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Articles by A. D Johnson
Total Records ( 5 ) for A. D Johnson
  N. L Smith , M. H Chen , A Dehghan , D. P Strachan , S Basu , N Soranzo , C Hayward , I Rudan , M Sabater Lleal , J. C Bis , M. P. M de Maat , A Rumley , X Kong , Q Yang , F. M. K Williams , V Vitart , H Campbell , A Malarstig , K. L Wiggins , C. M Van Duijn , W. L McArdle , J. S Pankow , A. D Johnson , A Silveira , B McKnight , A. G Uitterlinden , Aleksic Wellcome Trust Case Control Consortium; , J. B Meigs , A Peters , W Koenig , M Cushman , S Kathiresan , J. I Rotter , E. G Bovill , A Hofman , E Boerwinkle , G. H Tofler , J. F Peden , B. M Psaty , F Leebeek , A. R Folsom , M. G Larson , T. D Spector , A. F Wright , J. F Wilson , A Hamsten , T Lumley , J. C. M Witteman , W Tang and C. J. O'Donnell
 

Background— Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels.

Methods and Results— The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10–8 and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10–24), 4q25 (3.6x10–12), 11q12 (2.0x10–10), 13q34 (9.0x10–259), and 20q11.2 (5.7x10–37). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10–22), 8p21 (1.3x10–16), 9q34 (<5.0x10–324), 12p13 (1.7x10–32), 12q23 (7.3x10–10), 12q24.3 (3.8x10–11), 14q32 (2.3x10–10), and 19p13.2 (1.3x10–9). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated.

Conclusions— New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

  J. E Freedman , M. G Larson , K Tanriverdi , C. J O'Donnell , K Morin , A. S Hakanson , R. S Vasan , A. D Johnson , M. D Iafrati and E. J. Benjamin
 

Background— Although many genetic epidemiology and biomarker studies have been conducted to examine associations of genetic variants and circulating proteins with cardiovascular disease and risk factors, there has been little study of gene expression or transcriptomics. Quantitative differences in the abundance of transcripts has been demonstrated in malignancies, but gene expression from a large community-based cohort examining risk of cardiovascular disease has never been reported.

Methods and Results— On the basis of preliminary microarray data and previously suggested genes from the literature, we measured expression of 48 genes by high-throughput quantitative reverse-transcriptase polymerase chain reaction in 1846 participants of the Framingham Offspring cohort from RNA derived from isolated platelets and leukocytes. A multivariable stepwise regression model was used to assess clinical correlates of quantitative RNA expression. For specific inflammatory platelet-derived transcripts, including ICAM1, IFNG, IL1R1, IL6, MPO, COX2, TNF, TLR2, and TLR4, there were significant associations with higher body mass index (BMI). Compared with platelets, fewer leukocyte-derived transcripts were associated with BMI or other cardiovascular risk factors. Select transcripts were found to be highly heritable, including GPIBA and COX1. Almost uniformly, heritable transcripts were not those associated with BMI.

Conclusions— Inflammatory transcripts derived from platelets, particularly those part of the nuclear factor B pathway, are associated with BMI, whereas others are heritable. This is the first study, using a large community-based cohort, to demonstrate clinical correlates of gene expression and is consistent with the hypothesis that specific peripheral-blood transcripts play a role in the pathogenesis of coronary heart disease and its risk factors.

  A Dehghan , Q Yang , A Peters , S Basu , J. C Bis , A. R Rudnicka , M Kavousi , M. H Chen , J Baumert , G. D.O Lowe , B McKnight , W Tang , M de Maat , M. G Larson , S Eyhermendy , W. L McArdle , T Lumley , J. S Pankow , A Hofman , J. M Massaro , F Rivadeneira , M Kolz , K. D Taylor , C. M van Duijn , S Kathiresan , T Illig , Y. S Aulchenko , K. A Volcik , A. D Johnson , A. G Uitterlinden , G. H Tofler , C Gieger , Psaty Wellcome Trust Case Control Consortium , D. J Couper , E Boerwinkle , W Koenig , C. J O`Donnell , J. C Witteman , D. P Strachan , N. L Smith and A. R. Folsom
 

Background— Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

Methods and Results— We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0x10–8). These included a single-nucleotide polymorphism located in the fibrinogen β chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8x10–30), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3x10–15), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9x10–10), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04x10–8).

Conclusions— Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

  K Musunuru , W. S Post , W Herzog , H Shen , J. R O'Connell , P. F McArdle , K. A Ryan , Q Gibson , Y. C Cheng , E Clearfield , A. D Johnson , G Tofler , Q Yang , C. J O'Donnell , D. M Becker , L. R Yanek , L. C Becker , N Faraday , L. F Bielak , P. A Peyser , A. R Shuldiner and B. D. Mitchell
  Background—

Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that single nucleotide polymorphisms (SNPs) in this region would be associated with platelet reactivity across multiple populations.

Methods and Results—

Subjects in the initial population included 1402 asymptomatic Amish adults in whom we measured platelet reactivity (n=788) and coronary artery calcification (CAC) (n=939). Platelet reactivity on agonist stimulation was measured by impedance aggregometry, and CAC was measured by electron beam CT. Twenty-nine SNPs at the 9p21.3 locus were genotyped using the Affymetrix 500K array. Twelve correlated SNPs in the locus were significantly associated with platelet reactivity (all P≤0.001). The SNP most strongly associated with platelet reactivity, rs10965219 (P=0.0002), also was associated with CAC (P=0.002) along with 9 other SNPs (all P<0.004). Association of rs10965219 with platelet reactivity persisted after adjustment for CAC, a measure of underlying atherosclerotic burden known to affect platelet reactivity. We then tested rs10965219 for association with platelet function in 2364 subjects from the Framingham Heart Study and 1169 subjects from the Genetic Study of Aspirin Responsiveness. The rs10965219 G allele (frequency 51% across all 3 populations) was significantly associated with higher platelet reactivity in the Framingham Heart Study (P=0.001) and trended toward higher reactivity in the Genetic Study of Aspirin Responsiveness (P=0.087); the combined P value for metaanalysis was 0.0002.

Conclusions—

These results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on myocardial infarction/coronary artery disease and stroke risk, possibly through their influence on platelet reactivity.

  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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