Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis.
Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.
Division of Transplantation, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA; Genetic Epidemiology Group, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK. Electronic address: michael.holmes@uphs.upenn.edu.
Michael V
MV
Holmes
Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC 27514, USA.
Leslie A
LA
Lange
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
Tom
T
Palmer
Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
Matthew B
MB
Lanktree
Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Kari E
KE
North
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Berta
B
Almoguera
Jackson Heart Study Coordinating Center, Jackson State University, 350 West Woodrow Wilson Avenue, Suite 701, Jackson, MS 39213, USA.
Sarah
S
Buxbaum
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Hareesh R
HR
Chandrupatla
Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
Clara C
CC
Elbers
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Yiran
Y
Guo
Division of Atherosclerosis & Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Ron C
RC
Hoogeveen
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Jin
J
Li
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Yun R
YR
Li
Genetic Epidemiology Group, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Daniel I
DI
Swerdlow
Departments of Medicine and Pathology, University of Vermont, 208 South Park Drive, Colchester, VT 05446 USA.
Mary
M
Cushman
The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Tom S
TS
Price
Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
Sean P
SP
Curtis
The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Myriam
M
Fornage
Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Hakon
H
Hakonarson
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Sanjay R
SR
Patel
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Susan
S
Redline
Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA 98101, USA.
David S
DS
Siscovick
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55414, USA.
Michael Y
MY
Tsai
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
James G
JG
Wilson
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
Yvonne T
YT
van der Schouw
The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Garret A
GA
FitzGerald
Genetic Epidemiology Group, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
Aroon D
AD
Hingorani
Genetic Epidemiology Group, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK; Faculty of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
Juan P
JP
Casas
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands; Brigham and Women's Hospital, 77 Avenue Louis Pasteur, New Research Building, Room 168, Boston, MA 02115, USA.
Paul I W
PI
de Bakker
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
Stephen S
SS
Rich
Department of Genomics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Eric E
EE
Schadt
Division of Heart and Lungs, Department of Cardiology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN - Netherlands Heart Institute, Catharijnesingel 52, Postbus 19258, 3501 DG Utrecht, the Netherlands; Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.
Folkert W
FW
Asselbergs
Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Alex P
AP
Reiner
Division of Transplantation, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA; Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: bkeating@mail.med.upenn.edu.
Brendan J
BJ
Keating
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics; D005215:Fasting; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007328:Insulin / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D057182:Mendelian Randomization Analysis; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D012641:Selection, Genetic; D012680:Sensitivity and Specificity; D020521:Stroke / Q000097:blood / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
D001786:Blood Glucose; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D007328:Insulin; D015850:Interleukin-6