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Articles by V Gudnason
Total Records ( 5 ) for V Gudnason
  R. B Schnabel , T Aspelund , G Li , L. M Sullivan , A Suchy Dicey , T. B Harris , M. J Pencina , R. B D'Agostino , D Levy , W. B Kannel , T. J Wang , R. A Kronmal , P. A Wolf , G. L Burke , L. J Launer , R. S Vasan , B. M Psaty , E. J Benjamin , V Gudnason and S. R. Heckbert
 

Background  We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.

Methods  We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.

Results  We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.

Conclusions  Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.

  E Di Angelantonio , R Chowdhury , N Sarwar , K. K Ray , R Gobin , D Saleheen , A Thompson , V Gudnason , N Sattar and J. Danesh
 

Background— Measurement of B-type natriuretic peptide (BNP) concentration or its precursor (N-terminal fragment [NT-proBNP]) is recommended in patients with symptoms of left ventricular dysfunction and in other settings, but the relevance of these peptides to cardiovascular disease (CVD) in general populations or in patients with stable vascular disease is uncertain.

Methods and Results— Data were collated from 40 long-term prospective studies involving a total of 87 474 participants and 10 625 incident CVD outcomes. In a comparison of individuals in the top third with those in the bottom third of baseline values of natriuretic peptides, the combined risk ratio (RR), adjusted for several conventional risk factors, was 2.82 (95% confidence interval [CI], 2.40 to 3.33) for CVD. Analysis of the 6 studies with at least 250 CVD outcomes (which should be less prone to selective reporting than are smaller studies) yielded an adjusted RR of 1.94 (95% CI, 1.57 to 2.39). RRs were broadly similar with BNP or NT-proBNP (RR, 2.89 [95% CI, 1.91 to 4.38] and 2.82 [95% CI, 2.35 to 3.38], respectively) and by different baseline vascular risk (RR, 2.68 [95% CI, 2.07 to 3.47] in approximately general populations; RR, 3.35 [95% CI, 2.38 to 4.72] in people with elevated vascular risk factors; RR, 2.60 [95% CI, 1.99 to 3.38] in patients with stable CVD). Assay of BNP or NT-proBNP in addition to measurement of conventional CVD risk factors yielded generally modest improvements in risk discrimination.

Conclusions— Available prospective studies indicate strong associations between circulating concentration of natriuretic peptides and CVD risk under a range of different circumstances. Further investigation is warranted, particularly in large general population studies, to clarify any predictive utility of these markers and to better control for publication bias.

  R Sofat , A. D Hingorani , L Smeeth , S. E Humphries , P. J Talmud , J Cooper , T Shah , M. S Sandhu , S. L Ricketts , S. M Boekholdt , N Wareham , K. T Khaw , M Kumari , M Kivimaki , M Marmot , F. W Asselbergs , P van der Harst , R. P.F Dullaart , G Navis , D. J van Veldhuisen , W. H Van Gilst , J. F Thompson , P McCaskie , L. J Palmer , M Arca , F Quagliarini , C Gaudio , F Cambien , V Nicaud , O Poirer , V Gudnason , A Isaacs , J. C.M Witteman , C. M van Duijn , M Pencina , R. S Vasan , R. B D'Agostino , J Ordovas , T. Y Li , S Kakko , H Kauma , M. J Savolainen , Y. A Kesaniemi , A Sandhofer , B Paulweber , J. V Sorli , A Goto , S Yokoyama , K Okumura , B. D Horne , C Packard , D Freeman , I Ford , N Sattar , V McCormack , D. A Lawlor , S Ebrahim , G. D Smith , J. J.P Kastelein , J Deanfield and J. P. Casas
 

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target.

Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib.

Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

  A. D Johnson , M Kavousi , A. V Smith , M. H Chen , A Dehghan , T Aspelund , J. P Lin , C. M van Duijn , T. B Harris , L. A Cupples , A. G Uitterlinden , L Launer , A Hofman , F Rivadeneira , B Stricker , Q Yang , C. J O'Donnell , V Gudnason and J. C. Witteman
 

Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 x 10–324) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 x 10–13), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain ~18.0 and ~1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 x 10–13), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.

 
 
 
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