Background Calcium channel blockers (CCBs) are common antihypertensive medications. Pharmacogenetic variants affect CCB clinical outcomes, although effect sizes are modest in community samples. Variation in patient characteristics may also predict CCB outcomes, and variation attributable to relevant polygenic scores is less prone to confounding. We aimed to test associations between genetically predicted patient characteristics plus pharmacogenetic variants with CCB outcomes in a large community cohort.Methods We extended our analysis of 32,000 UK Biobank dihydropiridine CCBs treated participants (mean duration 5.9 years) testing 23 variants, where NUMA1 rs10898815 and RYR3 rs877087 showed the most robust associations (for discontinuation and heart failure, respectively). We calculated polygenic scores for systolic and diastolic blood pressures (SBP and DBP), body fat mass, waist hip ratio, lean mass, serum calcium, eGFR, lipoprotein A, urinary sodium, and liver fibrosis. Outcomes were CCB discontinuation, heart failure, coronary heart disease and chronic kidney disease.Results For heart failure, the highest risk 20% of polygenic scores for fat mass, lean mass and lipoprotein A were associated with increased risks (Hazard-Ratio (HR)Fat-mass 1.46, 95% CI 1.25-1.70, p=1*10-6; HRLean-mass 1.20, 95%CI 1.04-1.38, p=0.01; HRLipoproteinA 1.29, 95% CI 1.12 to 1.48, p= 4*10-4), versus the lowest risk 20% of each score respectively. Across the cohort, RYR3 T-allele modestly increased heart failure risks (HR 1.13: 1.02-1.25) versus non-carriers, but in subsets with high fat mass, lean mass, and lipoprotein A scores, estimates were substantially larger, e.g., in females aged 65-70 the heart failure Relative Risk was 4.4 (95% CI 1.54-12.4) versus no T-alleles and low scores.For CCB discontinuation, high polygenic scores for fat mass and lean mass increased risks versus the lowest 20%, whereas high SBP and DBP scores decreased discontinuation risks. Hazard ratios for discontinuation with the pharmacogenetic NUMA1 rs10898815 A-allele (overall HR 1.07: 1.02-1.12) were higher (HR 1.17: 1.05-1.29) in those with high polygenic scores for fat mass and lean mass.Conclusion Polygenic scores affecting adiposity and lipoprotein A levels add to known pharmacogenetic variants in predicting key clinical outcomes in CCB treatment. Combining pharmacogenetic variants and relevant individual characteristic polygenic scores may help for personalizing prescribing.What is needed, what do we add? We previously showed that pharmacogenetic variants in RYR3 and NUMA1 were associated with key clinical outcomes in community CCB patients, although effect sizes were modest. Various patient characteristics reportedly affect CCB outcomes. We therefore tested effects of relevant patient characteristics using polygenic scores. They minimize the effect of unmeasured confounders as genotypes are invariant since conception and reflect lifetime exposure to the risk factor. We showed that combining associated scores with the pharmacogenetic variants improved outcome prediction.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementDT is funded by the Ministry of National Education, Republic of Turkey. CP and DM are supported by the University of Exeter Medical School. JB is funded by an Expanding Excellence in England (E3) research grant awarded to the University of Exeter. JM is funded by a National Institute for Health Research Fellowship (NIHR301445). JD is also supported by the Alzheimers Society [grant, 338 (AS-JF-16b-007)]. This publication presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The funders had no input in the study design; in the collection, analysis, and interpretation of data, in the writing of the report; or in the decision to submit the article for publication. The researchers acted independently from the study sponsors in all aspects of this study.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Northwest Multi-Centre Research Ethics Committee approved the collection and use of UK Biobank data (Research Ethics Committee reference 11/NW/0382).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe genetic and phenotypic UK Biobank data are available upon application to the UK Biobank (www.ukbiobank.ac.uk/register-apply).
更多
原文链接
分享
引用
