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Varbo A.,Copenhagen University | Benn M.,Copenhagen University | Smith G.D.,MRC Integrative Epidemiology Unit | Smith G.D.,University of Bristol | And 4 more authors.
Circulation Research | Year: 2015

Rationale: Obesity leads to increased ischemic heart disease (IHD) risk, but the risk is thought to be mediated through intermediate variables and may not be caused by increased weight per se. Objective: To test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein. Methods and Results: Approximately 90 000 participants from Copenhagen were included in a Mendelian randomization design with mediation analyses. Associations were examined using conventional measurements of body mass index and intermediate variables and using genetic variants associated with these. During ≤22 years of follow-up 13 945 participants developed IHD. The increased IHD risk caused by obesity was partly mediated through elevated levels of nonfasting remnant cholesterol and low-density lipoprotein cholesterol, through elevated blood pressure, and possibly also through elevated nonfasting glucose levels; however, reduced high-density lipoprotein cholesterol and elevated C-reactive protein levels were not mediators in genetic analyses. The 3 intermediate variables that explained the highest excess risk of IHD from genetically determined obesity were low-density lipoprotein cholesterol with 8%, systolic blood pressure with 7%, and remnant cholesterol with 7% excess risk of IHD. Corresponding observational excess risks using conventional body mass index were 21%, 11%, and 20%, respectively. Conclusions: The increased IHD risk because of obesity was partly mediated through elevated levels of nonfasting remnant and low-density lipoprotein cholesterol and through elevated blood pressure. Our results suggest that there may be benefit to gain by reducing levels of these risk factors in obese individuals not able to achieve sustained weight loss. © 2014 American Heart Association, Inc.


Yoneyama S.,University of North Carolina at Chapel Hill | Guo Y.,Childrens Hospital of Philadelphia | Lanktree M.B.,Mc Master University | Barnes M.R.,National Health Research Institute | And 86 more authors.
Human Molecular Genetics | Year: 2014

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ̃50 000 cosmopolitan tagged SNPs across̃2100cardiovascular-related genes. Eachtraitwasmodeled asa function of age, study siteandprincipal components to control for population stratification, andweconducted a fixed-effectsmeta-analysis. Nonewloci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 ×10-6). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β±SE, 0.048±0.008, P=7.7×10-9) as was rs7302703-G in HOXC10 (β=0.044±0.008, P=2.9×10-7) and rs936108-C in PEMT (β-0.035±0.007, P=1.9×10-6). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β=0.10±0.02, P=1.9×10-6) and rs1037575-A in ATBDB4 (β=0.046±0.01, P=2.2×10-6), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue. © The Author 2013. Published by Oxford University Press. All rights reserved.


Artigas M.S.,University of Leicester | Wain L.V.,University of Leicester | Miller S.,University of Nottingham | Kheirallah A.K.,University of Nottingham | And 132 more authors.
Nature Communications | Year: 2015

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10-8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

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