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Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol
Diabetes Care
(
IF
14.8
)
Pub Date : 2021-11-17
, DOI:
10.2337/dc21-1284
Peitao Wu
1
,
Jee-Young Moon
2
,
Iyas Daghlas
3,
4
,
Giulianini Franco
5
,
Bianca C Porneala
6
,
Fariba Ahmadizar
7
,
Tom G Richardson
8,
9
,
Jonas L Isaksen
10
,
Georgy Hindy
11
,
Jie Yao
12
,
Colleen M Sitlani
13
,
Laura M Raffield
14
,
Lisa R Yanek
15
,
Mary F Feitosa
16
,
Rafael R C Cuadrat
17,
18
,
Qibin Qi
2
,
M Arfan Ikram
7
,
Christina Ellervik
19,
20
,
Ulrika Ericson
11
,
Mark O Goodarzi
21
,
Jennifer A Brody
13
,
Leslie Lange
22
,
Josep M Mercader
4,
23,
24
,
Dhananjay Vaidya
15
,
Ping An
16
,
Matthias B Schulze
17,
18,
25
,
Lluis Masana
26,
27
,
Mohsen Ghanbari
7
,
Morten S Olesen
28,
29
,
Jianwen Cai
30
,
Xiuqing Guo
12
,
James S Floyd
13,
31
,
Susanne Jäger
17,
18
,
Michael A Province
16
,
Rita R Kalyani
15
,
Bruce M Psaty
13,
31,
32
,
Marju Orho-Melander
11
,
Paul M Ridker
5,
24
,
Jørgen K Kanters
10
,
Andre Uitterlinden
7,
33
,
George Davey Smith
8
,
Dipender Gill
9,
34,
35,
36
,
Robert C Kaplan
2,
37
,
Maryam Kavousi
7
,
Sridharan Raghavan
38,
39
,
Daniel I Chasman
3,
4
,
Jerome I Rotter
12
,
James B Meigs
4,
6,
24
,
Jose C Florez
4,
23,
24
,
Josée Dupuis
1
,
Ching-Ti Liu
1
,
Jordi Merino
4,
23,
24,
26
Affiliation
- 1Department of Biostatistics, Boston University School of Public Health, Boston, MA.
- 2Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
- 3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
- 4Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
- 5Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
- 6Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
- 7Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
- 8MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K.
- 9Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, U.K.
- 10Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
- 11Department of Clinical Sciences, Skåne University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
- 12Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
- 13Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
- 14Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
- 15Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
- 16Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO.
- 17Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
- 18German Center for Diabetes Research, Neuherberg, Germany.
- 19Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
- 20Department of Research, Region Zealand, Sorø, Denmark.
- 21Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
- 22Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
- 23Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
- 24Department of Medicine, Harvard Medical School, Boston, MA.
- 25Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
- 26Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Rovira i Virgil University, IISPV, Reus, Spain.
- 27Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
- 28Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
- 29Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- 30Collaborative Studies Coordinating Center, Department of Biostatistics, The University of North Carolina at Chapel Hill, NC.
- 31Department of Epidemiology, University of Washington, Seattle, WA.
- 32Department of Health Services, University of Washington, Seattle, WA.
- 33Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
- 34Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K.
- 35Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, London, U.K.
- 36Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, U.K.
- 37Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle WA.
- 38Department of Veterans Affairs Medical Center, Eastern Colorado Health Care System, Denver, CO.
- 39Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Denver, CO.
OBJECTIVELDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.
RESEARCH DESIGN AND METHODSWe conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.
RESULTSA 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).
CONCLUSIONSThese findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.
中文翻译：
肥胖部分介导降低低密度脂蛋白胆固醇的致糖尿病作用
客观的降低 LDL 胆固醇 (LDLc) 的药物会适度增加体重和 2 型糖尿病风险，但降低 LDLc 的致糖尿病作用在多大程度上是通过增加 BMI 介导的尚不清楚。
研究设计和方法我们对 921,908 名参与者进行了总结水平的单变量和多变量孟德尔随机化 (MR) 分析，以调查降低 LDLc 对 2 型糖尿病风险的影响以及通过 BMI 介导的这种影响的比例。我们使用来自 14 项观察性研究的 92,532 名参与者的数据来复制个体水平 MR 分析中的发现。
结果基因预测的 LDLc 降低 1-SD 与 2 型糖尿病几率增加（优势比 [OR] 1.12 [95% CI 1.01, 1.24]）和 BMI（β = 0.07 SD 单位 [95% CI 0.02, 0.12]）相关在单变量 MR 分析中。多变量 MR 分析显示，有证据表明通过 BMI 降低 LDLc 对 2 型糖尿病有间接影响（OR 1.04 [95% CI 1.01, 1.08]），介导的比例占总影响的 38%（P = 0.03）。在许多敏感性分析中，总效应估计和间接效应估计是相似的。个体水平的 MR 分析证实了通过 BMI 降低 LDLc 对 2 型糖尿病的间接影响，估计介导的比例为 8% ( P = 0.04)。
结论这些发现表明，归因于降低 LDLc 的致糖尿病作用部分是通过增加 BMI 介导的。我们的结果可能有助于加深对 2 型糖尿病病理生理学中脂肪组织和脂质的理解，并为降低服用 LDLc 降低药物的个体患糖尿病风险的策略提供信息。
更新日期：2021-11-18
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