• Anette Varbo, Marianne Benn, George Davey Smith, Nicholas J Timpson, Anne Tybjaerg-Hansen, and Børge G Nordestgaard.
• From the Department of Clinical Biochemistry (A.V., B.G.N.) and The Copenhagen General Population Study (A.V., M.B., A.T.-H., B.G.N.), Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (A.V., M.B., A.T.-H., B.G.N.); Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Hellerup, Denmark (M.B.); MRC Integrative Epidemiology Unit, Oakfield House, Oakfield Grove (G.D.S., N.J.T.) and School of Social and Community Medicine (G.D.S., N.J.T.), University of Bristol, United Kingdom; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark (A.T.-H., B.G.N.); and Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (A.T.-H.).
• Circ. Res. 2015 Feb 13; 116 (4): 665-73.

RationaleObesity 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.ObjectiveTo test the hypothesis that the increased IHD risk because of obesity is mediated through lipoproteins, blood pressure, glucose, and C-reactive protein.Methods And ResultsApproximately 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.ConclusionsThe 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.

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