Dominique Arveiler

Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease

We identify the SLC22A3-LPAL2-LPA gene cluster as a strong susceptibility locus for coronary artery disease (CAD) through a genome-wide haplotype association (GWHA) study. This locus was not identified from previous genome-wide association (GWA) studies focused on univariate analyses of SNPs. The proposed approach may have wide utility for analyzing GWA data for other complex traits.

Successful overweight prevention in adolescents by increasing physical activity: a 4-year randomized controlled intervention

Background:Population-based studies directed at promoting physical activity in youth have shown limited success in obesity prevention.Objective:To assess whether an intervention integrating environmental changes to induce sustained changes in physical activity, prevents overweight in adolescents.Design:Four-year randomized trial started in 2002 in eight middle schools of Eastern France. The intervention, randomized at school level, was designed to promote physical activity by changing attitudes through debates and attractive activities, and by providing social support and environmental changes encouraging physical activity.Subjects:Nine hundred and fifty four 12-year-old six-graders.Measurements:Body mass index (BMI), body composition, physical activity by questionnaire, plasma lipids and glucose, insulin resistance.Results:Intervention students had a lower increase in BMI (P=0.01) and age- and gender-adjusted BMI (P<0.02) over time than controls. The differences across groups of the age- and gender-adjusted BMI changes (95% confidence interval (CI)) were −0.29 (−0.51; −0.07) kg/m2 at 3 years, −0.25 (−0.51; 0.01) kg/m2 at 4 years. An interaction with baseline weight status was noted. The intervention had a significant effect throughout the study in initially non-overweight adolescents (−0.36 (−0.60;−0.11) kg/m2 for adjusted BMI at 4 years), corresponding to a lower increase in fat mass index (P<0.001). In initially overweight adolescents, the differences observed across groups at 2 years (–0.40 (−0.94; 0.13) kg/m2 for adjusted BMI) did not persist over time. At 4 years, 4.2% of the initially non-overweight adolescents were overweight in the intervention schools, 9.8% in the controls (odds ratio=0.41 (0.22; 0.75); P<0.01). Independent of initial weight status, compared with controls, intervention adolescents had an increase in supervised physical activity (P<0.0001), a decrease of TV/video viewing (P<0.01) and an increase of high-density cholesterol concentrations (P<0.0001).Conclusion:Enhancing physical activity with a multilevel program prevents excessive weight gain in non-overweight adolescents. Our study provides evidence that prevention of obesity in youth is feasible.

Parent-child physical activity relationships in 12-year old French students do not depend on family socioeconomic status

OBJECTIVESnRegular physical activity (PA) in young needs to be promoted to prevent obesity and subsequent diabetes. Influences of parental PA on adolescents activity level have been studied with discordant results and the effect of socioeconomic status (SES) on these relationships is not clarified.nnnMETHODSnCross-sectional population-based survey of about 3000 12-year old French students and their parents. Familial associations were assessed with logistic regression models taking into account SES and childrens and parents corpulence. Sport involvement and sedentary behaviors were assessed by standardized questionnaires filled out separately by children and parents, the latter also reporting their educational data and family income tax.nnnRESULTSnParticipation in structured PA outside school was higher for boys (74%) than for girls (58%, p<10-5) and a high sedentary behavior (watching television, playing computer/video games and reading > or =2h/day) was observed in one-third of the sample, both in boys and in girls. Children were more likely to participate in structured PA outside school when both parents practiced sport as compared to neither parent practicing it, with an odd ratio OR (95%CI) of 1.97 (1.4-2.8) for boys and 1.56 (1.2-2.1) for girls. Familial associations of inactivity were significant for boys only. A greater percentage of adolescents had a high level of sedentary behavior when both parents versus no parents watched television > 2h/day (OR 1.95 (1.52.6)). Parent-child physical activity relationships were not modified by the family SES or the childrens or parents weight status.nnnCONCLUSIONnParental involvement in sport is an important correlate of a young adolescents participation in structured PA outside school, whatever the family SES or corpulence of the family members.

Trends in plasma lipids, lipoproteins and dyslipidaemias in French adults, 1996–2007

BACKGROUNDnIn France, the reported decrease in cardiovascular death is due partly to improved cardiovascular prevention. The management of dyslipidaemias remains a priority of preventive cardiology.nnnAIMnTo assess trends in lipids, lipoproteins and dyslipidaemias between 1996 and 2007 in France.nnnMETHODSnRepresentative surveys of the general population were carried out in Lille, Strasbourg and Toulouse during two periods, 1996 to 1997 and 2006 to 2007. Men and women aged 35 to 64 years were included. Investigators recorded cardiovascular risk factors, and a blood sample was drawn to measure glycaemia and to provide a complete lipid profile. The data were corrected according to the respective original populations to study 10-year trends in the parameters measured.nnnRESULTSnFrom 1996 to 2007, a significant 5.7% decrease in low-density lipoprotein (LDL)-cholesterol levels was observed in adults aged 35 to 64 years (p<0.001). This decrease was greater in those aged 55 to 64 years (10.8% in men, 8.4% in women). A significant 7.8% increase in triglycerides was observed (p<0.001) over the same period. Variation in LDL-cholesterol was more striking in subjects treated with a lipid-lowering drug, with a 17.6% reduction (p<0.001). A decrease in most of dyslipidaemias was also observed over this 10-year interval.nnnCONCLUSIONnThis study shows a favourable downward trend in LDL-cholesterol concentration and dyslipidaemias in France. The significant decrease in LDL-cholesterol observed among all the subjects and more particularly among subjects treated with lipid-lowering drugs should provide an incentive for physicians to support the management of all French adults.

Metabolic syndrome and coronary heart disease risk in a population-based study of middle-aged men from France and Northern Ireland: A nested case-control study from the PRIME cohort

Metabolic Syndrome (MetS) was found associated with an increased CHD risk in several studies but data about this relationship in Southern Europe are lacking. We studied the association of MetS according to three different indexes (the National Cholesterol Education Programs definition (NCEP), a modified World Health Organizations definition (WHO) and the recent International Diabetes Federations definition (IDF)) with CHD risk in a case-control study nested within the PRIME cohort, composed of subjects from France (Southern Europe) and Belfast (Northern Europe). The PRIME prospective study is composed of 10 592 men, aged 50-59 at baseline and followed for 5 years. Subjects included in this nested case-control study were 296 cases of incident CHD and 540 controls, who remained free of CHD during the 5 years of follow-up of the PRIME cohort and matched for age, recruitment centre and recruitment date. All subjects had questionnaires and a medical examination at baseline, and a blood sample was taken. Using the IDFs, the WHOs and the NCEPs definitions respectively, the frequency of MetS was 38.9%, 35.5% and 29.7% in cases and 32.4%, 28.7% and 22.6% in controls. After adjustment for physical activity, smoking and drinking habits, MetS was associated with CHD risk whichever the definition used (ORIDF=1.41 [1.02-1.95], P<0.04, ORWHO=1.40 [1.01-1.94], P<0.05 and ORNCEP=1.46[1.04-2.04], P<0.04). These results were homogeneous in France (low risk of CHD) and Belfast (high risk of CHD). Our results add further evidence that MetS is predictive of CHD risk in middle-aged men from Northern and Southern Europe, and highlight differences between the three definitions studied.

Ten-Year All-Cause Mortality in Presumably Healthy Subjects on Lipid-Lowering Drugs (from the Prospective Epidemiological Study of Myocardial Infarction [PRIME] prospective cohort)

Lipid-lowering drugs are one of the most prescribed drugs worldwide. The aim was to compare 10-year all-cause mortality according to initial dyslipidemia status and lipid-lowering drug exposure. The PRIME study was a multicenter population-based prospective cohort study of men recruited in 1991 to 1993, aged 50 to 59 years at baseline, and followed up for 10 years. The 4 groups compared were normolipidemic, untreated dyslipidemic, and dyslipidemic subjects on fibrate or statin therapy. Data were analyzed using multivariate Cox models. The cohort included 7,722 French men (statin group 4.0%, fibrate group 7.9%, untreated dyslipidemic subjects 19.0%, and normolipidemic subjects 69.1%). After 10 years, 4.8% of the sample was lost to follow-up and 416 deaths occurred (cancers 53.1%, cardiovascular diseases 17.1%, and other 29.8%). After adjustment for center, age, educational level, cardiovascular risk factors, lipids, alcohol intake, and history of cardiovascular and severe chronic diseases, hazard ratios (HRs) for all-cause mortality were 0.49 (95% confidence interval [CI] 0.26 to 0.94, p = 0.031) for subjects treated with a statin, 0.65 (95% CI 0.42 to 0.99, p = 0.046) for those on fibrate therapy, and 0.76 (95% CI 0.56 to 1.03, p = 0.080) for normolipidemic men compared with untreated dyslipidemic subjects. In the statin group, HRs for death from cardiovascular disease, cancer, and other causes were 0.55 (p = 0.348), 0.41 (p = 0.067), and 0.68 (p = 0.546) compared with dyslipidemic subjects, respectively. In the fibrate group, HRs were 0.76 (p = 0.499), 0.52 (p = 0.041), and 0.87 (p = 0.746). In conclusion, in this cohort study carried out in a real-life setting, all-cause mortality was significantly lower in dyslipidemic subjects on fibrate or statin therapy than in untreated dyslipidemic patients. No excess risk of noncardiovascular death was observed.

Adiponectin is associated with lipid profile and insulin sensitivity in French adolescents.

AIMnThe favourable relationship of adiponectin with the metabolic profile demonstrated in adults has been less studied in youths. The aim of this study was to examine cross-sectional and longitudinal associations between adiponectin and various metabolic risk factors in 12-year-old adolescents.nnnMETHODSnSubjects were participants in a randomized controlled study to promote physical activity (PA). Cross-sectional associations were assessed at entry in 2002 among 647 PA-exposed and control first-level students (49% male, 11.6+/-0.6 years of age). Longitudinal analyses involved 288 control students surveyed in 2002 and 2004. Baseline measurements included fasting serum adiponectin and anthropometric indices (body mass, waist size, body fat [BF] by bioimpedance), insulin concentration, homeostasis model assessment (HOMA), high-density lipoprotein (HDL) cholesterol, triglycerides (TG), soluble TNF-alpha receptor 1 (sTNF-alpha R1) and high-sensitivity C-reactive protein. Analyses were performed with generalized linear mixed-effects models, taking into account correlations among adolescents in the same school.nnnRESULTSnCross-sectionally, plasma adiponectin was inversely associated with obesity indices, especially waist size (P<10(-2)), HOMA (P<0.03), insulin (P<0.04), TG (P<10(-2)) and sTNF-alpha R1 (P<0.05), and positively related to HDL cholesterol (P<10(-4)), after adjusting for age, gender, sexual maturity, sports participation and adiposity when relevant. Longitudinally, a higher baseline adiponectin level was associated with a more favourable two-year change in TG (P<0.05), even after accounting for baseline TG, and two-year BF and insulin changes.nnnCONCLUSIONnThe findings of this study suggest a favourable relationship between adiponectin and both metabolic profile and subsequent changes in TG level in young adolescents.

Omega-3 index levels and associated factors in a middle-aged French population: the MONA LISA-NUT Study

Background/Objectives:The omega-3 index (the summed percentage content of eicosapentaenoic and docosahexaenoic acids in red blood cells) is associated with a lower risk of fatal coronary heart disease and sudden cardiac death. We aimed to determine which socio-demographic, behavioural or clinical factors are independently associated with the omega-3 index and the extent to which seafood consumption mediates the index’s association with socio-economic status (SES).Subjects/Methods:As part of the cross-sectional MONA LISA-NUT survey (2005–2007), gas chromatography was used to analyse the red blood cell fatty acid composition in 503 French subjects aged 35–64 years. Dietary data were collected by trained dieticians via a validated food frequency questionnaire and a prospective 3-day food record. Risk factors were estimated with standardised measurements and questionnaires. SES was assessed through the self-reported educational and income tax levels.Results:The mean±s.d. omega-3 index was 6.02±1.75%. In the best parsimonious predictive model (which explained 32% of the variability in the omega-3 index), age, educational level and seafood servings were significantly and positively associated with the index. In contrast, waist circumference and smoking were inversely associated with the index. In a mediation analysis that took account of all these factors, seafood servings explained about 40% of the association between educational level and the omega-3 index. Similar results were obtained for the income tax level.Conclusions:The inverse association between SES and omega-3 index is largely explained (40%) by an insufficient seafood intake. It remains to be seen which other factors mediate this association.

Lack of association of genetic variants in the LRP8 gene with familial and sporadic myocardial infarction.

Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either.

Type A behaviour and consumption of an atherogenic diet: no association in the PRIME study.

It has previously been suggested that the association between Type A behaviour and coronary heart disease (CHD) may be mediated through diet. This analysis investigates associations between Type A behaviour and diet, with particular focus on foods high in saturated fats and cholesterol (cake, cheese, eggs and fried potatoes), foods high in unsaturated fats (fish and nuts), and fruit and vegetables. The analysis was conducted on data collected from 10,602 men from Northern Ireland and France screened for inclusion in the PRIME cohort study. Type A behaviour was measured using the Framingham Type A Behaviour Patterns Questionnaire, diet was measured using a Food Frequency Questionnaire and various demographic details were also assessed. Levels of Type A behaviour and intakes of all food groups were similar to previous studies. Using regression, Type A behaviour was significantly associated with diet, and specifically with a higher consumption of cheese and vegetables in Northern Ireland, and a higher consumption of cake, fish and vegetables in France. These associations are most plausibly explained as a result of lifestyle, although the possibility of independent associations between Type A behaviour and diet remains. The work is limited by the use of questionnaires, but the findings available suggest that Type A behaviour is unlikely to be associated with the consumption of a diet that has previously been linked to CHD. These findings suggest that any association between Type A behaviour and CHD is unlikely to be mediated through diet.