Taller height and risk of coronary heart disease and cancer, a within-sibship Mendelian randomization study
- University of Bristol, United Kingdom
- Norwegian University of Science and Technology, Norway
Abstract
Background: Taller people have lower risk of coronary heart disease but higher risk of many cancers. Mendelian randomization (MR) studies in unrelated individuals (population MR) have suggested that these relationships are potentially causal. However, population MR studies are sensitive to demography (population stratification, assortative mating) and familial (indirect genetic) effects.
Methods: In this study, we performed within-sibship MR analyses using 78,988 siblings, a design robust against demography and indirect genetic effects of parents. For comparison we also applied population MR and estimated associations with measured height.
Results: Within-sibship Mendelian randomization estimated that one SD taller height lowers odds of coronary heart disease by 14% (95% CI: 3% to 23%) but increases odds of cancer by 18% (95% CI: 3% to 34%), highly consistent with population MR and height-disease association estimates. There was some evidence that taller height reduces systolic blood pressure and LDL cholesterol, which may mediate some of the protective effect of taller height on coronary heart disease risk.
Conclusions: For the first time, we have demonstrated that purported effects of height on adulthood disease risk are unlikely to be explained by demographic or familial factors, and so likely reflect an individual-level causal effect. Disentangling the mechanisms via which height affects disease risk may improve understanding of the aetiologies of atherosclerosis and carcinogenesis.
Funding: This project was conducted by researchers at the MRC Integrative Epidemiology Unit [MC_UU_00011/1] and also supported by a Norwegian Research Council Grant number 295989.
Data availability
We used individual level data from the UK Biobank and HUNT cohorts. Participants in these studies have consented to the use of their data in medical research and so these data are not publicly available. Data access can be applied for by qualified researchers.For access to UK Biobank individual level participant data, please send enquiries to access@ukbiobank.ac.uk and see information on the UK Biobank website http://www.ukbiobank.ac.uk. UK Biobank access generally involves submitting project proposals which are evaluated by the study data access committee.Researchers associated with Norwegian research institutes can apply for the use of HUNT data and samples with approval by the Regional Committee for Medical and Health Research Ethics. HUNT data is governed by Norwegian law, therefore researchers from other countries may apply if collaborating with a Norwegian Principal Investigator. Detailed information on the data access procedure of HUNT can be found at https://www.ntnu.edu/hunt/data.Statistical code for population and within-sibship models used in the manuscript is available on GitHub https://github.com/LaurenceHowe/WithinSibshipModels/
Article and author information
Author details
George Davey Smith
Neil Martin Davies
Funding
Norwegian Research Council (295989)
- Neil Martin Davies
Medical Research Council (00011/1)
- George Davey Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Edward D Janus, University of Melbourne, Australia
Ethics
Human subjects: This research has been conducted using the UK Biobank Resource under Application Number 15825. UK Biobank has ethical approval from the North West Multi-centre Research Ethics Committee (MREC). All UK Biobank participants provided written informed consent. The use of HUNT data in this study was approved by the Regional Committee for Ethics in Medical Research, Central Norway (2017/2479). All HUNT study participants provided written informed consent.
Version history
- Preprint posted: July 19, 2021 (view preprint)
- Received: August 11, 2021
- Accepted: March 9, 2022
- Accepted Manuscript published: March 18, 2022 (version 1)
- Version of Record published: March 24, 2022 (version 2)
Copyright
© 2022, Howe et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Taller height and risk of coronary heart disease and cancer, a within-sibship Mendelian randomization study
eLife 11:e72984.
https://doi.org/10.7554/eLife.72984
Further reading
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
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- Epidemiology and Global Health
Background:
Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.
Methods:
We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6461 died during follow-up, including 2794 from cancer and 1668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.
Results:
Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend <0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15–38%) higher total mortality, 14% (95% CI, 0–31%) higher cancer mortality, and 31% (95% CI, 10–55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.
Conclusions:
Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.
Funding:
Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under the award number R35GM143060 (KY). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
