Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge.

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

Effects of particulate matter on inflammatory markers in the general adult population.

BACKGROUND: Particulate air pollution is associated with increased risk of cardiovascular disease and stroke. Although the precise mechanisms underlying this association are still unclear, the induction of systemic inflammation following particle inhalation represents a plausible mechanistic pathway.¦METHODS: We used baseline data from the CoLaus Study including 6183 adult participants residing in Lausanne, Switzerland. We analyzed the association of short-term exposure to PM10 (on the day of examination visit) with continuous circulating serum levels of high-sensitive C-reactive protein (hs-CRP), interleukin 1-beta (IL-1β), interleukin 6 (IL-6), and tumor-necrosis-factor alpha (TNF-α) by robust linear regressions, controlling for potential confounding factors and assessing effect modification.¦RESULTS: In adjusted analyses, for every 10 μg/m3 elevation in PM10, IL-1ß increased by 0.034 (95 % confidence interval, 0.007-0.060) pg/mL, IL-6 by 0.036 (0.015-0.057) pg/mL, and TNF-α by 0.024 (0.013-0.035) pg/mL, whereas no significant association was found with hs-CRP levels.¦CONCLUSIONS: Short-term exposure to PM10 was positively associated with higher levels of circulating IL-1ß, IL-6 and TNF-α in the adult general population. This positive association suggests a link between air pollution and cardiovascular risk, although further studies are needed to clarify the mechanistic pathway linking PM10 to cardiovascular risk.

Distribution of plasma levels of adiponectin and leptin in an adult Caucasian population.

OBJECTIVES: Little is known regarding the distribution and the determinants of leptin and adiponectin levels in the general population. DESIGN: Cross-sectional study. PATIENTS: Women (3004) and men (2552) aged 35-74 living in Lausanne, Switzerland. MEASUREMENTS: Plasma levels of leptin and adiponectin (ELISA measurement). RESULTS: Women had higher leptin and adiponectin levels than men. In both genders, leptin and adiponectin levels increased with age. After adjusting for fat mass, leptin levels were significantly and negatively associated with age in women: 18.1 +/- 0.3, 17.1 +/- 0.3, 16.7 +/- 0.3 and 15.5 +/- 0.4 ng/ml (adjusted mean +/- SE) for age groups [35-44], [45-54], [55-64] and [65-75], respectively, P < 0.001. A similar but nonsignificant trend was also found in men. Conversely, the age-related increase of adiponectin was unrelated to body fat in both genders. Post-menopausal women had higher leptin and adiponectin levels than premenopausal women, independently of hormone replacement therapy. Although body fat mass was associated with leptin and adiponectin, the associations were stronger with body mass index (BMI), waist and hip in both genders. Finally, after adjusting for age and anthropometry, no relationships were found between leptin or adiponectin levels with alcohol, caffeine consumption and physical activity, whereas smoking and diabetes decreased leptin and adiponectin levels in women only. CONCLUSIONS: The age-related increase in leptin levels is attributable to changes in fat mass in women and probably also in men. Leptin and adiponectin levels are more related to BMI than to body fat mass. The effects of smoking and diabetes appear to be gender-specific.

Predictive accuracy of original and recalibrated Framingham risk score in the Swiss population.

OBJECTIVE: To compare the predictive accuracy of the original and recalibrated Framingham risk function on current morbidity from coronary heart disease (CHD) and mortality data from the Swiss population. METHODS: Data from the CoLaus study, a cross-sectional, population-based study conducted between 2003 and 2006 on 5,773 participants aged 35-74 without CHD were used to recalibrate the Framingham risk function. The predicted number of events from each risk function were compared with those issued from local MONICA incidence rates and official mortality data from Switzerland. RESULTS: With the original risk function, 57.3%, 21.2%, 16.4% and 5.1% of men and 94.9%, 3.8%, 1.2% and 0.1% of women were at very low (<6%), low (6-10%), intermediate (10-20%) and high (>20%) risk, respectively. With the recalibrated risk function, the corresponding values were 84.7%, 10.3%, 4.3% and 0.6% in men and 99.5%, 0.4%, 0.0% and 0.1% in women, respectively. The number of CHD events over 10 years predicted by the original Framingham risk function was 2-3 fold higher than predicted by mortality+case fatality or by MONICA incidence rates (men: 191 vs. 92 and 51 events, respectively). The recalibrated risk function provided more reasonable estimates, albeit slightly overestimated (92 events, 5-95th percentile: 26-223 events); sensitivity analyses showed that the magnitude of the overestimation was between 0.4 and 2.2 in men, and 0.7 and 3.3 in women. CONCLUSION: The recalibrated Framingham risk function provides a reasonable alternative to assess CHD risk in men, but not in women.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Lipoprotein distribution and biological variation of 24S- and 27-hydroxycholesterol in healthy volunteers.

24S- and 27-hydroxycholesterol are obligatory intermediates of cholesterol catabolism and play an important role in the maintenance of whole-body cholesterol homeostasis. Using an HPLC-MS method for oxysterol quantification, the distribution of esterified and unesterified oxysterols in lipoprotein subfractions as well as the influence of daytime, food intake and menstrual cycle on oxysterol concentrations were investigated in healthy volunteers. Moreover, reference intervals for 24S- and 27-hydroxycholesterol in plasma as well as the corresponding levels for 27-hydroxycholesterol in the HDL subfraction were established in 100 healthy volunteers. Both circulating oxysterols are mainly transported in association with HDL and LDL--primarily in the esterified form. No significant diurnal changes and no variations during menstrual cycle of either absolute or cholesterol-related plasma levels were detected. In contrast to 24S-hydroxycholesterol in plasma and 27-hydroxycholesterol in the HDL subfraction, the 95% reference intervals of 27-hydroxycholesterol both in plasma and the non-HDL subfraction were higher in males than in females. The concentrations of 27-hydroxycholesterol in plasma and the non-HDL subfraction showed strong positive correlations with the concentrations of cholesterol, non-HDL cholesterol and triglycerides. Our data on the lipoprotein distribution of oxysterols as well as on their intra- and inter-individual variation set the stage for future clinical studies.

Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Association entre consommation d'alcool et facteurs de risque cardiovasculaire: une étude sur la population lausannoise. [Association between alcohol consumption and cardiovascular risk factors: a narrative review]

Alors que la consommation modérée d'alcool est liée à un risque plus faible de développer une maladie coronarienne, l'impact d'une consommation plus importante d'alcool sur les facteurs de risque cardiovasculaire (FRCV) et la maladie coronarienne est moins clair. Nous avons étudié l'association entre la consommation d'alcool, les FRCV et l'estimation du risque à dix ans de faire un événement cardiovasculaire dans l'étude populationnelle lausannoise CoLaus. Dans cette étude, 73% des participants consomment de l'alcool, 16% consomment de 14 à 34 unités d'alcool par semaine et 2% consomment 35 unités ou plus par semaine. Cet article montre notamment l'impact d'une consommation importante d'alcool sur les FRCVet passe en revue les liens entre la consommation d'alcool, le type de boissons et les FRCV. [Abstract] Moderate alcohol consumption has been associated with lower coronary heart disease (CHD) risk. However, the impact of higher alcohol consumption on cardiovascular risk factors (CVRFs) is conflicting. We examined the association between alcohol consumption, CVRFs and the estimated 10-year CHD risk in the population-based CoLaus study in Lausanne, Switzerland. Among 5'769 participants without cardiovascular disease, 73% of the participants were alcohol drinkers; 16% consumed 14-34 drinks/week and 2% consumed >= 35 drinks/week. This article shows the impact of high alcohol consumption on CVRFs and reviews the literature on the associations between alcohol consumption and CVRFs.

Obesity markers and estimated 10 year fatal cardiovascular risk in Switzerland

Objective: To assess the effectiveness of obesity markers to detect high (>5%) 10- year risk of fatal cardiovascular disease (CVD) as estimated using the SCORE function. Methods: Cross-sectional study including 3,047 women and 2,689 men aged 35-75 years (CoLaus study). Body fat percentage was assessed by tetrapolar bioimpedance. CVD risk was assessed using the SCORE risk function and gender and age-specific cut points for body fat were derived. The diagnostic accuracy of each obesity marker was evaluated through receiver operating characteristics (ROC) analysis. Results: Body fat presented a higher correlation with 10-year CVD risk than waist/hip ratio (WHR), waist or BMI: in men, r=0.31, 0.22, 0.19 and 0.12 and for body fat, WHR, waist and BMI, respectively; the corresponding values in women were 0.18, 0.15, 0.11 and 0.05, respectively (all p<0.05). In both genders, body fat showed the highest area under the ROC curve (AUC): in men, the AUC (and 95% confidence interval) were 76.0 (73.8 - 78.2), 67.3 (64.6 - 69.9), 65.8 (63.1 - 68.5) and 60.6 (57.9 - 63.5) for body fat, WHR, waist and BMI, respectively. In women, the corresponding values were 72.3 (69.2 - 75.3), 66.6 (63.1 - 70.2), 64.1 (60.6 - 67.6) and 58.8 (55.2 - 62.4). The use of body fat percentage criterion enabled to capture three times more subjects with high CVD risk than BMI criterion, and almost twice as much as WHR criterion.. Conclusions: Obesity defined by body fat percentage is more accurate to detect high 10-year risk of fatal CVD than obesity markers based on WHR, waist or BMI.

Meta-analysis and imputation refines the association of 15q25 with smoking quantity.

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Effects of particulate matters on inflammatory markers in the general adult population

Summary: Particulate air pollution is associated with increased cardiovascular risk. The induction of systemic inflammation following particle inhalation represents a plausible mechanistic pathway. The purpose of this study was to assess the associations of short-term exposure to ambient particulate matters of aerodynamic diameter less than 10 μm (PM10) with circulating inflammatory markers in 6183 adults in Lausanne, Switzerland. The results show that short-term exposure to PM10 was associated with higher levels of circulating IL-6 and TNF-α. The positive association of PM10 with markers of systemic inflammation materializes the link between air pollution and cardiovascular risk. Background: Variations in short-term exposure to particulate matters (PM) have been repeatedly associated with daily all-cause mortality. Particle-induced inflammation has been postulated to be one of the important mechanisms for increased cardiovascular risk. Experimental in-vitro, in-vivo and controlled human studies suggest that interleukin 6 (IL-6) and tumor-necrosis-factor alpha (TNF-α) could represent key mediators of the inflammatory response to PM. The associations of short-term exposure to ambient PM with circulating inflammatory markers have been inconsistent in studies including specific subgroups so far. The epidemiological evidence linking short-term exposure to ambient PM and systemic inflammation in the general population is scarce. So far, large-scale population-based studies have not explored important inflammatory markers such as IL-6, IL-1β or TNF-α. We therefore analyzed the associations between short-term exposure to ambient PM10 and circulating levels of high-sensitive CRP (hs-CRP), IL-6, IL-1β and TNF-α in the population-based CoLaus study. Objectives: To assess the associations of short-term exposure to ambient particulate matters of aerodynamic diameter less than 10 μm (PM10) with circulating inflammatory markers, including hs-CRP, IL-6, IL-1β and TNF-α, in adults aged 35 to 75 years from the general population. Methodology: All study subjects were participants to the CoLaus study (www.colaus.ch) and the baseline examination was carried out from 2003 to 2006. Overall, 6184 participants were included. For the present analysis, 6183 participants had data on at least one of the four measured circulating inflammatory markers. The monitoring data was obtained from the website of Swiss National Air Pollution Monitoring Network (NABEL). We analyzed data on PM10 as well as outside air temperature, pressure and humidity. Hourly concentrations of PM10 were collected from 1 January 2003 to 31 December 2006. Robust linear regression (PROC ROBUSTREG) was used to evaluate the relationship between cytokine inflammatory and PM10. We adjusted all analyses for age, sex, body mass index, smoking status, alcohol consumption, diabetes status, hypertension status, education levels, zip code, and statin intake. All data were adjusted for the effects of weather by including temperature, barometric pressure, and season as covariates in the adjusted models. We performed simple and multiple logistic regression analyses. Descriptive statistical analysis used the Wilcoxon rank sum test (for medians). All data analyses were performed using SAS software (version 9.2; SAS Institute Inc., Cary, NC, USA), and a two-sided significance level of 5% was used. Results: PM10 levels averaged over 24 hours were significantly and positively associated with continuous IL-6 and TNF-α levels, in the whole study population both in unadjusted and adjusted analyses. For each cytokine, there was a similar seasonal pattern, with wider confidence intervals in summer than during the other seasons, which might partly be due to the smaller number of participants examined in summer. The associations of PM10 with IL-6 and TNF-α were also found after having dichotomized these cytokines into high versus low levels, which suggests that the associations of PM10 with the continuous cytokine levels are very robust to any distributional assumption and to potential outlier values. In contrast with what we observed for continuous IL-1β levels, high PM10 levels were significantly associated with high IL-1β. PM10 was significantly associated with IL-6 and TNF-α in men, but with TNF-α only in women. However, there was no significant statistical interaction between PM10 and sex. For IL-6 and TNF-α, the associations tended to be stronger in younger people, with a significant interaction between PM10 and age groups for IL-6. PM10 was significantly associated with IL-6 and TNF-α in the healthy group and also in the "non-healthy" group, although the statistical interaction between healthy status and PM10 was not significant. Conclusion: In summary, we found significant independent positive associations of short-term exposure to PM10 with circulating levels of IL-6 and TNF-α in the adult population of Lausanne. Our findings strongly support the idea that short-term exposure to PM10 is sufficient to induce systemic inflammation on a broad scale in the general population. From a public health perspective, the reported association of elevated inflammatory cytokines with short-term exposure to PM10 in a city with relatively clean air such as Lausanne supports the importance of limiting urban air pollution levels.

Diabetes risk scores and death: predictability and practicability in two different populations.

The aim was to examine the capacity of commonly used type 2 diabetes mellitus (T2DM) risk scores to predict overall mortality. The US-based NHANES III (n = 3138; 982 deaths) and the Swiss-based CoLaus study (n = 3946; 191 deaths) were used. The predictive value of eight T2DM risk scores regarding overall mortality was tested. The Griffin score, based on few self-reported parameters, presented the best (NHANES III) and second best (CoLaus) predictive capacity. Generally, the predictive capacity of scores based on clinical (anthropometrics, lifestyle, history) and biological (blood parameters) data was not better than of scores based solely on clinical self-reported data. T2DM scores can be validly used to predict mortality risk in general populations without diabetes. Comparison with other scores could further show whether such scores also suit as a screening tool for quick overall health risk assessment.