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Articles by D. J Rader
Total Records ( 4 ) for D. J Rader
  K Musunuru , G Lettre , T Young , D. N Farlow , J. P Pirruccello , K. G Ejebe , B. J Keating , Q Yang , M. H Chen , N Lapchyk , A Crenshaw , L Ziaugra , A Rachupka , E. J Benjamin , L. A Cupples , M Fornage , E. R Fox , S. R Heckbert , J. N Hirschhorn , C Newton Cheh , M. M Nizzari , D. N Paltoo , G. J Papanicolaou , S. R Patel , B. M Psaty , D. J Rader , S Redline , S. S Rich , J. I Rotter , H. A Taylor , R. P Tracy , R. S Vasan , J. G Wilson , S Kathiresan , R. R Fabsitz , E Boerwinkle , S. B Gabriel and for the NHLBI Candidate Gene Association Resource
  Background—

The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40 000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

Methods and Results—

CARe has assembled DNA samples for >40 000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

Conclusions—

The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of 2000 biological candidate loci in all participants and genome-wide association study in 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

  M Preuss , I. R Konig , J. R Thompson , J Erdmann , D Absher , T. L Assimes , S Blankenberg , E Boerwinkle , L Chen , L. A Cupples , A. S Hall , E Halperin , C Hengstenberg , H Holm , R Laaksonen , M Li , W Marz , R McPherson , K Musunuru , C. P Nelson , M Susan Burnett , S. E Epstein , C. J O'Donnell , T Quertermous , D. J Rader , R Roberts , A Schillert , K Stefansson , A. F. R Stewart , G Thorleifsson , B. F Voight , G. A Wells , A Ziegler , S Kathiresan , M. P Reilly , N. J Samani , H Schunkert and on behalf of the CARDIoGRAM Consortium
  Background—

Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed.

Methods and Results—

CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2x10–20).

Conclusion—

CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.

  E. T Alexander , M Tanaka , M Kono , H Saito , D. J Rader and M. C. Phillips
 

Carriers of the apolipoprotein A-IMilano (apoA-IM) variant, R173C, have reduced levels of plasma HDL but no increase in cardiovascular disease. Despite intensive study, it is not clear whether the removal of the arginine or the introduction of the cysteine is responsible for this altered functionality. We investigated this question using two engineered variations of the apoA-IM mutation: R173S apoA-I, similar to apoA-IM but incapable of forming a disulfide bond, and R173K apoA-I, a conservative mutation. Characterization of the lipid-free proteins showed that the order of stability was wild typeR173K>R173S>R173C. Compared with wild-type apoA-I, apoA-IM had a lower affinity for lipids, while R173S apoA-I displayed intermediate affinity. The in vivo effects of the apoA-I variants were measured by injecting apoA-I-expressing adeno-associated virus into apoA-I-null mice. Mice that expressed the R173S variant again showed an intermediate phenotype. Thus, both the loss of the arginine and its replacement by a cysteine contribute to the altered properties of apoA-IM. The arginine is potentially involved in an intrahelical salt bridge with E169 that is disrupted by the loss of the positively charged arginine and repelled by the cysteine, destabilizing the helix bundle domain in the apoA-I molecule and modifying its lipid binding characteristics.

  M. E Brousseau , J. S Millar , M. R Diffenderfer , C Nartsupha , B. F Asztalos , M. L Wolfe , J. P Mancuso , A. G Digenio , D. J Rader and E. J. Schaefer
 

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-2H3]l-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (–9.4%, P < 0.003) and nonatorvastatin once- (–9.9%, P = 0.02) and twice- (–13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the -2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in -3-migrating HDL, with mean reductions of –14% (P = 0.23), –18% (P < 0.02), and –18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

 
 
 
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