Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis

doi:10.1016/j.ajhg.2013.12.014

Observational Study

. 2014 Feb 6;94(2):198-208.

doi: 10.1016/j.ajhg.2013.12.014. Epub 2014 Jan 23.

Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis

Michael V Holmes¹, Leslie A Lange², Tom Palmer³, Matthew B Lanktree⁴, Kari E North⁵, Berta Almoguera⁶, Sarah Buxbaum⁷, Hareesh R Chandrupatla⁶, Clara C Elbers⁸, Yiran Guo⁶, Ron C Hoogeveen⁹, Jin Li⁶, Yun R Li⁶, Daniel I Swerdlow¹⁰, Mary Cushman¹¹, Tom S Price¹², Sean P Curtis¹³, Myriam Fornage¹⁴, Hakon Hakonarson⁶, Sanjay R Patel¹⁵, Susan Redline¹⁵, David S Siscovick¹⁶, Michael Y Tsai¹⁷, James G Wilson¹⁸, Yvonne T van der Schouw¹⁹, Garret A FitzGerald¹², Aroon D Hingorani¹⁰, Juan P Casas²⁰, Paul I W de Bakker²¹, Stephen S Rich²², Eric E Schadt²³, Folkert W Asselbergs²⁴, Alex P Reiner²⁵, Brendan J Keating²⁶

Affiliations

¹ 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.
² Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC 27514, USA.
³ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
⁴ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁶ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁷ Jackson Heart Study Coordinating Center, Jackson State University, 350 West Woodrow Wilson Avenue, Suite 701, Jackson, MS 39213, USA.
⁸ Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
⁹ Division of Atherosclerosis & Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Genetic Epidemiology Group, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
¹¹ Departments of Medicine and Pathology, University of Vermont, 208 South Park Drive, Colchester, VT 05446 USA.
¹² The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹³ Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
¹⁴ The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹⁵ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁶ Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA 98101, USA.
¹⁷ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55414, USA.
¹⁸ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
²⁰ 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.
²¹ 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.
²² Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
²³ Department of Genomics, Mount Sinai School of Medicine, New York, NY 10029, USA.
²⁴ 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.
²⁵ 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.
²⁶ 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.

PMID: 24462370
PMCID: PMC3928659
DOI: 10.1016/j.ajhg.2013.12.014

Observational Study

Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis

Michael V Holmes et al. Am J Hum Genet. 2014.

. 2014 Feb 6;94(2):198-208.

doi: 10.1016/j.ajhg.2013.12.014. Epub 2014 Jan 23.

Authors

Affiliations

¹ 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.
² Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC 27514, USA.
³ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
⁴ Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁶ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁷ Jackson Heart Study Coordinating Center, Jackson State University, 350 West Woodrow Wilson Avenue, Suite 701, Jackson, MS 39213, USA.
⁸ Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
⁹ Division of Atherosclerosis & Vascular Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁰ Genetic Epidemiology Group, Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK.
¹¹ Departments of Medicine and Pathology, University of Vermont, 208 South Park Drive, Colchester, VT 05446 USA.
¹² The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹³ Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
¹⁴ The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹⁵ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁶ Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA 98101, USA.
¹⁷ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55414, USA.
¹⁸ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
¹⁹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
²⁰ 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.
²¹ 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.
²² Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
²³ Department of Genomics, Mount Sinai School of Medicine, New York, NY 10029, USA.
²⁴ 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.
²⁵ 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.
²⁶ 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.

PMID: 24462370
PMCID: PMC3928659
DOI: 10.1016/j.ajhg.2013.12.014

Erratum in

Am J Hum Genet. 2014 Feb 6;94(2):312

Abstract

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.

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Figures

**Figure 1**
Association between the BMI GS and Cardiometabolic Traits Effect estimates represent the beta (plotted) or regression (tabulated) coefficients (±95% CI) per 1-unit increase in weighted GS. The GS consisted of 14 SNPs taken from Guo et al. For log-transformed variables (marked by an asterisk), the regression coefficients are presented as a percent difference in the geometric mean.

**Figure 2**
Association between the BMI GS and Cardiometabolic Events Effect estimates represent the OR (±95% CI) for each outcome per 1-unit increase in weighted GS. The GS consisted of 14 SNPs (taken from Guo et al.²³) that associated with a 1.08 kg/m² increase in BMI (Figure 1).

**Figure 3**
Observational and Instrumental Variable Estimates of the Effect of BMI on Cardiometabolic Traits Effect estimates represent the beta (plotted) or regression (tabulated) coefficients (±95% CI) per 1 kg/m² increase in BMI. Observational estimates were adjusted for age, sex, and study. For log-transformed variables (marked by an asterisk), the summary estimates are presented as a percent difference in the geometric mean. Causal estimates were derived from instrumental variable (IV) analysis.

**Figure 4**
Observational and Instrumental Variable Estimates of the Effect of BMI on Cardiometabolic Events Effect estimates represent the OR (±95% CI) per 1 kg/m² increase in BMI. Observational estimates were adjusted for age, sex, and study. Causal estimates were derived from instrumental variable (IV) analysis.

**Figure 5**
Meta-analysis of Studies Investigating the Effect of BMI on CHD through Mendelian Randomization Analysis Effect estimates represent the OR (±95% CI) per 1 kg/m² increase in BMI on the odds of CHD.

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References

1. Global Health Observatory (GHO). (2013). Obesity: Situation and Trends. World Health Organization, http://www.who.int/gho/ncd/risk_factors/obesity_text/en/index.html.
1. Lewis C.E., McTigue K.M., Burke L.E., Poirier P., Eckel R.H., Howard B.V., Allison D.B., Kumanyika S., Pi-Sunyer F.X. Mortality, health outcomes, and body mass index in the overweight range: a science advisory from the American Heart Association. Circulation. 2009;119:3263–3271. - PubMed
1. Hebebrand J., Volckmar A.L., Knoll N., Hinney A. Chipping away the ‘missing heritability’: GIANT steps forward in the molecular elucidation of obesity - but still lots to go. Obes Facts. 2010;3:294–303. - PMC - PubMed
1. Berrington de Gonzalez A., Hartge P., Cerhan J.R., Flint A.J., Hannan L., MacInnis R.J., Moore S.C., Tobias G.S., Anton-Culver H., Freeman L.B. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 2010;363:2211–2219. - PMC - PubMed
1. Zheng W., McLerran D.F., Rolland B., Zhang X., Inoue M., Matsuo K., He J., Gupta P.C., Ramadas K., Tsugane S. Association between body-mass index and risk of death in more than 1 million Asians. N. Engl. J. Med. 2011;364:719–729. - PMC - PubMed

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[1] Global Health Observatory (GHO). (2013). Obesity: Situation and Trends. World Health Organization, http://www.who.int/gho/ncd/risk_factors/obesity_text/en/index.html.

[2] Global Health Observatory (GHO). (2013). Obesity: Situation and Trends. World Health Organization, http://www.who.int/gho/ncd/risk_factors/obesity_text/en/index.html.

[3] Lewis C.E., McTigue K.M., Burke L.E., Poirier P., Eckel R.H., Howard B.V., Allison D.B., Kumanyika S., Pi-Sunyer F.X. Mortality, health outcomes, and body mass index in the overweight range: a science advisory from the American Heart Association. Circulation. 2009;119:3263–3271. - PubMed

[4] Lewis C.E., McTigue K.M., Burke L.E., Poirier P., Eckel R.H., Howard B.V., Allison D.B., Kumanyika S., Pi-Sunyer F.X. Mortality, health outcomes, and body mass index in the overweight range: a science advisory from the American Heart Association. Circulation. 2009;119:3263–3271. - PubMed

[5] Hebebrand J., Volckmar A.L., Knoll N., Hinney A. Chipping away the ‘missing heritability’: GIANT steps forward in the molecular elucidation of obesity - but still lots to go. Obes Facts. 2010;3:294–303. - PMC - PubMed

[6] Hebebrand J., Volckmar A.L., Knoll N., Hinney A. Chipping away the ‘missing heritability’: GIANT steps forward in the molecular elucidation of obesity - but still lots to go. Obes Facts. 2010;3:294–303. - PMC - PubMed

[7] Berrington de Gonzalez A., Hartge P., Cerhan J.R., Flint A.J., Hannan L., MacInnis R.J., Moore S.C., Tobias G.S., Anton-Culver H., Freeman L.B. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 2010;363:2211–2219. - PMC - PubMed

[8] Berrington de Gonzalez A., Hartge P., Cerhan J.R., Flint A.J., Hannan L., MacInnis R.J., Moore S.C., Tobias G.S., Anton-Culver H., Freeman L.B. Body-mass index and mortality among 1.46 million white adults. N. Engl. J. Med. 2010;363:2211–2219. - PMC - PubMed

[9] Zheng W., McLerran D.F., Rolland B., Zhang X., Inoue M., Matsuo K., He J., Gupta P.C., Ramadas K., Tsugane S. Association between body-mass index and risk of death in more than 1 million Asians. N. Engl. J. Med. 2011;364:719–729. - PMC - PubMed

[10] Zheng W., McLerran D.F., Rolland B., Zhang X., Inoue M., Matsuo K., He J., Gupta P.C., Ramadas K., Tsugane S. Association between body-mass index and risk of death in more than 1 million Asians. N. Engl. J. Med. 2011;364:719–729. - PMC - PubMed

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Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis

Affiliations

Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis

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Erratum in

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Medical