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Sonja I Berndt,
Stefan Gustafsson,
Reedik Magi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
Andre Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
[show abstract]
[hide abstract]
ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
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Sonja I Berndt,
Stefan Gustafsson,
Reedik Mägi,
Andrea Ganna,
Eleanor Wheeler,
Mary F Feitosa,
Anne E Justice,
Keri L Monda,
Damien C Croteau-Chonka,
Felix R Day, [......],
Joel N Hirschhorn,
Cecilia M Lindgren,
Andrew P Morris,
David Meyre,
André Scherag,
Mark I McCarthy,
Elizabeth K Speliotes,
Kari E North,
Ruth J F Loos,
Erik Ingelsson
[show abstract]
[hide abstract]
ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Nature Genetics 04/2013; · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Taking antiobesity medication can be a cost effective way to lose weight. Uptake is determined in part by a General Practitioner's decision to prescribe weight loss medication and, in part, by patient preference. It is probable that the latter may indicate a patient's readiness to lose weight. METHODS: Analysis of cross-sectional data (from February 2003 to March 2011) from a population based prescribing database (∼1.75 million people) using an adjusted Poisson regression. RESULTS: The number of antiobesity medications increased from 23.4 per 1000 population in 2004 to 30.7 per 1000 population in 2010 and was three times higher in female than in male subjects. Against this background, a marked seasonal variation in the number of antiobesity medications dispensed was evident (p<0.001), peaking in June/July with a trough in December/January (±8.0% peak to trough). The seasonal component was stronger in female subjects, ±11.2% peak to trough, compared with ±3.5% for male subjects. CONCLUSIONS: Obese patients, particularly women, increase their uptake of weight loss medication in the months leading up to the summer holiday period. The period prior to the summer may represent a time that health professionals could promote increased participation of obese patients in weight loss programmes.
Journal of epidemiology and community health 01/2013; · 3.04 Impact Factor
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[show abstract]
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ABSTRACT: OBJECTIVE: To simultaneously evaluate 14 biomarkers from distinct biological pathways for risk prediction of ischemic stroke, including biomarkers of hemostasis, inflammation, and endothelial activation as well as chemokines and adipocytokines. METHODS AND RESULTS: The Prospective Epidemiological Study on Myocardial Infarction (PRIME) is a cohort of 9771 healthy men 50 to 59 years of age who were followed up over 10 years. In a nested case-control study, 95 ischemic stroke cases were matched with 190 controls. After multivariable adjustment for traditional risk factors, fibrinogen (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.03-2.28), E-selectin (OR, 1.76; 95% CI, 1.06-2.93), interferon-γ-inducible-protein-10 (OR, 1.72; 95% CI, 1.06-2.78), resistin (OR, 2.86; 95% CI, 1.30-6.27), and total adiponectin (OR, 1.82; 95% CI, 1.04-3.19) were significantly associated with ischemic stroke. Adding E-selectin and resistin to a traditional risk factor model significantly increased the area under the receiver-operating characteristic curve from 0.679 (95% CI, 0.612-0.745) to 0.785 and 0.788, respectively, and yielded a categorical net reclassification improvement of 29.9% (P=0.001) and 28.4% (P=0.002), respectively. Their simultaneous inclusion in the traditional risk factor model increased the area under the receiver-operating characteristic curve to 0.824 (95% CI, 0.770-0.877) and resulted in an net reclassification improvement of 41.4% (P<0.001). Results were confirmed when using continuous net reclassification improvement. CONCLUSIONS: Among multiple biomarkers from distinct biological pathways, E-selectin and resistin provided incremental and additive value to traditional risk factors in predicting ischemic stroke.
Arteriosclerosis Thrombosis and Vascular Biology 01/2013; · 6.37 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer,
Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani,
Klaus Stark
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Sekar Kathiresan,
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer,
Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Sekar Kathiresan,
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer,
Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: To investigate the association between periodontitis and mortality from all causes in a prospective study in a homogenous group of 60- to 70-year-old West European men.
A representative sample of 1400 dentate men, (mean age 63.8, SD 3.0 years), drawn from the population of Northern Ireland, had a comprehensive periodontal examination between 2001 and 2003. Men were divided into thirds on the basis of their mean periodontal attachment loss (PAL). The primary endpoint, death from any cause, was analysed using Kaplan-Meier survival plots and Cox's proportional hazards model.
In total, 152 (10.9%) of the men died during a mean follow-up of 8.9 (SD 0.7) years; 37 (7.9%) men in the third with the lowest PAL (<1.8 mm) died compared with 73 (15.7%) in the third with the highest PAL (>2.6 mm). The unadjusted hazard ratio (HR) for death in the men with the highest level of PAL compared with those with the lowest PAL was 2.11 (95% CI 1.42-3.14), p < 0.0001. After adjustment for confounding variables (age, smoking, hypertension, BMI, diabetes, cholesterol, education, marital status and previous history of a cardiovascular event) the HR was 1.57 (1.04-2.36), p = 0.03.
The European men in this prospective cohort study with the most severe loss of periodontal attachment were at an increased risk of death compared with those with the lowest loss of periodontal attachment.
Journal Of Clinical Periodontology 06/2012; 39(10):940-6. · 3.00 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Current cardiovascular risk prediction is imprecise, with clinical treatment aimed at those with high risk of disease while
neglecting those at intermediate risk who might benefit from early treatment. Biomarkers can capture features of subclinical
atherosclerosis, but although many studies have shown their association with cardiovascular risk, whether they can improve
the performance of prediction algorithms is contested. The combined use of multiple biomarkers offers promise for refining
risk assessment by adding incremental information from different pathophysiologic pathways. The utility of certain combinations
of multiple biomarkers has been shown to have greatest effect in selected patient subgroups (ie, middle-aged men and those
at intermediate risk). Carefully designed randomized controlled trials are needed to understand the clinical implications
of risk stratification using multiple biomarker panels.
KeywordsCardiovascular disease–Clinical utility–Multiple biomarkers–Risk scores
Current Cardiovascular Risk Reports 04/2012; 5(2):165-173.
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Bilal Majed,
Dominique Arveiler,
Annie Bingham,
Jean Ferrieres,
Jean-Bernard Ruidavets,
Michèle Montaye,
Katherine Appleton,
Bernadette Haas, Frank Kee,
Philippe Amouyel,
Pierre Ducimetiere,
Jean-Philippe Empana
[show abstract]
[hide abstract]
ABSTRACT: To date, the association between depressive symptoms and the risk of cardiovascular diseases remains controversial. We investigated prospectively, within the same population, the time course of the association between baseline depressive symptoms and first stroke or coronary heart disease event.
In the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study, a multicenter, observational, prospective cohort, 9601 men from France and Northern Ireland were surveyed for the occurrence of first coronary heart disease (n=647) and stroke events (n=136) over 10 years. At baseline, the fourth quartile of a 13-item modified Center for Epidemiological Studies questionnaire was used to define the presence of depressive symptoms. We sought the best time-dependent function to assess the association between depressive symptoms and outcomes. Thus, the hazard ratios were estimated by a Cox proportional hazard model after splitting the follow-up before and after 5 years of follow-up time periods.
Depressive symptoms at baseline were associated with coronary heart disease in the first 5 years of follow-up (hazard ratio, 1.43; 1.10-1.87) and with stroke in the second 5 years of follow up (hazard ratio, 1.96; 1.21-3.19) after adjustment for age, study centers, baseline socioeconomic factors, traditional vascular risk factors, and antidepressant treatment. The association was even stronger for ischemic stroke (n=108; hazard ratio, 2.48; 1.45-4.25).
The current study suggests that in healthy, European, middle-aged men, baseline depressive symptoms are associated with an increased risk of coronary heart disease in the short-term, and for stroke in the long-term.
Stroke 04/2012; 43(7):1761-7. · 5.73 Impact Factor
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Christof Prugger,
Gérald Luc,
Bernadette Haas,
Dominique Arveiler,
Emeline Machez,
Jean Ferrieres,
Jean-Bernard Ruidavets,
Annie Bingham,
Michèle Montaye,
Philippe Amouyel,
John Yarnell, Frank Kee,
Pierre Ducimetiere,
Jean-Philippe Empana
[show abstract]
[hide abstract]
ABSTRACT: Adipocytokines are hormones secreted from adipose tissue that possibly link adiposity and the risk of cardiovascular disease, but limited prospective data exist on plasma adipocytokines and ischemic stroke risk. We investigated associations and predictive properties of 4 plasma adipocytokines, namely resistin, adipsin, leptin, and total adiponectin, with regard to incident ischemic stroke in the PRIME Study.
A cohort of 9,771 healthy men 50 to 59 years of age at baseline was followed up over a period of 10 years. In a nested case-control study, 95 ischemic stroke cases were matched with 190 controls on age, study center, and date of examination. Hazard ratios (HRs) per standard deviation increase in plasma adipocytokine levels were estimated using conditional logistic regression analysis. The additive value of adipocytokines in stroke risk prediction was evaluated by discrimination and reclassification metrics.
Resistin (HR, 1.88; 95% confidence interval [CI], 1.16-3.03), adipsin (HR, 2.01; 95% CI, 1.33-3.04), and total adiponectin (HR, 1.53; 95% CI, 1.01-2.34), but not leptin, were independent predictors of ischemic stroke. The performance of a traditional risk factor model predicting ischemic stroke was significantly improved by the simultaneous inclusion of resistin, adipsin, and total adiponectin (c-statistic: 0.673 [95% CI, 0.631-0.766] vs 0.826 [95% CI, 0.792-0.892], p < 0.001; net reclassification improvement: 38.1%, p < 0.001).
Higher plasma levels of resistin, adipsin, and total adiponectin were associated with an increased 10-year risk of ischemic stroke among healthy middle-aged men. Resistin, adipsin, and total adiponectin provided incremental value over traditional risk factors for the prediction of ischemic stroke risk.
Annals of Neurology 04/2012; 71(4):478-86. · 11.09 Impact Factor
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ABSTRACT: Aims: To quantify how much of the coronary heart disease (CHD) mortality decline in Northern Ireland between 1987 and 2007 could be attributed to medical and surgical treatments and how much to changes in population cardiovascular risk factors.Methods and Results: The IMPACT mortality model was used to integrate data on uptake and effectiveness of cardiological treatments and risk factor trends in the Northern Ireland population between 1987 and 2007. The main data sources were official population and mortality statistics, hospital administration systems, primary care datasets, published trials and meta-analyses, clinical audits, and national surveys. Between 1987 and 2007, CHD mortality rates in Northern Ireland decreased by 52% in men and 60% in women aged 25-84 years. This resulted in 3180 fewer deaths in 2007 than expected if 1987 mortality rates had persisted. Approximately 35% of this decrease was attributed to increased uptake of treatments in individuals and 60% to population risk factor reductions (principally blood pressure, total cholesterol, and smoking); however, these reductions were partially offset by adverse trends in diabetes, physical inactivity, and obesity.Conclusion: Approximately 60% of the substantial CHD mortality decline in Northern Ireland between 1987 and 2007 was attributable to major cardiovascular risk factor changes and approximately 35% was attributable to treatments. However, adverse trends in diabetes, obesity, and physical inactivity are of major concern.
European journal of preventive cardiology. 03/2012;
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Maria F Hughes,
Olli Saarela,
Jan Stritzke, Frank Kee,
Kaisa Silander,
Norman Klopp,
Jukka Kontto,
Juha Karvanen,
Christina Willenborg,
Veikko Salomaa, [......],
Patrick Diemert,
David-Alexandre Trégouët,
Christian Hengstenberg,
Annette Peters,
Alun Evans,
Wolfgang Koenig,
Jeanette Erdmann,
Nilesh J Samani,
Kari Kuulasmaa,
Heribert Schunkert
[show abstract]
[hide abstract]
ABSTRACT: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design.
Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5-18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived.
Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50-59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events.
Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.
PLoS ONE 01/2012; 7(7):e40922. · 4.09 Impact Factor
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Mervi Oikonen,
Emmi Tikkanen,
Jonna Juhola,
Tarja Tuovinen,
Ilkka Seppälä,
Markus Juonala,
Leena Taittonen,
Vera Mikkilä,
Mika Kähönen,
Samuli Ripatti, [......], Frank Kee,
Christopher Newton-Cheh,
Leena Peltonen,
Nicholas J Schork,
Sarah S Murray,
Gerald S Berenson,
Wei Chen,
Sathanur R Srinivasan,
Veikko Salomaa,
Olli T Raitakari
[show abstract]
[hide abstract]
ABSTRACT: Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2357). Blood pressure was measured at baseline in 1980 (age 3-18 years) and in follow-ups in 1983, 1986, 2001, and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped, and 3 genetic risk scores associated with systolic and diastolic blood pressures and their combination were derived for all of the participants. Effects of the genetic risk score were 0.47 mm Hg for systolic and 0.53 mm Hg for diastolic blood pressures (both P<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 years onward (β=0.68 mm Hg; P=0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood (P<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood; individuals with several susceptibility alleles have, on average, a 0.5-mm Hg higher blood pressure, and this trajectory continues from childhood to adulthood.
Hypertension 12/2011; 58(6):1079-85. · 6.21 Impact Factor
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[show abstract]
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ABSTRACT: Excess fat accumulates in the subcutaneous and visceral adipose tissue compartments. We tested the hypothesis that indicators of visceral adiposity, namely, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), are better predictors of stroke risk than body mass index (BMI).
The association of BMI, WC, WHR, and WHtR with stroke was assessed in 31,201 men and 23,516 women, free of vascular disease at baseline, from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) study. During a mean follow-up of 11 years, 1130 strokes were recorded. Relative risks (95% CI) were calculated by Cox regression after stratification for center and adjustment for age, smoking, educational level, alcohol consumption, hypertension, diabetes, total cholesterol, high-density lipoprotein cholesterol, and BMI and model fit was assessed using log-likelihoods.
BMI, WC, WHR, and WHtR were associated with the risk of stroke in men. After full adjustment including BMI, the relative risks for stroke remained significant for WC (1.19 [1.02 to 1.34] per 1 SD increase in WC), WHR (1.14 [1.03 to 1.26]), and WHtR (1.50 [1.28 to 1.77]). Among women, the extent of the associations with stroke risk was similar for WHtR (1.31 [1.04 to 1.65]), WC (1.19 [0.96 to 1.47]), and WHR (1.08 [0.97 to 1.22]). Further analyses by World Health Organization obesity categories showed that WC, WHR, and WHtR were associated with the risk of stroke also in lean men and women (BMI<25 kg/m2), independently of confounders, cardiovascular risk factors, and BMI.
Indicators of abdominal adiposity, especially WHtR, are more strongly associated with stroke risk than BMI. These results emphasize the importance of measuring abdominal adiposity, especially in lean subjects.
Stroke 08/2011; 42(10):2872-7. · 5.73 Impact Factor
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Maria F Hughes,
Olli Saarela,
Stefan Blankenberg,
Tanja Zeller,
Aki S Havulinna,
Kari Kuulasmaa,
John Yarnell,
Renate B Schnabel,
Laurence Tiret,
Veikko Salomaa,
Alun Evans, Frank Kee
[show abstract]
[hide abstract]
ABSTRACT: We assessed whether a cardiovascular risk model based on classic risk factors (e.g. cholesterol, blood pressure) could refine disease prediction if it included novel biomarkers (C-reactive protein, N-terminal pro-B-type natriuretic peptide, troponin I) using a decision curve approach which can incorporate clinical consequences.
We evaluated whether a model including biomarkers and classic risk factors could improve prediction of 10 year risk of cardiovascular disease (CVD; chronic heart disease and ischaemic stroke) against a classic risk factor model using a decision curve approach in two prospective MORGAM cohorts. This included 7739 men and women with 457 CVD cases from the FINRISK97 cohort; and 2524 men with 259 CVD cases from PRIME Belfast. The biomarker model improved disease prediction in FINRISK across the high-risk group (20-40%) but not in the intermediate risk group, at the 23% risk threshold net benefit was 0.0033 (95% CI 0.0013-0.0052). However, in PRIME Belfast the net benefit of decisions guided by the decision curve was improved across intermediate risk thresholds (10-20%). At p(t) = 10% in PRIME, the net benefit was 0.0059 (95% CI 0.0007-0.0112) with a net increase in 6 true positive cases per 1000 people screened and net decrease of 53 false positive cases per 1000 potentially leading to 5% fewer treatments in patients not destined for an event.
The biomarker model improves 10-year CVD prediction at intermediate and high-risk thresholds and in particular, could be clinically useful at advising middle-aged European males of their CVD risk.
European journal of preventive cardiology. 07/2011; 19(4):874-84.
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Louisa Goumidi,
Karine Gauthier,
Vanessa Legry,
Thérèse Hèrvée Mayi,
Alexia Houzet,
Dominique Cottel,
Michèle Montaye,
Carole Proust, Frank Kee,
Jean Ferrières,
Dominique Arveiler,
Pierre Ducimetière,
Bart Staels,
Jean Dallongeville,
Giulia Chinetti,
Frédéric Flamant,
Philippe Amouyel,
Aline Meirhaeghe
[show abstract]
[hide abstract]
ABSTRACT: Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor-β whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-α (TR-α) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-α (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk.
We analyzed the associations between five THRA polymorphisms and (i) BP level in two population-based studies (MONICA Lille n = 1,155; MONICA Toulouse n = 1,170) and (ii) the risk of CHD in two case-control studies (Lille CHD n = 558 cases/568 controls; PRIME n = 527 cases/584 controls).
Individuals carrying the rs939348 T allele had higher systolic BP (~+1.3 mm Hg) than CC individuals in both the MONICA Lille (P = 0.02) and Toulouse (P = 0.03) studies. The odds ratio (OR) for hypertension was 1.25 (P = 0.02) in the combined sample. Concerning the CHD risk, no significant association could be detected.
For the first time, our study showed associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension but not with CHD, although we admit that the statistical power available to study any relationship with CHD was very limited. Further larger association studies are needed to confirm our findings.
American Journal of Hypertension 06/2011; 24(9):1027-34. · 3.18 Impact Factor
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Louisa Goumidi,
Karine Gauthier,
Vanessa Legry,
Th|[eacute]|r|[egrave]|se H|[egrave]|rv|[eacute]|e Mayi,
Alexia Houzet,
Dominique Cottel,
Mich|[egrave]|le Montaye,
Carole Proust, Frank Kee,
Jean Ferri|[egrave]|res,
Dominique Arveiler,
Pierre Ducimeti|[egrave]|re,
Bart Staels,
Jean Dallongeville,
Giulia Chinetti,
Fr|[eacute]|d|[eacute]|ric Flamant,
Philippe Amouyel,
Aline Meirhaeghe
[show abstract]
[hide abstract]
ABSTRACT: Background Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor-β whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-α (TR-α) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-α (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk.
American Journal of Hypertension 06/2011; 24(9):1027-1034. · 3.18 Impact Factor
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Philipp S Wild,
Tanja Zeller,
Arne Schillert,
Silke Szymczak,
Christoph R Sinning,
Arne Deiseroth,
Renate B Schnabel,
Edith Lubos,
Till Keller,
Medea S Eleftheriadis, [......],
Christopher J O'Donnell,
Nilesh J Samani,
Heribert Schunkert,
Francois Cambien,
Karl J Lackner,
Laurence Tiret,
Veikko Salomaa,
Thomas Munzel,
Andreas Ziegler,
Stefan Blankenberg
[show abstract]
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ABSTRACT: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD).
In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)).
The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
Circulation Cardiovascular Genetics 05/2011; 4(4):403-12. · 6.11 Impact Factor
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ABSTRACT: CKD as defined by KDIGO/KDOQI has been shown to affect ~ 8.5% of the UK population. The prevalence of CKD in the UK is similar to that in the USA, yet incident dialysis rates are dramatically different. This retrospective cohort study investigates the association between reduced kidney function and mortality in a large UK population.
All serum creatinine results covering Northern Ireland's 1.7 million population were collected between 1 January 2001 and 31 December 2002. Estimated glomerular filtration rates (eGFR) were calculated for all serum creatinine measurements using four-variable MDRD equation (IDMS aligned). Patients were followed up for both all-cause and cardiovascular mortality data until the end of December 2006. Patients on renal replacement therapy were excluded. Subgroup analysis in the 75,345 subjects enrolled within a parallel primary care study permitted additional survival analysis with adjustment for traditional cardiovascular risk factors.
A total of 1,967,827 serum creatinine results from 533,798 patients were collected. During the period of follow-up, 59,980 deaths occurred. In multivariate survival analysis, using eGFR as a time-varying covariate, a graded association between CKD (defined by eGFR) and all-cause mortality was identified. Compared with participants with an eGFR of > 60 mL/min/1.73 m(2), the adjusted hazard ratios (and 95% confidence intervals) for participants with an eGFR of 45-59 mL/min/1.73 m(2) was 1.02 (0.99-1.04), an eGFR of 30-44 mL/min/1.73 m(2) was 1.44 (1.40-1.47), an eGFR of 15-29 mL/min/1.73 m(2) was 2.12 (2.05-2.20) and an eGFR of < 15 mL/min/1.73 m(2) was 3.46 (3.24-3.70). Significantly, increased all-cause mortality was associated with an eGFR < 45 mL/min/1.73 m(2) following adjustment for age and gender. The association between cardiovascular mortality and reduced renal function continued to be significant for participants with an eGFR of 45-65 mL/min/1.73 m(2). Subgroup analysis in 75,345 individuals with more detailed clinical information available confirmed this association following adjustment for traditional cardiovascular risk factors in addition to age and gender.
This study demonstrates a graded association between reduced renal function as represented by eGFR and mortality in a UK population. The all-cause and cardiovascular mortality risk increases sharply when estimated GFR falls < 45 mL/min/1.73 m(2). The association between an eGFR measured between 45 and 65 mL/min/1.73 m(2) and cardiovascular mortality persists in this cohort and highlights the ongoing uncertainty in accurately categorizing renal dysfunction.
Nephrology Dialysis Transplantation 03/2011; 26(3):875-80. · 3.40 Impact Factor
