The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study
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Abstract
Abstract Background The extent to which effects of BMI on coronary heart disease (CHD) are mediated by gylcaemic and lipid risk factors is unclear. Methods We used two-sample Mendelian randomization to determine the causal effect of: (i) BMI on CHD (60,801 cases; 123, 504 controls), type 2 diabetes (T2DM; 34,840 cases; 114,981 controls), fasting glucose (n=46,186), insulin (n=38,238), HbA 1c (n=46,368), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglycerides (n=188,577); (ii) glycaemic and lipids traits on CHD; and (iii) extent to which these traits mediated any effect of BMI on CHD. Findings One standard deviation (SD) increase in BMI (~ 4.5kg/m 2 ) increased CHD (odds ratio=1.45 (95% confidence interval (CI): 1.27, 1.66)) and T2DM (1.96 (1.35, 2.83)), and levels of fasting glucose (0.07mmol/l (95%CI 0.03, 0.11)), HbA 1c (0.05% (95%CI 0.01, 0.08)), fasting insulin (0.18log pmol/l (95%CI 0.14, 0.22)) and triglycerides (0.20 SD (95%CI 0.14, 0.26)), and lowered levels of HDL-C (−0.23 SD (95%CI −0.32, −0.15)). BMI was not causally related to LDL-C. After accounting for potential pleiotropy, triglycerides, HbA 1c and T2DM were causally related to CHD. The BMI-CHD effect reduced from 1.45 to 1.16 (95%CI 0.99, 1.36) and to 1.36 (95%CI 1.19, 1.57) with genetic adjustment for triglycerides or HbA 1c respectively, and to 1.09 (95%CI 0.94, 1.27) with adjustment for both. Interpretation Increased triglyceride levels and poor glycaemic control appear to mediate much of the effect of BMI on CHD. Funding European Research Council (669545), European Union (733206), China Medical Board (CMB_2015/16), Conselho Nacional de Desenvolvimento Científico e Tecnológico and UK Medical Research Council (MC_UU_12013/5).
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References 51 · Cited by 104
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- [6]Hemani G, Tilling K, Davey Smith G (2017) Orienting the causal relationship between imprecisely measured traits using genetic instruments. bioRxiv. doi:10.1101/117101 PMC5711033 29149188 · DOI
- Authors
- Xu, L., Borges, M. C., Hemani, G., & Lawlor, D. A.
- Affiliations
- Sun Yat-sen University (CN)
- Universidade Federal de Pelotas (BR)
- University of Bristol (GB)
- Corresponding author
- Lawlor, Debbie A.
- Venue
- Diabetologia
- Published
- 2017-09-09
- Volume
- 60
- Issue
- 11
- Pages
- 2210-2220
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC6342872
- OpenAlex
- W2950172732
- Cited by
- 104
- References
- 51
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 16 · 2023: 14 · 2022: 21 · 2021: 12 · 2020: 12 · 2019: 9 · 2018: 5 · 2017: 1
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- Funders
- University of Bristol
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- body mass index, coronary artery disease, type 2 diabetes, glycemic traits, lipid traits, mediation analysis, fasting blood glucose, HbA1c, fasting insulin, triglycerides, HDL cholesterol, LDL cholesterol, causal effects, horizontal pleiotropy, genetic evidence, obesity risk factors, cardiovascular risk factors
- MeSH terms
- Blood Glucose, Coronary Disease, Female, Humans, Cholesterol, HDL, Cholesterol, LDL, Male, Risk Factors, Triglycerides, Body Mass Index, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis
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