Rare and low-frequency coding variants alter human adult height.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Developing a data-driven spatial approach to assessment of neighbourhood influences on the spatial distribution of myocardial infarction.

BACKGROUND: There is a growing understanding of the role played by 'neighbourhood' in influencing health status. Various neighbourhood characteristics-such as socioeconomic environment, availability of amenities, and social cohesion, may be combined-and this could contribute to rising health inequalities. This study aims to combine a data-driven approach with clustering analysis techniques, to investigate neighbourhood characteristics that may explain the geographical distribution of the onset of myocardial infarction (MI) risk. METHODS: All MI events in patients aged 35-74 years occurring in the Strasbourg metropolitan area (SMA), from January 1, 2000 to December 31, 2007 were obtained from the Bas-Rhin coronary heart disease register. All cases were geocoded to the census block for the residential address. Each areal unit, characterized by contextual neighbourhood profile, included socioeconomic environment, availability of amenities (including leisure centres, libraries and parks, and transport) and psychosocial environment as well as specific annual rates standardized (per 100,000 inhabitants). A spatial scan statistic implemented in SaTScan was then used to identify statistically significant spatial clusters of high and low risk of MI. RESULT: MI incidence was non-randomly spatially distributed, with a cluster of high risk of MI in the northern part of the SMA [relative risk (RR) = 1.70, p = 0.001] and a cluster of low risk of MI located in the first and second periphery of SMA (RR 0.04, p value  =  0.001). Our findings suggest that the location of low MI risk is characterized by a high socioeconomic level and a low level of access to various amenities; conversely, the location of high MI risk is characterized by a high level of socioeconomic deprivation-despite the fact that inhabitants have good access to the local recreational and leisure infrastructure. CONCLUSION: Our data-driven approach highlights how the different contextual dimensions were inter-combined in the SMA. Our spatial approach allowed us to identify the neighbourhood characteristics of inhabitants living within a cluster of high versus low MI risk. Therefore, spatial data-driven analyses of routinely-collected data georeferenced by various sources may serve to guide policymakers in defining and promoting targeted actions at fine spatial level.

All-Cause Mortality up to and After Coronary Heart Disease and Stroke Events in European Middle-Aged Men: The PRIME Study.

BACKGROUND AND PURPOSE: The aim was to investigate prospectively the all-cause mortality risk up to and after coronary heart disease (CHD) and stroke events in European middle-aged men. METHODS: The study population comprised 10 424 men 50 to 59 years of age recruited between 1991 and 1994 in France (N=7855) and Northern Ireland (N=2747) within the Prospective Epidemiological Study of Myocardial Infarction. Incident CHD and stroke events and deaths from all causes were prospectively registered during the 10-year follow-up. In Cox's proportional hazards regression analysis, CHD and stroke events during follow-up were used as time-dependent covariates. RESULTS: A total of 769 CHD and 132 stroke events were adjudicated, and 569 deaths up to and 66 after CHD or stroke occurred during follow-up. After adjustment for study country and cardiovascular risk factors, the hazard ratios of all-cause mortality were 1.58 (95% confidence interval 1.18-2.12) after CHD and 3.13 (95% confidence interval 1.98-4.92) after stroke. CONCLUSIONS: These findings support continuous efforts to promote both primary and secondary prevention of cardiovascular disease.

Expired-air carbon monoxide as a predictor of 16-year risk of all-cause, cardiovascular and cancer mortality.

BACKGROUND: Measurement of expired-air carbon monoxide (EACO) is commonly used to ascertain non-smoking status, although it can also reflect exposures not related to smoking. Our aim was to assess 16-year mortality according to EACO measured at baseline, in a general population. METHODS: Our analysis was based on the Third French MONICA population survey (1994-1997). Causes of death were obtained 16 years after inclusion, and assessment of determinants of mortality was based on Cox modeling. RESULTS: EACO was measured in 2232 apparently healthy participants aged 35-64. During follow-up, 195 deaths occurred (19% were due to cardio-vascular (CV) causes and 49% to cancer). At baseline, the mean EACO was 11.8 (±7.4)ppm, 4.6 (±2.5)ppm, 4.3 (±2.2)ppm for current, former and never smokers, respectively (P<0.001). After adjustment for main mortality risk factors and smoking, the hazard ratio (HR) for total mortality was 1.03[95% confidence interval: 1.01-1.06] per 1-unit increase in EACO, and it was 1.04[1.01-1.07] for cancer mortality. Adjusted HR for CV mortality was 1.05[1.01-1.10] but did not remain significant after additional adjustment for smoking (0.98[0.91-1.04]). Interactions between EACO and smoking were not significant. CONCLUSIONS: In a general population, baseline EACO is an independent predictor of 16-year all-cause and cancer mortality, after adjustment for confounders including smoking. Given that the effect of EACO is similar among smokers and non-smokers, EACO is probably not solely related to smoking but could also be a marker of inhaled ambient carbon monoxide and/or endogenous production. Besides, smoking better predicts CV mortality than EACO.

Ischemic stroke is associated with the ABO locus: the EuroCLOT study.

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

Adipocytokines and the risk of ischemic stroke: the PRIME Study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). INTERPRETATION: 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.

External validation of the 2008 Framingham cardiovascular risk equation for CHD and stroke events in a European population of middle-aged men. The PRIME study.

OBJECTIVE: To test the applicability of the sex-specific 2008 Framingham general cardiovascular risk equation for coronary heart disease (CHD) and stroke in European middle-aged men from Ireland and France. METHODS: In the PRIME study, 9638 healthy middle-aged men recruited in France and Ireland were surveyed for 10 years for the occurrence of first CHD and stroke events. The original Framingham equation, the partially calibrated Framingham equation (using the PRIME baseline survival at 10 years), and the completely calibrated Framingham equation (additionally using risk factor means calculated in PRIME) were assessed. Model fit (expected versus observed events) and discrimination ability were assessed using a modified Hosmer-Lemeshow Chi-square statistic and Harrell's c-index respectively. RESULTS: The original (uncalibrated) Framingham equation overestimated by 1.94-fold the risk of CHD and stroke combined in PRIME, and by 2.23 and 1.42-fold in PRIME-France and PRIME-Ireland respectively. Adequate fit was found after complete calibration. However, discrimination ability of the Framingham equation was poor as shown by Harrell's c-index lower than 0.70. CONCLUSION: The (completely) calibrated 2008 Framingham equation predicted accurate number of CHD and stroke events but discriminated poorly individuals at higher from those at lower event risk in a European population of middle-aged men.

Association of vascular risk factors with cervical artery dissection and ischemic stroke in young adults.

BACKGROUND: Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study. METHODS AND RESULTS: The study sample comprised 690 CEAD patients (mean age, 44.2 ± 9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7 ± 10.5 years; 39.9% women), and 1170 referents (45.9 ± 8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥ 30 kg/m²) or overweightness (body mass index ≥ 25 kg/m² and <30 kg/m²) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents. CONCLUSION: These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD.

Depressive symptoms, a time-dependent risk factor for coronary heart disease and stroke in middle-aged men: the PRIME Study.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: the PRIME study.

OBJECTIVE: To examine prospectively the association of high-sensitivity C-reactive protein, interleukin 6, and fibrinogen with sudden death in asymptomatic European men. METHODS AND RESULTS: Among the 9771 men from the Etude PRospective de l'Infarctus du Myocarde (PRIME) Study, 664 had a first coronary heart disease over 10 years, including 50 sudden deaths, 34 nonsudden coronary deaths, and 580 nonfatal coronary heart disease events. For each outcome, 2 matched controls, who were free of coronary heart disease at the index date, were randomly selected from the initial cohort (nested case control study design). There was a 3-fold increased risk (95% CI, 1.20 to 7.81) of sudden death between the upper and the lower third of interleukin 6 after adjustment for baseline confounders in conditional logistic regression analysis. Neither high-sensitivity C-reactive protein (hazard ratio(third versus first tertile)=1.27; 95% CI, 0.51 to 3.17) nor fibrinogen (hazard ratio(third versus first tertile)=1.90; 95% CI, 0.76 to 4.75) was associated with sudden death. For comparison, there was a 6-fold increased risk of nonsudden coronary death from the highest compared with the lowest tertile of fibrinogen and a trend toward an association with higher C-reactive protein and higher interleukin 6. All 3 inflammatory biomarkers were moderately, but significantly, associated with nonfatal coronary heart disease. CONCLUSIONS: Interleukin 6, but not high-sensitivity C-reactive protein or fibrinogen, is an independent predictor of sudden death in asymptomatic European men.

Could clinical decision rules relying on cardiovascular risk models increase psychosocial inequalities in health? Results from the PRIME cohort study.

OBJECTIVE: Guidelines on cardiovascular prevention relying on common cardiovascular risk scoring could result in delayed drug therapy for patients with low psychosocial status because of underestimation of true cardiovascular risk. We aimed to assess the potential delay in drug therapy for subjects with adverse psychosocial factors. METHOD: The study population consisted of 6185 French men from the PRIME (Prospective Epidemiological Study of Myocardial Infarction) cohort study (1991-2003). The number of extra years to reach a risk threshold for subjects without adverse psychosocial factor compared to subject with adverse psychosocial factor was estimated using a coronary risk model including biomedical factors and a psychosocial variable (education, occupation, living conditions or a depression score). RESULTS: Coronary risk was significantly higher only for subjects with a high depression score (odds ratio=1.34; 95% confidence interval 1.04, 1.72) or low educational attainment (odds ratio=1.39; 95% confidence interval=1.07, 1.81). For a given risk threshold, subjects with high depression scores were 4.5 years (95% confidence interval=0.0, 15.4 years) younger than subjects with low depression scores. The age difference was 4.1 years (95% confidence interval=-0.5, 15.8 years) between subjects with low and high educational attainment. CONCLUSION: Clinical decision rules relying on classic cardiovascular risk scoring could result in delayed drug therapy for patients with depression or low educational attainment.

Effects of occupational and educational changes on obesity trends in France: the results of the MONICA-France survey 1986-2006.

OBJECTIVE: In the past decade, the obesity prevalence in France steadily increased. In the meantime the occupational and educational status of the population improved. This study examined the impact of these changes on obesity trends in France. METHODS: In the MONICA-France surveys in 1986, 1996 and 2006, 5423 men and 5271 women (35-64 yr old) were randomly recruited from electoral rolls in three areas of France (northern, eastern and south-western). We used a logistic regression to assess the association between obesity and time and occupational/educational categories and their interactions and a counterfactual analysis to assess the contributions of occupational and educational changes to obesity trends. RESULTS: Between 1986 and 2006, the prevalence of obesity rose from 15.0% to 18.4% (p < 0.004) in men and remained stable between 15.9% and 17.2% (p = 0.72) in women. Obesity increased in all occupational categories only in men (men: p = 0.0005; women: p < 0.22) and all educational categories in both genders (p < 0.0001). The estimated contributions of occupational (educational) changes to obesity trends were -0.3% (-2.8%) in men and -1.9% (-4.6%) in women. CONCLUSION: The improvement in the French population's occupational status and educational level between 1986 and 2006 tended to reduce the impact of secular trends on the obesity prevalence.

Ten-year risk of all-cause mortality: assessment of a risk prediction algorithm in a French general population.

While assessment of global cardiovascular risk is uniformly recommended for risk factor management, prediction of all-cause death has seldom been considered in available charts. We established an updated algorithm to predict absolute 10-year risk of all-cause mortality in apparently healthy subjects living in France, a country with high life expectancy. Analyses were based on the Third French MONICA Survey on cardiovascular risk factors (1995-1996) carried out in 3,208 participants from the general population aged 35-64. Vital status was obtained 10 years after inclusion and assessment of determinants of mortality was based on multivariable Cox modelling. One-hundred-fifty-six deaths were recorded. Independent determinants of mortality were living area (Northern France), older age, male gender, no high-school completion, smoking, systolic blood pressure ≥ 160 mmHg, LDL-cholesterol ≥ 5.2 mmol/l, and diabetes. Score sheets were developed to easily estimate 10-year risk of death. For example, a non diabetic, heavy smoker, 46-year old man, living in South-Western France, who did not complete high-school, with LDL-cholesterol ≥ 5.2 mmol/l and systolic blood pressure < 160 mmHg, has a 17% probability of death in the ten coming years. The C-statistic of the prediction model was 0.76 [95% CI: 0.72-0.80] with a degree of overoptimism estimated at 0.0058 in a bootstrap sample. Calibration was satisfying: P value for Hosmer-Lemeshow χ(2) test was 0.483. This prediction algorithm is a simple tool for guiding practitioners towards a more or less aggressive management of risk factors in apparently healthy subjects.

A small-area ecologic study of myocardial infarction, neighborhood deprivation, and sex: a Bayesian modeling approach.

BACKGROUND: Socioeconomic inequalities in the risk of coronary heart disease (CHD) are well documented for men and women. CHD incidence is greater for men but its association with socioeconomic status is usually found to be stronger among women. We explored the sex-specific association between neighborhood deprivation level and the risk of myocardial infarction (MI) at a small-area scale. METHODS: We studied 1193 myocardial infarction events in people aged 35-74 years in the Strasbourg metropolitan area, France (2000-2003). We used a deprivation index to assess the neighborhood deprivation level. To take into account spatial dependence and the variability of MI rates due to the small number of events, we used a hierarchical Bayesian modeling approach. We fitted hierarchical Bayesian models to estimate sex-specific relative and absolute MI risks across deprivation categories. We tested departure from additive joint effects of deprivation and sex. RESULTS: The risk of MI increased with the deprivation level for both sexes, but was higher for men for all deprivation classes. Relative rates increased along the deprivation scale more steadily for women and followed a different pattern: linear for men and nonlinear for women. Our data provide evidence of effect modification, with departure from an additive joint effect of deprivation and sex. CONCLUSIONS: We document sex differences in the socioeconomic gradient of MI risk in Strasbourg. Women appear more susceptible at levels of extreme deprivation; this result is not a chance finding, given the large difference in event rates between men and women.

Characteristics of current smokers, former smokers, and second-hand exposure and evolution between 1985 and 2007.

AIMS: The aim of this study was to assess trends in the prevalence of adult smoking habits between 1985-1987 and 2005-2007 in three distinct areas of France and their contribution to coronary heart disease (CHD) death rates. METHODS: Participants were recruited as part of the French Monitoring trends and determinants in Cardiovascular disease survey in 1985-1987 (n=3760), 1995-1997 (n=3347), and 2005-2007 (n=3573). They were randomly selected from electoral rolls after stratification for sex, 10-year age group (35-64 years), and town size. Smoking habits were analyzed by questioning the participants about earlier or current consumption, the number of cigarettes smoked per day, age at first cigarette, pipe tobacco and cigarillo consumption, quit attempts, age at quitting, and second-hand exposure. Predicted CHD death rates as a function of smoking were predicted with the SCORE risk equation. RESULTS: In men, a significant decrease in tobacco exposure (from 40 to 24.3%) between 1985-1987 and 2005-2007 was observed. In women, the prevalence of current smokers increased from 18.9 to 20% and that of former smokers rose from 8.7 to 25.5%. In both men and women, average daily cigarette consumption and second-hand exposure to smoke fell between 1995-1997 and 2005-2007. Predicted CHD death rates as a function of smoking trends decreased in men (range 10-15%) but increased in women (range 0.1-3.6%). CONCLUSION: This study found divergent trends in the prevalence of smoking in men and women aged between 35 and 64 years over the period of 1985 to 2007. These changes may have contributed to the decline in CHD death in men but not in women.

Relative contribution of lipids and apolipoproteins to incident coronary heart disease and ischemic stroke: the PRIME Study.

AIM: To compare within the same cohort the association of a large panel of lipids with the risk of incident coronary heart disease (CHD) and ischemic stroke events in participants of the Prospective Epidemiological Study of Myocardial Infarction. METHODS: In this binational (Northern Ireland and France) prospective cohort, we considered 9,711 men aged 50-59 years free of CHD and stroke at baseline (1991-1993). The hazard ratios of each lipid marker for CHD and ischemic stroke events were estimated in separate Cox proportional hazard models adjusted for age, study center, systolic blood pressure, antihypertensive treatment, current smoking status, body mass index and diabetes. RESULTS: After 10 years of follow-up, 635 men had a first CHD and 98 a first ischemic stroke event. Total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) A1 and Apo B100, their ratios and lipoprotein (a) [Lp(a)] were all significantly predictive of future CHD. Associations with ischemic stroke followed the same trend as for CHD, but with lower strength, and none were statistically significant. However, none of the differences between the hazard ratios for CHD and for ischemic stroke were statistically significant. CONCLUSIONS: In healthy, middle-aged men, total-C, HDL-C, LDL-C, non-HDL-C, triglycerides, Apo A1 and Apo B100, their ratios and Lp(a) are, if anything, weak predictors of ischemic stroke events over a 10-year period.

Study of the genetic variability of ZAC1 (PLAGL1) in French population-based samples.

OBJECTIVES: ZAC1 (zinc finger protein regulating apoptosis and cell cycle arrest) is a member of the new subfamily of zinc-finger transcription factors, designated as PLAG (pleomorphic adenoma gene) family. The ZAC1 gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus. We wanted to assess whether the genetic variability of the ZAC1 gene was associated with anthropometric (weight, BMI, waist-to-hip ratio) or biochemical (plasma lipid, insulin, glucose levels, blood pressure level) phenotypes. METHODS: We selected 37 independent SNPs (single nucleotide polymorphisms) or tagSNPs in the ZAC1 locus from the literature and several databases and, based on the linkage disequilibrium map, identified 27 independent SNPs. Those 27 SNPs were genotyped in a French population-based sample (n = 1155). Associations with a P value lower than 0.0019 (Bonferroni correction) were considered significant. RESULTS: We found that women carrying the T allele of rs9403542 had lower waist-to-hip ratio (P = 0.0006) than women with the CC genotype. Also, men bearing the T allele of rs13218225 had lower systolic (P = 3.6 x 10(-5)) and diastolic (P = 4.1 x 10(-4)) blood pressure than GG men. As a consequence, the adjusted (for age, smoking habit, alcohol consumption, physical activity level and BMI) odds ratio (95% confidence interval) of hypertension for T allele carrier men was 0.55 [0.35-0.86], P = 0.009. We genotyped two other independent samples (MONICA Toulouse, n = 1130 and MONICA Strasbourg, n = 1048) for rs9403542 and rs13218225 but we could not confirm these associations. CONCLUSION: We found no evidence that polymorphisms in ZAC1 might influence anthropometric, biochemical or clinical parameters in French individuals.

Respective contribution of conventional risk factors and antihypertensive treatment to stable angina pectoris and acute coronary syndrome as the first presentation of coronary heart disease: the PRIME Study.

OBJECTIVE: To test whether conventional risk factors and antihypertensive treatment were more predictive of stable angina (SA) than acute coronary syndrome (ACS) as the first presentation of coronary heart disease (CHD). DESIGN: We used data from the PRIME Study (Prospective Epidemiological Study of Myocardial Infarction), a prospective cohort of 9758 asymptomatic middle-aged men recruited from WHO MONICA centers in Northern Ireland and France between 1991 and 1993. SA and ACS events were registered during 5 years of follow-up. METHODS: Hazard ratios (HRs) of each risk factor measured at baseline for SA and ACS events were assessed using separate Cox proportional hazard models. Difference between HRs was estimated by the bootstrap method. RESULTS: After 5 years of follow-up, there were 114 SA and 178 ACS as the first presentation of CHD. Diastolic blood pressure [adjusted HRs for 1 standard deviation increase = 1.34; 95% confidence interval (CI): 1.17-1.54 vs. 1.04; 95% CI: 0.87-1.25; P for comparison between HRs = 0.012], and possibly cigarette smoking over or equal to 20 pack-years (adjusted HR = 2.07; 95% CI: 1.43-2.99 vs. 1.29; 95% CI: 0.83-2.01; P for comparison between HRs = 0.062) were more predictive of ACS than SA, whereas this was the opposite for antihypertensive treatment (adjusted HR = 2.18; 95% CI: 1.39-3.41 for SA vs. 1.28; 95% CI: 0.85-1.93 for ACS, P for comparison between HRs = 0.049). CONCLUSION: The present data support that SA and ACS, as the first presentation of CHD, may not share exactly the same determinants.

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.

Contribution of novel biomarkers to incident stable angina and acute coronary syndrome: the PRIME Study.

AIMS: To compare whether novel inflammatory and haemostatic biomarkers are more predictive of well-characterized incident acute coronary syndrome (ACS) than stable angina (SA). METHODS AND RESULTS: We used data from the PRIME Study, a prospective cohort of 9758 asymptomatic middle-aged men recruited in Northern Ireland and France between 1991 and 1993. A nested case-control study was established with the baseline plasma sample of 269 incident cases and 538 matched controls. Odds ratios (ORs) for SA and ACS were estimated by conditional logistic regression analysis. After 5 years of follow-up, 107 incident SA and 162 ACS cases were validated. After adjustment for traditional risk factors, higher circulating levels of hs-CRP, ICAM1, interleukin 6 and interleukin 18 were equally predictive of SA and ACS (all P-values of OR comparison >0.05). In contrast, elevated levels of fibrinogen, von Willebrand factor, and possibly higher level of D-dimers and lower level of tissue factor pathway inhibitor were associated with ACS only. The comparison of the ORs showed a statistically significant difference for von Willebrand factor only [OR(4th vs. 1st quartile) = 2.99 (1.49-6.02) for ACS vs. 0.80 (0.33-1.94) for SA; P(z test) = 0.02]. CONCLUSION: This is the first population-based study suggesting that higher levels of circulating haemostatic markers and of von Willebrand factor, in particular, are significantly more predictive of incident ACS than SA.