The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: A collaborative analysis of ten large cohort studies.

BACKGROUND: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. METHODS: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease. RESULTS: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes. CONCLUSIONS: Through a rigorous harmonization process, the BioSHaRE-EU consortium was able to compare key characteristics defining the metabolically healthy obese phenotype across ten cohort studies. There is considerable variability in the prevalence of healthy obesity across the different European populations studied, even when unified criteria were used to classify this phenotype

Adiposity as a cause of cardiovascular disease: a Mendelian randomization study

Background: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. Methods: The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. Results: There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9·10-7), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9·10-19) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3·10-107). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Conclusions: Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke

Age- and sex-specific causal effects of adiposity on cardiovascular risk factors

88siObservational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.noneFall, T.; Hägg, S.; Ploner, A.; Mägi, R.; Fischer, K.; Draisma, H.H.; Sarin, A.-P.; Benyamin, B.; Ladenvall, C.; Åkerlund, M.; Kals, M.; Esko, T.; Nelson, C.P.; Kaakinen, M.; Huikari, V.; Mangino, M.; Meirhaeghe, A.; Kristiansson, K.; Nuotio, M.-L.; Kobl, M.; Grallert, H.; Dehghan, A.; Kuningas, M.; de Vries, P.S.; de Bruijn, R.F.; Willems, S.M.; Heikkilä, K.; Silventoinen, K.; Pietiläinen, K.H.; Legry, V.; Giedraitis, V.; Goumidi, L.; Syvänen, A.-C.; Strauch, K.; Koenig, W.; Lichtner, P.; Herder, C.; Palotie, A.; Menni, C.; Uitterlinden, A.G.; Kuulasmaa, K.; Havulinna, A.S.; Moreno, L.A.; Gonzalez-Gross, M.; Evans, A.; Tregouet, D.-A.; Yarnell, J.W.; Virtamo, J.; Ferrières, J.; Veronesi, G.; Perola, M.; Arveiler, D.; Brambilla, P.; Lind, L.; Kaprio, J.; Hofman, A.; Stricker, B.H.; van Duijn, C.M.; Ikram, M.A.; Franco, O.H.; Cottel, D.; Dallongeville, J.; Hall, A.S.; Jula, A.; Tobin, M.D.; Penninx, B.W.; Peters, A.; Gieger, C.; Samani, N.J.; Montgomery, G.W.; Whitfield, J.B.; Martin, N.G.; Groop, L.; Spector, T.D.; Magnusson, P.K.; Amouyel, P.; Boomsma, D.I.; Nilsson, P.M.; Järvelin, M.-R.; Lyssenko, V.; Metspalu, A.; Strachan, D.P.; Salomaa, V.; Ripatti, S.; Pedersen, N.L.; Prokopenko, I.; Mccarthy, M.I.; Ingelsson, E.Fall, T.; Hägg, S.; Ploner, A.; Mägi, R.; Fischer, K.; Draisma, H. H.; Sarin, A. P.; Benyamin, B.; Ladenvall, C.; Åkerlund, M.; Kals, M.; Esko, T.; Nelson, C. P.; Kaakinen, M.; Huikari, V.; Mangino, M.; Meirhaeghe, A.; Kristiansson, K.; Nuotio, M. L.; Kobl, M.; Grallert, H.; Dehghan, A.; Kuningas, M.; de Vries, P. S.; de Bruijn, R. F.; Willems, S. M.; Heikkilä, K.; Silventoinen, K.; Pietiläinen, K. H.; Legry, V.; Giedraitis, V.; Goumidi, L.; Syvänen, A. C.; Strauch, K.; Koenig, W.; Lichtner, P.; Herder, C.; Palotie, A.; Menni, C.; Uitterlinden, A. G.; Kuulasmaa, K.; Havulinna, A. S.; Moreno, L. A.; Gonzalez Gross, M.; Evans, A.; Tregouet, D. A.; Yarnell, J. W.; Virtamo, J.; Ferrières, J.; Veronesi, Giovanni; Perola, M.; Arveiler, D.; Brambilla, P.; Lind, L.; Kaprio, J.; Hofman, A.; Stricker, B. H.; van Duijn, C. M.; Ikram, M. A.; Franco, O. H.; Cottel, D.; Dallongeville, J.; Hall, A. S.; Jula, A.; Tobin, M. D.; Penninx, B. W.; Peters, A.; Gieger, C.; Samani, N. J.; Montgomery, G. W.; Whitfield, J. B.; Martin, N. G.; Groop, L.; Spector, T. D.; Magnusson, P. K.; Amouyel, P.; Boomsma, D. I.; Nilsson, P. M.; Järvelin, M. R.; Lyssenko, V.; Metspalu, A.; Strachan, D. P.; Salomaa, V.; Ripatti, S.; Pedersen, N. L.; Prokopenko, I.; Mccarthy, M. I.; Ingelsson, E

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance