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1. Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study

Author

de Vries, Paul S, Sabater-Lleal, Maria, Chasman, Daniel I, Trompet, Stella, Ahluwalia, Tarunveer S, Teumer, Alexander, Kleber, Marcus E, Chen, Ming-Huei, Wang, Jie Jin, Attia, John R, Marioni, Riccardo E, Steri, Maristella, Weng, Lu-Chen, Pool, Rene, Grossmann, Vera, Brody, Jennifer A, Venturini, Cristina, Tanaka, Toshiko, Rose, Lynda M, Oldmeadow, Christopher, Mazur, Johanna, Basu, Saonli, Frånberg, Mattias, Yang, Qiong, Ligthart, Symen, Hottenga, Jouke J, Rumley, Ann, Mulas, Antonella, de Craen, Anton JM, Grotevendt, Anne, Taylor, Kent D, Delgado, Graciela E, Kifley, Annette, Lopez, Lorna M, Berentzen, Tina L, Mangino, Massimo, Bandinelli, Stefania, Morrison, Alanna C, Hamsten, Anders, Tofler, Geoffrey, de Maat, Moniek PM, Draisma, Harmen HM, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Lackner, Karl J, Völker, Uwe, McKnight, Barbara, Huang, Jie, Holliday, Elizabeth G, McEvoy, Mark A, Starr, John M, Hysi, Pirro G, Hernandez, Dena G, Guan, Weihua, Rivadeneira, Fernando, McArdle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Psaty, Bruce M, Uitterlinden, André G, de Geus, Eco JC, Stott, David J, Binder, Harald, Hofman, Albert, Franco, Oscar H, Rotter, Jerome I, Ferrucci, Luigi, Spector, Tim D, Deary, Ian J, März, Winfried, Greinacher, Andreas, Wild, Philipp S, Cucca, Francesco, Boomsma, Dorret I, Watkins, Hugh, Tang, Weihong, Ridker, Paul M, Jukema, Jan W, Scott, Rodney J, Mitchell, Paul, Hansen, Torben, O'Donnell, Christopher J, Smith, Nicholas L, Strachan, David P, and Dehghan, Abbas

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Genome-Wide Association Study, HapMap Project, Humans, General Science & Technology
Abstract

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

Published
2017

2. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

de Vries, Paul S, Chasman, Daniel I, Sabater-Lleal, Maria, Chen, Ming-Huei, Huffman, Jennifer E, Steri, Maristella, Tang, Weihong, Teumer, Alexander, Marioni, Riccardo E, Grossmann, Vera, Hottenga, Jouke J, Trompet, Stella, Müller-Nurasyid, Martina, Zhao, Jing Hua, Brody, Jennifer A, Kleber, Marcus E, Guo, Xiuqing, Wang, Jie Jin, Auer, Paul L, Attia, John R, Yanek, Lisa R, Ahluwalia, Tarunveer S, Lahti, Jari, Venturini, Cristina, Tanaka, Toshiko, Bielak, Lawrence F, Joshi, Peter K, Rocanin-Arjo, Ares, Kolcic, Ivana, Navarro, Pau, Rose, Lynda M, Oldmeadow, Christopher, Riess, Helene, Mazur, Johanna, Basu, Saonli, Goel, Anuj, Yang, Qiong, Ghanbari, Mohsen, Willemsen, Gonneke, Rumley, Ann, Fiorillo, Edoardo, de Craen, Anton JM, Grotevendt, Anne, Scott, Robert, Taylor, Kent D, Delgado, Graciela E, Yao, Jie, Kifley, Annette, Kooperberg, Charles, Qayyum, Rehan, Lopez, Lorna M, Berentzen, Tina L, Räikkönen, Katri, Mangino, Massimo, Bandinelli, Stefania, Peyser, Patricia A, Wild, Sarah, Trégouët, David-Alexandre, Wright, Alan F, Marten, Jonathan, Zemunik, Tatijana, Morrison, Alanna C, Sennblad, Bengt, Tofler, Geoffrey, de Maat, Moniek PM, de Geus, Eco JC, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Binder, Harald, Völker, Uwe, Waldenberger, Melanie, Khaw, Kay-Tee, Mcknight, Barbara, Huang, Jie, Jenny, Nancy S, Holliday, Elizabeth G, Qi, Lihong, Mcevoy, Mark G, Becker, Diane M, Starr, John M, Sarin, Antti-Pekka, Hysi, Pirro G, Hernandez, Dena G, Jhun, Min A, Campbell, Harry, Hamsten, Anders, Rivadeneira, Fernando, Mcardle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Koenig, Wolfgang, Psaty, Bruce M, Haritunians, Talin, Liu, Jingmin, Palotie, Aarno, Uitterlinden, André G, Stott, David J, Hofman, Albert, and Franco, Oscar H

Subjects
Biological Sciences, Genetics, Human Genome, Adult, Aged, Aged, 80 and over, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Published
2016

5. Fibrinolytic and endothelial markers in cardiovascular disease and diabetes mellitus

Author

Rumley, Ann

Subjects
610, Fibrinolysis, Platelet function
Abstract

Plasminogen activator inhibitor (PAI) activity, tissue plasminogen activator (tPA) antigen and von Willebrand factor (VWF) antigen are endothelial products with roles in fibrinolysis and platelet function respectively. Fibrin D-dimer antigen (D-dimer) is a marker of cross-linked fibrin formation and lysis. Plasma levels of these four haemostatic variables (as well as the acute phase reactants, fibrinogen and red cell aggregation) were studied with regard to variability, associations with ischaemic heart disease (IHD) and its risk factors, and associations with diabetes mellitus (including microalbuminuria and response to insulin and exercise). Laboratory, biological and total variability were defined and appeared satisfactory for clinical studies. In a population sample (North Glasgow MONICA study) distributions and independent associations were defined. PAI was related to time of day, serum triglyceride, alcohol intake, diabetes and interleukin-6. tPA was related to PAI, age, male sex, time of day, cigarette smoking, triglyceride and alcohol use. VWF was related to age, smoking and diabetes. D-dimer was related to age, VWF, fibrinogen and red cell aggregation. In a case control study, survivors of premature myocardial infarction had higher levels of PAI, VWF, D-dimer, fibrinogen and red cell aggregation (which were independent of standard risk factors); and of tPA (which was not independent). In a prospective population study (Caerphilly Heart Study), D-dimer and VWF were independent predictors of IHD events, while PAI and tPA were not. In a prospective study of patients with peripheral arterial disease (Edinburgh Claudication Study), D-dimer was an independent predictor of IHD events and progression of arterial disease; while fibrinogen was an independent predictor of mortality. Non-insulin-dependent diabetic patients with microalbuminuria (a predictor of IHD) had higher levels of tPA and VWF than diabetic or non-diabetic controls without microalbuminuria. Compared to nondiabetic controls, insulin-dependent diabetic patients had lower increments in tPA in response to insulin induced hypoglycaemia or exercise, suggesting an endothelial defect. The results of these studies are consistent with potential roles of disturbed fibrinolysis, endothelial and platelet function, and fibrin turnover in the pathogenesis of ischaemic heart disease and of diabetic vascular complications.

Published
1996

15. Effects of Isolation and Inbreeding on Human Quantitative Traits: An Example of Biochemical Markers of Hemostasis and Inflammation

Author

PULANIĆ, DRAŽEN, POLAŠEK, OZREN, PETROVEČKI, MLADEN, VORKO-JOVIĆ, ARIANA, PERIČIĆ, MARIJANA, LAUC, LOVORKA BARAĆ, KLARIĆ, IRENA MARTINOVIĆ, BILOGLAV, ZRINKA, KOLČIĆ, IVANA, ZGAGA, LINA, CAROTHERS, ANDREW D., RAMIĆ, SENAD, ŠETIĆ, MIA, JANIĆIJEVIĆ, BRANKA, NARANČIĆ, NINA SMOLEJ, BUČAN, KAJO, RUDAN, DIANA, LOWE, GORDON, RUMLEY, ANN, RUDAN, PAVAO, CAMPBELL, HARRY, and RUDAN, IGOR

Published
2008

24. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the ADVANCE Study

Author

Lowe, Gordon, Woodward, Mark, Hillis, Graham, Rumley, Ann, Li, Qiang, Harrap, Stephen, Marre, Michel, Hamet, Pavel, Patel, Anushka, Poulter, Neil, and Chalmers, John

Subjects
C-reactive protein -- Identification and classification, Cardiovascular diseases -- Risk factors, Type 2 diabetes -- Physiological aspects, Health
Abstract

C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) are associated with cardiovascular disease (CVD) and death in general populations. However, studies of these factors in type 2 diabetes are limited. We studied their associations with the risk of major macrovascular events, microvascular complications, and mortality in patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study. Plasma CRP, fibrinogen, and IL-6 levels were determined in a case-cohort study (n = 3,865) nested within the 11,140 men and women with type 2 diabetes and baseline CVD or risk factors in the ADVANCE Study. All three biomarkers of inflammation were associated with an increased risk of macrovascular events and death in analyses adjusted for age, sex, and treatment groups. After further adjustment, only IL-6 was an independent predictor of macrovascular events (hazard ratio per SD increase 1.37 [95% CI 1,24-1.51]) and death (1.35 [1.23-1,49]). IL-6 significantly improved the prediction of macrovascular events and death. After adjustment, none of the markers predicted microvascular complications. We conclude that IL-6 levels, but not CRP or fibrinogen levels, add significantly to the prediction of macrovascular events and mortality in individuals with type 2 diabetes who have baseline CVD or risk factors. DOI: 10.2337/db12-1625, Type 2 diabetes mellitus (T2DM) is a major and growing health problem worldwide, increasing the risk of both macrovascular and microvascular disease, as well as nonvascular mortality (1). Although control [...]

Published
2014
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25. Blood rheology and cognition in the Edinburgh type 2 diabetes study

Author

Marioni, Riccardo E., Deary, Ian J., Strachan, Mark W., Lowe, Gordon D., Rumley, Ann, Murray, Gordon D., and Price, Jackie F.

Subjects
Type 2 diabetes -- Physiological aspects, Cognition disorders -- Risk factors, Cognition disorders -- Demographic aspects, Cognition disorders -- Development and progression, Aging -- Psychological aspects, Aging -- Health aspects, Blood -- Rheology, Blood -- Health aspects, Health, Psychology and mental health, Seniors, Social sciences
Published
2010

26. Haemorheological predictors of cognitive decline: the Edinburgh artery study

Author

Rafnsson, Snorri, Deary, Ian J., Whiteman, Martha C., Rumley, Ann, Lowe, G.D.O., and Fowkes, F. Gerry R.

Subjects
Cognition disorders -- Risk factors, Cognition disorders -- Development and progression, Aging -- Physiological aspects, Aging -- Health aspects, Aged -- Physiological aspects, Aged -- Health aspects, Blood -- Rheology, Blood -- Health aspects, Health, Psychology and mental health, Seniors, Social sciences
Published
2010

28. Inflammation, insulin resistance, and diabetes--Mendelian randomization using CRP haplotypes points upstream

Author

Brunner, Eric J., Kivimaki, Mika, Witte, Daniel R., Lawlor, Debbie A., Smith, George Davey, Cooper, Jackie A., Miller, Michelle, Lowe, Gordon D.O., Rumley, Ann, Casas, Juan P., Shah, Tina, Humphries, Steve E., Hingorani, Aroon D., Marmot, Michael G., Timpson, Nicholas J., and Kumari, Meena

Subjects
Diabetes -- Risk factors -- Genetic aspects, Insulin resistance -- Risk factors -- Genetic aspects, C-reactive protein -- Health aspects -- Genetic aspects, Biological sciences
Abstract

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP+2302G > A; CRP+1444T > C; CRP+4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP. The Editors' Summary of this article follows the references., Introduction C-reactive protein (CRP) is a nonspecific marker of systemic inflammation that predicts incident type 2 diabetes. Chronic low-grade inflammation may induce insulin resistance and is a candidate pathway leading [...]

Published
2008

29. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review

Author

Danesh, John, Kaptoge, Stephen, Mann, Andrea G., Sarwar, Nadeem, Wood, Angela, Angleman, Sara B., Wensley, Frances, Higgins, Julian P.T., Lennon, Lucy, Eiriksdottir, Gudny, Rumley, Ann, Whincup, Peter H., Lowe, Gordon D.O., and Gudnason, Vilmundur

Subjects
Biological sciences
Abstract

Background The relevance to coronary heart disease (CHD) of cytokines that govern inflammatory cascades, such as interleukin-6 (IL-6), may be underestimated because such mediators are short acting and prone to fluctuations. We evaluated associations of long-term circulating IL-6 levels with CHD risk (defined as nonfatal myocardial infarction [MI] or fatal CHD) in two population-based cohorts, involving serial measurements to enable correction for within-person variability. We updated a systematic review to put the new findings in context. Methods and Findings Measurements were made in samples obtained at baseline from 2,138 patients who had a first-ever nonfatal MI or died of CHD during follow-up, and from 4,267 controls in two cohorts comprising 24,230 participants. Correction for within-person variability was made using data from repeat measurements taken several years apart in several hundred participants. The yearto-year variability of IL-6 values within individuals was relatively high (regression dilution ratios of 0.41, 95% confidence interval [CI] 0.28-0.53, over 4 y, and 0.35, 95% CI 0.23-0.48, over 12 y). Ignoring this variability, we found an odds ratio for CHD, adjusted for several established risk factors, of 1.46 (95% CI 1.29-1.65) per 2 standard deviation (SD) increase of baseline IL-6 values, similar to that for baseline C-reactive protein. After correction for within-person variability, the odds ratio for CHD was 2.14 (95% CI 1.45-3.15) with long-term average ('usual') IL-6, similar to those for some established risk factors. Increasing IL-6 levels were associated with progressively increasing CHD risk. An updated systematic review of electronic databases and other sources identified 15 relevant previous population-based prospective studies of IL-6 and clinical coronary outcomes (i.e., MI or coronary death). Including the two current studies, the 17 available prospective studies gave a combined odds ratio of 1.61 (95% CI 1.42-1.83) per 2 SD increase in baseline IL-6 (corresponding to an odds ratio of 3.34 [95% CI 2.45-4.56] per 2 SD increase in usual [long-term average] IL-6 levels). Conclusions Long-term IL-6 levels are associated with CHD risk about as strongly as are some major established risk factors, but causality remains uncertain. These findings highlight the potential relevance of IL-6-mediated pathways to CHD., Introduction As atherosclerosis may be an inflammatory condition [1], there is interest in the relevance of various circulating inflammatory markers to cardiovascular diseases [2]. Inflammatory cascades are propagated by proximal [...]

Published
2008

32. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study

Author

Timpson, Nicholas J., Lawlor, Debbie A., Harbord, Roger M., Gaunt, Tom R., Day, Ian N.M., Palmer, Lyle J., Hattersley, Andrew T., Ebrahim, Shah, Lowe, Gordon, D.O., Rumley, Ann, and Smith, George Davey

Subjects
C-reactive protein -- Genetic aspects, Metabolic syndrome X -- Causes of, Metabolic syndrome X -- Genetic aspects, Genetic research
Published
2005

33. C-reactive prorein and other circulating markers of inflammation in the prediction of coronary heart disease

Author

Danesh, John, Wheeler, Jeremy G., Hirschfield, Gideon M., Eda, Shinichi, Eiriksdottir, Gudny, Rumley, Ann, Lowe, Gordon D.O., Pepys, Mark B., and Gudnason, Vilmundur

Subjects
C-reactive protein -- Usage, Coronary heart disease -- Diagnosis
Abstract

C-reactive protein is a relatively moderate predictor of coronary heart disease. The long-term stability of C-reactive protein values are similar to that of both blood pressure and total serum cholesterol.

Published
2004

40. Genetic Variants Associated with von Willebrand Factor Levels in Healthy Men and Women Identified Using the HumanCVD BeadChip

Author

Zabaneh, Delilah, Gaunt, Tom R., Kumari, Meena, Drenos, Fotios, Shah, Sonia, Berry, Diane, Power, Chris, Hypponen, Elina, Shah, Tina, Palmen, Jutta, Pallas, Jacky, Talmud, Philippa J., Casas, Juan Pablo, Sofat, Reecha, Lowe, Gordon, Rumley, Ann, Morris, Richard W., Whincup, Peter H., Rodriguez, Santiago, Ebrahim, Shah, Marmot, Michael G., Smith, George Davey, Lawlor, Debbie A., Kivimaki, Mika, Whittaker, John, Hingorani, Aroon D., Day, Ian N., and Humphries, Steve E.

Published
2011
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42. Lipoprotein-associated phospholipase A(sub 2) as an independent predictor of coronary heart disease

Author

Packard, Chris J., O'Reilly, Denis S.J., Caslake, Muriel J., McMahon, Alex D., Ford, Ian, Cooney, Josephine, Macphee, Colin H., Suckling, Keith E., Krishna, Mala, Wilkinson, Francis E., Rumley, Ann, and Lowe, Gordon D.O.

Subjects
Phospholipases -- Health aspects, Coronary heart disease -- Patient outcomes, Heart attack -- Risk factors
Abstract

Elevated blood levels of lipoprotein-associated phospholipase A(sub 2) may predict which men will have a heart attack or die from coronary artery disease. This enzyme may modify low-density lipoproteins inside coronary arteries.

Published
2000

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