Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Directed evolution of biomass intensive CHO cells by adaptation to sub-physiological temperature

We report a simple and effective means to increase the biosynthetic capacity of host CHO cells. Lonza proprietary CHOK1SV® cells were evolved by serial sub-culture for over 150 generations at 32 °C. During this period the specific proliferation rate of hypothermic cells gradually recovered to become comparable to that of cells routinely maintained at 37 °C. Cold-adapted cell populations exhibited (1) a significantly increased volume and biomass content (exemplified by total RNA and protein), (2) increased mitochondrial function, (3) an increased antioxidant capacity, (4) altered central metabolism, (5) increased transient and stable productivity of a model IgG4 monoclonal antibody and Fc-fusion protein, and (6) unaffected recombinant protein N-glycan processing. This phenotypic transformation was associated with significant genome-scale changes in both karyotype and the relative abundance of thousands of cellular mRNAs across numerous functional groups. Taken together, these observations provide evidence of coordinated cellular adaptations to sub-physiological temperature. These data reveal the extreme genomic/functional plasticity of CHO cells, and that directed evolution is a viable genome-scale cell engineering strategy that can be exploited to create host cells with an increased cellular capacity for recombinant protein production

Lifetime body mass index, other anthropometric measures of obesity and risk of knee or hip osteoarthritis in the GOAL case-control study

Objective: To examine the risk of large joint osteoarthritis (OA) in those becoming overweight during early adult life, and to assess the risks associated with high body mass index (BMI) and other anthropometric measures of obesity. Methods: BMI, waist and hip circumference were measured in the GOAL case-control study comprising hip OA cases (n = 1007), knee OA cases (n = 1042) and asymptomatic controls (n = 1121). Retrospective estimates of lifetime weight, body shape and other risk factors were collected using an interview-lead questionnaire. Odds ratios (ORs), adjusted OR (aOR), 95% confidence intervals (Os) and P values were calculated using logistic regression analysis. Results: BMI was associated with knee OA (aOR 2.68, 95% CI 2.33-3.09, P-trend <0.001) and hip OA (aOR 1.65, 95% CI 1.46-1.87, P-trend <0.001). Those who became overweight earlier in adulthood showed higher risks of lower limb OA (P-trend < 0.001 for knee OA and hip OA). Self-reported body shape was also associated with knee OA and hip OA, following a similar pattern to current and life-course BMI measures. Waist:hip ratio (WHR) at time of examination did not associate with OA independently of BMI, except in women-only analysis. Waist circumference was associated with lower limb OA risk. Conclusions: Becoming overweight earlier in adult life increased the risks of knee OA and hip OA. Different distribution patterns of adiposity may be related to OA risk in women. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved

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