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Articles by E Boerwinkle
Total Records ( 9 ) for E Boerwinkle
  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.

  R. I Dmitrieva , C. A Hinojos , M. L Grove , R. J Bell , E Boerwinkle , M Fornage and P. A. Doris

Background— Identification of genes involved in complex cardiovascular disease traits has proven challenging. Inbred animal models can facilitate genetic studies of disease traits. The spontaneously hypertensive rat (SHR) is an inbred model of hypertension that exists in several closely related but genetically distinct lines.

Methods and Results— We used renal gene-expression profiling across 3 distinct SHR lines to identify genes that show different expression in SHR than in the genetically related normotensive control strain, Wistar-Kyoto. To ensure robust discovery of genes showing SHR-specific expression differences, we considered only those genes in which differential expression is replicated in multiple animals of each of multiple hypertensive rat lines at multiple time points during the ontogeny of hypertension. Mutation analysis was performed on the identified genes to uncover allelic variation. We identified those genes in which all SHR lines share a single allele of the gene when normotensive controls (Wistar-Kyoto) have fixed the alternative allele. We then identified which of the differentially expressed genes show expression that is controlled by the alleleic variation present in and around the gene. Allelic expression was demonstrated by observing the effect on gene expression of alleles inherited in the freely segregating F2 progeny of a cross between SHR and Wistar-Kyoto animals.

Conclusions— The result of these studies is the identification of several genes (Ptprj, Ela1, Dapk-2, and Gstt2) in which each of 4 SHR lines examined have fixed the same allele and in which each of 2 Wistar-Kyoto lines have a contrasting allele for which the inherited allele influences the level of gene expression. We further show that alleles of these genes lie in extensive haplotype blocks that have been inherited identical by descent in the hypertensive lines.

  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.

  C. C Huang , M Fornage , D. M Lloyd Jones , G. S Wei , E Boerwinkle and K. Liu

Background— Mutations of PCSK9 are associated cross-sectionally with plasma low-density lipoprotein cholesterol (LDL-C) levels, but little is known about their longitudinal association with LDL-C levels from young adulthood to middle age.

Methods and Results— We investigated the associations of 6 PCSK9 variants with LDL-C over 20 years in 1750 blacks and 1828 whites from the Coronary Artery Risk Development In Young Adults study. Generalized estimating equations were used to assess longitudinal differences in LDL-C levels between genotype categories. For blacks, LDL-C levels at age 18 were significantly lower (P<0.001) among those with 3 genetic variants (L253F, C679X, and Y142X; 81.5 mg/dL) and A443T (95.5 mg/dL) compared with noncarriers (109.6 mg/dL). The difference in LDL-C levels from noncarriers tended to widen for those with the 3 variants only, by 0.24 mg/dL per year of age (P=0.14). For whites with the R46L variant, compared with noncarriers, LDL-C levels at age 18 were significantly lower (84.4 mg/dL versus 100.9 mg/dL; P<0.001), and the increase in LDL-C with age was similar to noncarriers. The 3 genetic variants and the A443T variant in black men were associated with lower carotid intima-media thickness and lower prevalence of coronary calcification measured at ages 38 to 50.

Conclusions— Our results suggest that participants with several genetic variants of PCSK9 have persistently lower serum LDL-C levels than noncarriers from ages 18 to 50. Such long-term reduction in LDL-C levels is associated with reduced subclinical atherosclerosis burden in black men.

  W Tang , G Apostol , P. J Schreiner , D. R Jacobs , E Boerwinkle and M. Fornage

Background— Genome-wide association studies in European Americans have reported several single-nucleotide polymorphisms (SNPs) in the lipoprotein lipase gene associated with plasma levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides. However, the influences of the lipoprotein lipase SNPs on longitudinal changes of these lipids have not been systematically examined.

Methods and Results— On the basis of data from 2045 African Americans and 2116 European Americans in the Coronary Artery Risk Development in Young Adults study, we investigated cross-sectional and longitudinal associations of lipids with 8 lipoprotein lipase SNPs, including the 2 that have been reported in genome-wide association studies. Plasma levels of HDL-C and triglycerides were measured at 7 examinations during 20 years of follow-up. In European Americans, rs328 (Ser447Stop), rs326, and rs13702 were significantly associated with cross-sectional interindividual variations in triglycerides and HDL-C (P<0.005) and with their longitudinal changes over time (P<0.05). The minor alleles in rs326, rs328, and rs13702 that predispose an individual to lower triglycerides and higher HDL-C levels at young adulthood further slow down the trajectory increase in triglycerides and decrease in HDL-C during 20 years of follow-up. In African Americans, these 3 SNPs were significantly associated with triglycerides, but only rs326 and rs13702 were associated with HDL-C (P<0.008). Rs328 showed a stronger association in European Americans than in African Americans, and adjustment for it did not remove all of the associations for the other SNPs. Longitudinal changes in either trait did not differ significantly by SNP genotypes in African Americans.

Conclusions— Our data suggest that aging interacts with LPL gene variants to influence the longitudinal lipid variations, and there is population-related heterogeneity in the longitudinal associations.

  A. C Morrison , J. F Felix , L. A Cupples , N. L Glazer , L. R Loehr , A Dehghan , S Demissie , J. C Bis , W. D Rosamond , Y. S Aulchenko , Y. A Wang , T Haritunians , A. R Folsom , F Rivadeneira , E. J Benjamin , T Lumley , D Couper , B. H Stricker , C. J O'Donnell , K. M Rice , P. P Chang , A Hofman , D Levy , J. I Rotter , E. R Fox , A. G Uitterlinden , T. J Wang , B. M Psaty , J. T Willerson , C. M van Duijn , E Boerwinkle , J. C. M Witteman , R. S Vasan and N. L. Smith

Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2 366 858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

Methods and Results—

Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10–7. Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10–7). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10–5) but did not meet genome-wide significance.


This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

  N. L Smith , J. F Felix , A. C Morrison , S Demissie , N. L Glazer , L. R Loehr , L. A Cupples , A Dehghan , T Lumley , W. D Rosamond , W Lieb , F Rivadeneira , J. C Bis , A. R Folsom , E Benjamin , Y. S Aulchenko , T Haritunians , D Couper , J Murabito , Y. A Wang , B. H Stricker , J. S Gottdiener , P. P Chang , T. J Wang , K. M Rice , A Hofman , S. R Heckbert , E. R Fox , C. J O'Donnell , A. G Uitterlinden , J. I Rotter , J. T Willerson , D Levy , C. M van Duijn , B. M Psaty , J. C. M Witteman , E Boerwinkle and R. S. Vasan

Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2 478 304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

Methods and Results—

Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10–7. During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10–8), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10–8), which was 6.3 kb from LRIG3.


We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

  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

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.


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

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).


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

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