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3 results on '"Lowe, G.D.O. (Gordon)"'

1. Genome-wide association studies identify genetic loci for low von Willebrand factor levels

Author

Loon, J.E. (Janine ) van, Dehghan, A. (Abbas), Tang, W. (Weihong), Trompet, S. (Stella), McArdle, W.L. (Wendy), Asselbergs, F.F.W. (Folkert F W), Chen, M.-H. (Ming-Huei), Lopez, L.M. (Lorna), Huffman, J.E. (Jennifer), Leebeek, F.W.G. (Frank), Basu, S. (Saonli), Stott, D.J. (David. J.), Rumley, A. (Ann), Gansevoort, R.T. (Ron), Davies, G. (Gail), Wilson, J.J.F. (James J F), Witteman, J.C.M. (Jacqueline), Cao, X. (Xiting), Craen, A.J. (Anton) de, Bakker, S.J.L. (Stephan), Psaty, B.M. (Bruce), Starr, J.M. (John), Hofman, A. (Albert), Jukema, J.W. (Jan Wouter), Deary, I.J. (Ian), Hayward, C. (Caroline), Harst, P. (Pim) van der, Lowe, G.D.O. (Gordon), Folsom, A.R. (Aaron), Strachan, D.P. (David), Smith, N.L. (Nicholas), Maat, M.P.M. (Moniek) de, O'Donnell, C.J. (Christopher), Loon, J.E. (Janine ) van, Dehghan, A. (Abbas), Tang, W. (Weihong), Trompet, S. (Stella), McArdle, W.L. (Wendy), Asselbergs, F.F.W. (Folkert F W), Chen, M.-H. (Ming-Huei), Lopez, L.M. (Lorna), Huffman, J.E. (Jennifer), Leebeek, F.W.G. (Frank), Basu, S. (Saonli), Stott, D.J. (David. J.), Rumley, A. (Ann), Gansevoort, R.T. (Ron), Davies, G. (Gail), Wilson, J.J.F. (James J F), Witteman, J.C.M. (Jacqueline), Cao, X. (Xiting), Craen, A.J. (Anton) de, Bakker, S.J.L. (Stephan), Psaty, B.M. (Bruce), Starr, J.M. (John), Hofman, A. (Albert), Jukema, J.W. (Jan Wouter), Deary, I.J. (Ian), Hayward, C. (Caroline), Harst, P. (Pim) van der, Lowe, G.D.O. (Gordon), Folsom, A.R. (Aaron), Strachan, D.P. (David), Smith, N.L. (Nicholas), Maat, M.P.M. (Moniek) de, and O'Donnell, C.J. (Christopher)

Abstract

Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10-8 and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10-10), 9q34 (2.4 × 10-64), 12p13 (5.3 × 10-22), 12q23 (1.2 × 10-8) and 13q13 (2.6 × 10-8). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels.European Journal of Human Genetics advance online publication, 21 October 2015; doi:10.1038/ejhg.2015.222.

Published
2016
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2. C-reactive protein, fibrinogen, and cardiovascular disease prediction

Author

Kaptoge, S. (Stephen), Angelantonio, E. (Emanuele) di, Pennells, L. (Lisa), Wood, A.M. (Angela), White, I.R. (Ian), Gao, P. (Pei), Walker, M. (Mark), Thompson, A. (Alexander), Sarwar, S. (Sheryar), Caslake, M. (Muriel), Butterworth, A.S. (Adam), Amouyel, P. (Philippe), Assmann, G. (Gerd), Bakker, S.J.L. (Stephan), Barr, E.L.M., Barrett-Connor, E. (Elizabeth), Benjamin, E.J. (Emelia), Björkelund, C. (Cecilia), Brenner, H. (Hermann), Brunner, E. (Eric), Clarke, R. (Robert), Cooper, J.A. (Jackie), Cremer, P., Cushman, M. (Mary Ann), Dagenais, G.R. (Gilles R), D'Agostino, R.B. (Ralph), Dankner, R. (Rachel), Davey-Smith, G. (George), Deeg, D.J.H. (Dorly), Dekker, J.M. (Jacqueline), Engström, G., Folsom, A.R. (Aaron), Fowkes, F.G.R. (F. Gerald R.), Gallacher, J. (John), Gaziano, J.M. (J. Michael), Giampaoli, S. (Simona), Gillum, R.F. (Richard), Hofman, A. (Albert), Howard, B.V. (Barbara), Ingelsson, E. (Erik), Iso, H. (Hiroyasu), Jorgensen, T. (Torben), Kiechl, S. (Stefan), Kitamura, A., Kiyohara, Y. (Yutaka), Koenig, W. (Wolfgang), Kromhout, D. (Daan), Kuller, L.H. (Lewis), Lawlor, D.A. (Debbie), Meade, T. (Tom), Nissinen, A. (Aulikki), Nordestgaard, B.G. (Børge), Onat, A. (Altan), Panagiotakos, D.B. (Demosthenes), Psaty, B.M. (Bruce), Rodriguez, B. (Beatriz), Rosengren, A. (Annika), Salomaa, V. (Veikko), Kauhanen, J. (Jussi), Salonen, J.T., Shaffer, J.A. (Jonathan), Shea, S. (Steven), Ford, I. (Ian), Stehouwer, C.D. (Coen), Strandberg, T.E. (Timo), Tipping, A. (Alex), Tosetto, A. (Alberto), Wassertheil-Smoller, S. (Sylvia), Wennberg, P. (Patrik), Westendorp, R.G.J. (Rudi), Whincup, P.H. (Peter), Wilhelmsen, L. (Lars), Woodward, M. (Mark), Lowe, G.D.O. (Gordon), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Sattar, N. (Naveed), Packard, C. (Chris), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Pepys, M.B. (Mark), Thompson, S.G. (Simon), Danesh, J. (John), Kaptoge, S. (Stephen), Angelantonio, E. (Emanuele) di, Pennells, L. (Lisa), Wood, A.M. (Angela), White, I.R. (Ian), Gao, P. (Pei), Walker, M. (Mark), Thompson, A. (Alexander), Sarwar, S. (Sheryar), Caslake, M. (Muriel), Butterworth, A.S. (Adam), Amouyel, P. (Philippe), Assmann, G. (Gerd), Bakker, S.J.L. (Stephan), Barr, E.L.M., Barrett-Connor, E. (Elizabeth), Benjamin, E.J. (Emelia), Björkelund, C. (Cecilia), Brenner, H. (Hermann), Brunner, E. (Eric), Clarke, R. (Robert), Cooper, J.A. (Jackie), Cremer, P., Cushman, M. (Mary Ann), Dagenais, G.R. (Gilles R), D'Agostino, R.B. (Ralph), Dankner, R. (Rachel), Davey-Smith, G. (George), Deeg, D.J.H. (Dorly), Dekker, J.M. (Jacqueline), Engström, G., Folsom, A.R. (Aaron), Fowkes, F.G.R. (F. Gerald R.), Gallacher, J. (John), Gaziano, J.M. (J. Michael), Giampaoli, S. (Simona), Gillum, R.F. (Richard), Hofman, A. (Albert), Howard, B.V. (Barbara), Ingelsson, E. (Erik), Iso, H. (Hiroyasu), Jorgensen, T. (Torben), Kiechl, S. (Stefan), Kitamura, A., Kiyohara, Y. (Yutaka), Koenig, W. (Wolfgang), Kromhout, D. (Daan), Kuller, L.H. (Lewis), Lawlor, D.A. (Debbie), Meade, T. (Tom), Nissinen, A. (Aulikki), Nordestgaard, B.G. (Børge), Onat, A. (Altan), Panagiotakos, D.B. (Demosthenes), Psaty, B.M. (Bruce), Rodriguez, B. (Beatriz), Rosengren, A. (Annika), Salomaa, V. (Veikko), Kauhanen, J. (Jussi), Salonen, J.T., Shaffer, J.A. (Jonathan), Shea, S. (Steven), Ford, I. (Ian), Stehouwer, C.D. (Coen), Strandberg, T.E. (Timo), Tipping, A. (Alex), Tosetto, A. (Alberto), Wassertheil-Smoller, S. (Sylvia), Wennberg, P. (Patrik), Westendorp, R.G.J. (Rudi), Whincup, P.H. (Peter), Wilhelmsen, L. (Lars), Woodward, M. (Mark), Lowe, G.D.O. (Gordon), Wareham, N.J. (Nick), Khaw, K-T. (Kay-Tee), Sattar, N. (Naveed), Packard, C. (Chris), Gudnason, V. (Vilmundur), Ridker, P.M. (Paul), Pepys, M.B. (Mark), Thompson, S.G. (Simon), and Danesh, J. (John)

Abstract

BACKGROUND: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 ye

Published
2012
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3. Genetic predictors of fibrin D-dimer levels in healthy adults

Author

Smith, N.L. (Nicholas), Huffman, J.E. (Jennifer E.), Strachan, D.P. (David), Huang, J. (Jian), Dehghan, A. (Abbas), Trompet, S. (Stella), Lopez, L.M. (Lorna M.), Shin, S.Y. (So Youn), Baumert, J. (Jens), Vitart, V. (Veronique), Bis, J.C. (Joshua), Wild, S.H. (Sarah), Rumley, A. (Ann), Yang, Q. (Qiong Fang), Uitterlinden, A.G. (André), Stott, D.J. (David. J.), Davies, G. (Gareth), Carter, A.M. (Angela M.), Thorand, B. (Barbara), Polašek, O. (Ozren), McKnight, B. (Barbara), Campbell, H. (Harry), Rudnicka, A.R. (Alicja), Chen, M.H. (Min-hsin), Buckley, B.M. (Brendan M.), Harris, S.E. (Sarah), Peters, A. (Annette), Pulanic, D. (Drazen), Lumley, T. (Thomas), de Craen, A.J.M. (Anton J.M.), Liewald, D.C.M. (David), Gieger, C. (Christian), Ford, I. (Ian), Gow, A.J. (Alan J.), Luciano, M. (Michelle), Porteous, D.J. (David J.), Guo, X. (Xiuqing), Sattar, N. (Naveed), Tenesa, A. (Albert), Cushman, M. (Mary Ann), Slagboom, P.E. (Eline), Visscher, P.M. (Peter M.), Spector, T.D. (Timothy), Illig, T. (Thomas), Rudan, I. (Igor), Bovill, E.G. (Edwin G.), Wright, A.F. (Alan), McArdle, W.L. (Wendy), Tofler, G.H. (Geoffrey), Hofman, A. (Albert), Westendorp, R.G.J. (Rudi), Starr, J.M. (John), Grant, P.J. (Peter J.), Karakas, M. (Mahir), Hastie, N.D. (Nicholas D.), Psaty, B.M. (Bruce), Wilson, J.F. (James), Lowe, G.D.O. (Gordon), O'Donnell, C.J. (Christopher), Witteman, J.C.M. (Jacqueline), Jukema, J.W. (Jan Wouter), Deary, I.J. (Ian), Soranzo, N. (Nicole), Koenig, W. (Wolfgang), Hayward, C. (Caroline), Smith, N.L. (Nicholas), Huffman, J.E. (Jennifer E.), Strachan, D.P. (David), Huang, J. (Jian), Dehghan, A. (Abbas), Trompet, S. (Stella), Lopez, L.M. (Lorna M.), Shin, S.Y. (So Youn), Baumert, J. (Jens), Vitart, V. (Veronique), Bis, J.C. (Joshua), Wild, S.H. (Sarah), Rumley, A. (Ann), Yang, Q. (Qiong Fang), Uitterlinden, A.G. (André), Stott, D.J. (David. J.), Davies, G. (Gareth), Carter, A.M. (Angela M.), Thorand, B. (Barbara), Polašek, O. (Ozren), McKnight, B. (Barbara), Campbell, H. (Harry), Rudnicka, A.R. (Alicja), Chen, M.H. (Min-hsin), Buckley, B.M. (Brendan M.), Harris, S.E. (Sarah), Peters, A. (Annette), Pulanic, D. (Drazen), Lumley, T. (Thomas), de Craen, A.J.M. (Anton J.M.), Liewald, D.C.M. (David), Gieger, C. (Christian), Ford, I. (Ian), Gow, A.J. (Alan J.), Luciano, M. (Michelle), Porteous, D.J. (David J.), Guo, X. (Xiuqing), Sattar, N. (Naveed), Tenesa, A. (Albert), Cushman, M. (Mary Ann), Slagboom, P.E. (Eline), Visscher, P.M. (Peter M.), Spector, T.D. (Timothy), Illig, T. (Thomas), Rudan, I. (Igor), Bovill, E.G. (Edwin G.), Wright, A.F. (Alan), McArdle, W.L. (Wendy), Tofler, G.H. (Geoffrey), Hofman, A. (Albert), Westendorp, R.G.J. (Rudi), Starr, J.M. (John), Grant, P.J. (Peter J.), Karakas, M. (Mahir), Hastie, N.D. (Nicholas D.), Psaty, B.M. (Bruce), Wilson, J.F. (James), Lowe, G.D.O. (Gordon), O'Donnell, C.J. (Christopher), Witteman, J.C.M. (Jacqueline), Jukema, J.W. (Jan Wouter), Deary, I.J. (Ian), Soranzo, N. (Nicole), Koenig, W. (Wolfgang), and Hayward, C. (Caroline)

Abstract

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search. METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log-transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4×10) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4×10) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9×10) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log-transformed D-dimer and together accounted for 1.8% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus. CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

Published
2011
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