 ± 2.0 years, 664 incident CVD events occurred. The risk allele (A) was associated with higher prevalence of hypertension, diabetes, and metabolic syndrome (all P < .05). In a multivariate model, there was significant association of the risk allele with CVD (hazard ratio HR per allele copy 1.14, 95% CI 1.01-1.28) that was no longer significant after additional adjustment for body mass index (BMI) (HR 1.10, 95% CI 0.97-1.23). There was statistical evidence of an interaction between FTO and physical activity ( P = .048). We found a significant association of FTO with CVD only among less-active (≤8.8 metabolic equivalent-h/wk) women (HR 1.19, 95% CI 1.02-1.38) in multivariate analyses that included BMI. More-active women did not have this increased risk (HR 0.96, 95% CI 0.79-1.16). In a model that adjusted for BMI, less-active/high-risk (A/A) women were at 54% increased risk of developing CVD (HR 1.54, 95% CI 1.13-2.11), compared to more-active/low-risk (C/C) women. Conclusions Carriers of the FTO risk allele have an increased risk of CVD mediated by BMI. There appears to be an interaction with physical activity, such that this risk increase is only in less-active women.
Abstract Background We have recently shown that the C-reactive protein (CRP) response to statin therapy is highly variable, with 45% of people on atorvastatin having no decrease in CRP. Whether there ...is any genetic component to this variability is unclear. We sought to identify genetic determinants and quantify the single nucleotide polymorphism based heritability of CRP response to statins. Methods In a meta-analysis of genome-wide association studies, we included datasets from both randomised controlled trials and observational studies. There were about 10 000 statin-treated individuals overall, grouped into a first discovery stage (from the CARDS trial and PROSPER, PARC, and FSH studies) and a second replication stage (from the JUPITER trial). CRP response was modelled as log(CRP follow-up/CRP baseline) adjusted for baseline CRP and other covariates. Genome-complex trait analysis (GCTA) was used to identify the narrow-sense heritability of CRP response. Findings The study consisted of about 5300 statin users in the discovery cohort and 4000 statin users as replication cohort. On the GCTA analysis narrow-sense heritability ( h2 ) for CRP response was 0·19 (SE 0·24) and was higher than that reported for LDL cholesterol response to statin therapy 0·05 (SE 0·14). Preliminary results of the genome-wide association meta-analysis identified three loci that achieved genome-wide statistical significance: APOE , rs429358 (p=7·91E–10); RP11-458D21.5 , rs184819447 (p=2·32E–9); MYT1L , rs79020661 (p=3·21E–8). Other than APOE none of these was associated with LDL response to statin therapy or baseline CRP. Interpretation These data are consistent with statin-induced change in CRP having a mechanism distinct from LDL cholesterol change. We identified several loci associated with CRP-response to statin therapy and they need to be investigated further by additional replication analysis. Funding HD is funded by a National Institute for Health Research Clinical Academic Fellowship.
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