Dataset Information

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.

ABSTRACT:

Background

Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood.

Methods

We used large-scale metabolomics data in a two-sample reverse Mendelian randomization (MR) framework to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites in the UK Biobank (N = 118,466). We examined the potential for medication use to distort effect estimates by conducting age-stratified metabolite analyses.

Findings

Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g.

, hdl-c

-0.05 SD; 95% CI -0.07 to -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). IVW estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C. In pleiotropy-robust models, T2D liability was still estimated to increase BCAAs, but several estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed substantially by age for non-HDL-C traits, with higher CAD liability lowering LDL-C only at older ages when statin use was common.

Interpretation

Overall, our results support largely distinct metabolic features of genetic liability to T2D and CAD, illustrating both challenges and opportunities for preventing these commonly co-occurring diseases.

Funding

Wellcome Trust [218495/Z/19/Z], UK MRC [MC_UU_00011/1; MC_UU_00011/4], the University of Bristol, Diabetes UK [17/0005587], World Cancer Research Fund [IIG_2019_2009].

SUBMITTER: Smith ML

PROVIDER: S-EPMC10009453 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.

Smith Madeleine L ML Bull Caroline J CJ Holmes Michael V MV Davey Smith George G Sanderson Eleanor E Anderson Emma L EL Bell Joshua A JA

EBioMedicine 20230302

<h4>Background</h4>Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood.<h4>Methods</h4>We used large-scale metabolomics data in a two-sample reverse Mendelian randomization (MR) framework to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites in the UK Biobank (N = 118,466). We examined the potential for medica ...[more]

PMID: 36870196

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Dataset Information

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.

Background

Methods

Findings

, hdl-c

Interpretation

Funding

Publications

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.

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