Causal relationship between obesity, lifestyle factors and risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study

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Abstract

Background

Obesity (waist circumference, body mass index (BMI)) and lifestyle factors (dietary habits, smoking, alcohol drinking, Sedentary behavior) have been associated with risk of benign prostatic hyperplasia (BPH) in observational studies, but whether these associations are causal is unclear.

Methods

We performed a univariable and multivariable Mendelian randomization study to evaluate these associations. Genetic instruments associated with exposures at the genome-wide significance level ( P < 5 × 10 ^–8) were selected from corresponding genome-wide associations studies (n = 216,590 to 1,232,091 individuals). Summary-level data for BPH were obtained from the UK Biobank (14,126 cases and 169,762 non-cases) and FinnGen consortium (13,118 cases and 72,799 non-cases). Results from UK Biobank and FinnGen consortium were combined using fixed-effect meta-analysis.

Results

The combined odds ratios (ORs) of BPH were 1.24 (95% confidence interval (CI), 1.07–1.43, P = 0.0045), 1.08 (95% CI 1.01–1.17, P = 0.0175), 0.94 (95% CI 0.67–1.30, P = 0.6891), 1.29 (95% CI 0.88–1.89, P = 0.1922), 1.23 (95% CI 0.85–1.78, P = 0.2623), and 1.04 (95% CI 0.76–1.42, P = 0.8165) for one standard deviation (SD) increase in waist circumference, BMI, and relative carbohydrate, fat, protein and sugar intake, 1.05 (95% CI 0.92–1.20, P = 0.4581) for one SD increase in prevalence of smoking initiation, 1.10 (95% CI 0.96–1.26, P = 0.1725) and 0.84 (95% CI 0.69–1.02, P = 0.0741) for one SD increase of log-transformed smoking per day and drinks per week, and 1.31 (95% CI 1.08–1.58, P = 0.0051) for one SD increase in sedentary behavior. Genetically predicted waist circumference (OR = 1.26, 95% CI 1.11–1.43, P = 0.0004) and sedentary behavior (OR = 1.14, 95% CI 1.05–1.23, P = 0.0021) were associated with BPH after the adjustment of BMI.

Conclusion

This study supports independent causal roles of high waist circumference, BMI and sedentary behavior in BPH.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-022-03722-y.

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Most cited references 58

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Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

Jack Bowden, George Davey Smith, Stephen Burgess (2017)

Background: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). Methods: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger’s test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. Results: We illustrate the use of this approach by re-analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. Conclusions: An adaption of Egger regression (which we call MR-Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation.

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UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

Cathie Sudlow, John Gallacher, Naomi Allen … (2017)

Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.

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Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator

Jack Bowden, George Davey Smith, Philip C. Haycock … (2018)

ABSTRACT Developments in genome‐wide association studies and the increasing availability of summary genetic association data have made application of Mendelian randomization relatively straightforward. However, obtaining reliable results from a Mendelian randomization investigation remains problematic, as the conventional inverse‐variance weighted method only gives consistent estimates if all of the genetic variants in the analysis are valid instrumental variables. We present a novel weighted median estimator for combining data on multiple genetic variants into a single causal estimate. This estimator is consistent even when up to 50% of the information comes from invalid instrumental variables. In a simulation analysis, it is shown to have better finite‐sample Type 1 error rates than the inverse‐variance weighted method, and is complementary to the recently proposed MR‐Egger (Mendelian randomization‐Egger) regression method. In analyses of the causal effects of low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol on coronary artery disease risk, the inverse‐variance weighted method suggests a causal effect of both lipid fractions, whereas the weighted median and MR‐Egger regression methods suggest a null effect of high‐density lipoprotein cholesterol that corresponds with the experimental evidence. Both median‐based and MR‐Egger regression methods should be considered as sensitivity analyses for Mendelian randomization investigations with multiple genetic variants.

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Author and article information

Contributors

Ping Chen: chenping2008@whu.edu.cn

Xian-Tao Zeng:

ORCID: http://orcid.org/0000-0003-1262-725X

zengxiantao1128@163.com , zengxiantao1128@whu.edu.cn

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 29 October 2022

Publication date PMC-release: 29 October 2022

Publication date Collection: 2022

Volume: 20

Electronic Location Identifier: 495

Affiliations

[1 ]GRID grid.413247.7, ISNI 0000 0004 1808 0969, Center for Evidence-Based and Translational Medicine, , Zhongnan Hospital of Wuhan University, ; Wuhan, 430071 China

[2 ]GRID grid.413247.7, ISNI 0000 0004 1808 0969, Division of Medical Affairs, , Zhongnan Hospital of Wuhan University, ; Wuhan, 430071 China

[3 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Department of Urology, , The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, ; Wuhan, 430014 China

[4 ]GRID grid.413247.7, ISNI 0000 0004 1808 0969, Department of Urology, , Zhongnan Hospital of Wuhan University, ; No. 169, Donghu Road, Wuchang District, Wuhan, 430071 China

Author information

Xian-Tao Zeng http://orcid.org/0000-0003-1262-725X

Article

Publisher ID: 3722

DOI: 10.1186/s12967-022-03722-y

PMC ID: 9617448

PubMed ID: 36309747

SO-VID: 4ae9d138-ea14-4f08-855b-63d71df4cb66

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 5 August 2022

Date accepted : 21 October 2022

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ScienceOpen disciplines: Medicine

Keywords: obesity,lifestyle factors,benign prostatic hyperplasia (bph),mendelian randomization (mr),causal effect

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ScienceOpen disciplines: Medicine

Keywords: obesity, lifestyle factors, benign prostatic hyperplasia (bph), mendelian randomization (mr), causal effect

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Causal relationship between obesity, lifestyle factors and risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study

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Abstract

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Conclusion

Supplementary Information

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Karger: Nutrition and Dietetics

Most cited references 58

Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression

UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator

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