Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

doi:10.1093/ije/dyv074

Meta-Analysis

. 2016 Dec 1;45(6):1927-1937.

doi: 10.1093/ije/dyv074.

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Eveline Nüesch^{1

2}, Caroline Dale¹, Tom M Palmer^{3

4}, Jon White⁵, Brendan J Keating^{6

7

8}, Erik Pa van Iperen^{9

10}, Anuj Goel¹¹, Sandosh Padmanabhan¹², Folkert W Asselbergs^{13

10

14}; EPIC-Netherland Investigators; W M Verschuren, C Wijmenga, Y T Van der Schouw, N C Onland-Moret¹⁵, Leslie A Lange¹⁶, G K Hovingh¹⁷, Suthesh Sivapalaratnam¹⁷, Richard W Morris¹⁸, Peter H Whincup¹⁹, Goya S Wannamethe¹⁸, Tom R Gaunt^{20

21}, Shah Ebrahim¹, Laura Steel⁶, Nikhil Nair⁶, Alexander P Reiner²², Charles Kooperberg²³, James F Wilson^{24

25}, Jennifer L Bolton²⁴, Stela McLachlan²⁴, Jacqueline F Price²⁴, Mark Wj Strachan²⁶, Christine M Robertson²⁴, Marcus E Kleber²⁷, Graciela Delgado²⁷, Winfried März²⁸, Olle Melander²⁹, Anna F Dominiczak¹², Martin Farrall¹¹, Hugh Watkins¹¹, Maarten Leusink^{30

31}, Anke H Maitland-van der Zee³⁰, Mark Ch de Groot^{30

31}, Frank Dudbridge¹, Aroon Hingorani³², Yoav Ben-Shlomo²¹, Debbie A Lawlor^{20

21}; UCLEB Investigators; A Amuzu, M Caufield, A Cavadino, J Cooper, T L Davies; IN Day; F Drenos, J Engmann, C Finan, C Giambartolomei, R Hardy, S E Humphries, E Hypponen, M Kivimaki, D Kuh, M Kumari, K Ong, V Plagnol, C Power, M Richards, S Shah, T Shah, R Sofat, P J Talmud, N Wareham, H Warren, J C Whittaker, A Wong, D Zabaneh³³, George Davey Smith^{20

21}, Jonathan C Wells³⁴, David A Leon^{1

35}, Michael V Holmes^{14

36

37}, Juan P Casas^{1

14}

Affiliations

¹ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
² CTU Bern, Department of Clinical Research and Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.
³ Warwick Medical School, University of Warwick, Coventry, UK.
⁴ Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
⁵ UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK.
⁶ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Surgery.
⁸ Division of Genetics, University of Pennsylvania, Philadelphia.
⁹ Department of Biostatistics, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
¹⁰ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
¹¹ Wellcome Trust Centre for Human Genetics and Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹² Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
¹³ Department of Cardiology, Division Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands.
¹⁴ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
¹⁵ EPIC-NL, Bilthoven and Utrecht, The Netherlands.
¹⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ Department of Vascular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
¹⁸ Department of Primary Care & Population Health, University College London, London, UK.
¹⁹ Population Health Research Institute, St George's, University of London, London, UK.
²⁰ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
²¹ School of Social and Community Medicine, University of Bristol, Bristol, UK.
²² Department of Epidemiology, University of Washington, Seattle, WA, USA / Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁴ Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
²⁵ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
²⁶ Metabolic Unit, Western General Hospital, Edinburgh, UK.
²⁷ Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
²⁸ Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetolgy, and Rheumatology), Mannheim Medical Faculty, University of Heidelberg, Germany, Synlab Academy, Synlab Services GmbH, Mannheim and Augsburg, Germany, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria.
²⁹ Lund University, Sweden.
³⁰ Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
³¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³² Department of Epidemiology and Public Health, University College London Medical School, London, UK.
³³ UCLEB, London, Edinburgh and Bristol, UK.
³⁴ Childhood Nutrition Research Centre, UCL Institute of Child Health, London, UK.
³⁵ Department of Community Medicine, Arctic University of Norway, UiT.
³⁶ Department of Surgery and Clinical Epidemiology Unit, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁷ Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

PMID: 25979724
PMCID: PMC5841831
DOI: 10.1093/ije/dyv074

Meta-Analysis

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Eveline Nüesch et al. Int J Epidemiol. 2016.

. 2016 Dec 1;45(6):1927-1937.

doi: 10.1093/ije/dyv074.

Authors

Affiliations

¹ Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
² CTU Bern, Department of Clinical Research and Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.
³ Warwick Medical School, University of Warwick, Coventry, UK.
⁴ Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
⁵ UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK.
⁶ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Department of Surgery.
⁸ Division of Genetics, University of Pennsylvania, Philadelphia.
⁹ Department of Biostatistics, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
¹⁰ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
¹¹ Wellcome Trust Centre for Human Genetics and Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹² Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
¹³ Department of Cardiology, Division Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands.
¹⁴ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
¹⁵ EPIC-NL, Bilthoven and Utrecht, The Netherlands.
¹⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁷ Department of Vascular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
¹⁸ Department of Primary Care & Population Health, University College London, London, UK.
¹⁹ Population Health Research Institute, St George's, University of London, London, UK.
²⁰ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
²¹ School of Social and Community Medicine, University of Bristol, Bristol, UK.
²² Department of Epidemiology, University of Washington, Seattle, WA, USA / Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁴ Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
²⁵ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
²⁶ Metabolic Unit, Western General Hospital, Edinburgh, UK.
²⁷ Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
²⁸ Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetolgy, and Rheumatology), Mannheim Medical Faculty, University of Heidelberg, Germany, Synlab Academy, Synlab Services GmbH, Mannheim and Augsburg, Germany, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria.
²⁹ Lund University, Sweden.
³⁰ Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
³¹ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
³² Department of Epidemiology and Public Health, University College London Medical School, London, UK.
³³ UCLEB, London, Edinburgh and Bristol, UK.
³⁴ Childhood Nutrition Research Centre, UCL Institute of Child Health, London, UK.
³⁵ Department of Community Medicine, Arctic University of Norway, UiT.
³⁶ Department of Surgery and Clinical Epidemiology Unit, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁷ Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.

PMID: 25979724
PMCID: PMC5841831
DOI: 10.1093/ije/dyv074

Abstract

Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis.

Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D.

Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index ( P < 0.001), triglycerides ( P < 0.001), non high-density (non-HDL) cholesterol ( P < 0.001), C-reactive protein ( P = 0.042), and systolic blood pressure ( P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity ( P < 0.001 for both).

Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

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Figures

**Figure 1.**
Meta-analysis pooled estimates for the association between deciles of the allele score and adult height. Presented are pooled differences in mean adult height with corresponding 95% confidence intervals as compared with the 5th decile, derived from fixed-effect meta-analysis. N, numbers analysed in each decile.

**Figure 2.**
Meta-analysis pooled causal effects for a 6.5-cm increase in adult height on the risk of cardiovascular disease. Odds ratios and corresponding 95% confidence intervals (CI) are estimated from fixed-effect meta-analysis of instrumental variable (IV) estimates from individual studies. Hazard ratios are taken from estimates published by the Emerging Risk Factors Collaboration (ERFC). Effect estimates are per 6.5 cm increase in adult height. An estimate below 1 indicates that increasing adult height decreases the risk of cardiovascular events.

See this image and copyright information in PMC

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References

1. Waaler HT. Height, weight and mortality. The Norwegian experience. Acta med Scand Suppl 1984;679:1–56. - PubMed
1. Davey Smith G, Hart C, Upton M et al. . Height and risk of death among men and women: aetiological implications of associations with cardiorespiratory disease and cancer mortality. J Epidemiol Community Health 2000;54:97–103. - PMC - PubMed
1. Green J, Cairns BJ, Casabonne D et al. . Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. Lancet Oncoly 2011;12:785–94. - PMC - PubMed
1. The Emerging Risk Factors Collaboration. Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. Int J Epidemiol 2012;41:1419–33. - PMC - PubMed
1. Leon DA, Davey Smith G, Shipley M, Strachan D. Adult height and mortality in London: early life, socioeconomic confounding, or shrinkage? J Epidemiol Community Healthh 1995;49:5–9. - PMC - PubMed

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[1] Waaler HT. Height, weight and mortality. The Norwegian experience. Acta med Scand Suppl 1984;679:1–56. - PubMed

[2] Waaler HT. Height, weight and mortality. The Norwegian experience. Acta med Scand Suppl 1984;679:1–56. - PubMed

[3] Davey Smith G, Hart C, Upton M et al. . Height and risk of death among men and women: aetiological implications of associations with cardiorespiratory disease and cancer mortality. J Epidemiol Community Health 2000;54:97–103. - PMC - PubMed

[4] Davey Smith G, Hart C, Upton M et al. . Height and risk of death among men and women: aetiological implications of associations with cardiorespiratory disease and cancer mortality. J Epidemiol Community Health 2000;54:97–103. - PMC - PubMed

[5] Green J, Cairns BJ, Casabonne D et al. . Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. Lancet Oncoly 2011;12:785–94. - PMC - PubMed

[6] Green J, Cairns BJ, Casabonne D et al. . Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk. Lancet Oncoly 2011;12:785–94. - PMC - PubMed

[7] The Emerging Risk Factors Collaboration. Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. Int J Epidemiol 2012;41:1419–33. - PMC - PubMed

[8] The Emerging Risk Factors Collaboration. Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis. Int J Epidemiol 2012;41:1419–33. - PMC - PubMed

[9] Leon DA, Davey Smith G, Shipley M, Strachan D. Adult height and mortality in London: early life, socioeconomic confounding, or shrinkage? J Epidemiol Community Healthh 1995;49:5–9. - PMC - PubMed

[10] Leon DA, Davey Smith G, Shipley M, Strachan D. Adult height and mortality in London: early life, socioeconomic confounding, or shrinkage? J Epidemiol Community Healthh 1995;49:5–9. - PMC - PubMed

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Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

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Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

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