A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Ong, Jue‐Sheng; Dixon-Suen, Suzanne C.; Han, Xikun; An, Jiyuan; Liyanage, Upekha E.; Dusingize, Jean-Cluade; Schumacher, Johannes; Gockel, Ines; Böhmer, Anne C.; Jankowski, Janusz; Palles, Claire; O’Mara, Tracy A.; Spurdle, Amanda B.; Law, Matthew H.; Iles, Mark M.; Pharoah, Paul; Berchuck, Andrew; Zheng, Wei; Thrift, Aaron P.; Olsen, Catherine M.; Gharahkhani, Puya; Webb, Penelope M.; MacGregor, Stuart; Fitzgerald, Rebecca C.; Buas, Matt; Gammon, Marilie D.; Corley, Douglas A.; Shaheen, Nicholas J.; Hardie, Laura J.; Bird, Nigel C.; Reid, Brian J.; Chow, Wong‐Ho; Risch, Harvey A.; Ye, Weimin; Liu, Geoffrey; Romero, Yvonne; Bernstein, Leslie; Wu, Anna H.; Whiteman, David; Vaughan, Thomas L.; Agee, Michelle; Alipanahi, Babak; Auton, Adam; Bell, Robert K.; Bryc, Katarzyna; Elson, Sarah L.; Fontanillas, Pierre; Furlotte, Nicholas A.; Hinds, David A.; Kleinman, Aaron; Litterman, Nadia K.; McIntyre, Matthew H.; Mountain, Joanna L.; Noblin, Elizabeth S.; Northover, Carrie A. M.; Pitts, Steven J.; Sathirapongsasuti, J. Fah; Sazonova, Olga V.; Shelton, Janie F.; Shringarpure, Suyash; Tian, Chao; Tung, Joyce Y.; Vacic, Vladimir; Wilson, Carla

doi:10.1038/s41467-020-20368-w

Cited by 48 publications

(39 citation statements)

References 65 publications

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“…The latest study by Ong and co-workers in the face of horizontal pleiotropy involving analysis with 74 SNPs further validated this result. Increase in vitamin D concentration may thus be related to decreased risk of OC ( 47 ).…”

Section: Application Of Mr In Ocmentioning

confidence: 99%

Review of Mendelian Randomization Studies on Ovarian Cancer

et al. 2021

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Ovarian cancer (OC) is one of the deadliest gynecological cancers worldwide. Previous observational epidemiological studies have revealed associations between modifiable environmental risk factors and OC risk. However, these studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) analysis has been established as a reliable method to investigate the causal relationship between risk factors and diseases using genetic variants to proxy modifiable exposures. Over recent years, MR analysis in OC research has received extensive attention, providing valuable insights into the etiology of OC as well as holding promise for identifying potential therapeutic interventions. This review provides a comprehensive overview of the key principles and assumptions of MR analysis. Published MR studies focusing on the causality between different risk factors and OC risk are summarized, along with comprehensive analysis of the method and its future applications. The results of MR studies on OC showed that higher BMI and height, earlier age at menarche, endometriosis, schizophrenia, and higher circulating β-carotene and circulating zinc levels are associated with an increased risk of OC. In contrast, polycystic ovary syndrome; vitiligo; higher circulating vitamin D, magnesium, and testosterone levels; and HMG-CoA reductase inhibition are associated with a reduced risk of OC. MR analysis presents a2 valuable approach to understanding the causality between different risk factors and OC after full consideration of its inherent assumptions and limitations.

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Section: Application Of Mr In Ocmentioning

confidence: 99%

Review of Mendelian Randomization Studies on Ovarian Cancer

et al. 2021

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“…MR studies compare the estimated effect of SNPs associated with variation in 25(OH)D concentrations on the health outcomes seen in large numbers of participants, often up to 100,000. Although some MR studies report inverse correlations between the SNPs increasing serum 25(OH)D and several health outcomes [ 130 ] such as the incidence of multiple sclerosis [ 131 ] and ovarian cancer [ 132 ], no such effects were seen for eight other types of cancer [ 133 ]. The primary reasons for MRA failure are likely to include the fact that total SNP-induced variation in 25(OH)D has often been less than 25(OH)D assay variance [ 134 ] and that genome-wide association studies’ (GWAS) analyses of the total percentage of SNP effects are made on the 25(OH)D data as a whole, although such data is non-linear with much of it lying in the low and high plateaus of the 25(OH)D–health outcome relationships, a problem that the GWAS analysis of 25(OH)D data stratified for different ranges of 25(OH)D efficacy might overcome [ 135 ].…”

Section: Discussionmentioning

confidence: 99%

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health

et al. 2022

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Vitamin D3 has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world’s population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.

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“…Details of MR analysis have been described in previous reports ( Davey Smith and Hemani, 2014 ; Bowden et al, 2015 , 2016 ; Yavorska and Burgess, 2017 ; Cheng et al, 2018 , 2019b ; Hemani et al, 2018 ; Hu et al, 2020 , 2021 ; Qiu et al, 2021 ). Herein, we first aligned alleles on the forward strand and harmonized SNP effects of exposure and outcome ( Ong et al, 2021 ). If the variant in IVs was lacking in outcome, we allowed the proxy SNP with a strong LD to replace it ( Hemani et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Rheumatoid Arthritis and Cardio-Cerebrovascular Disease: A Mendelian Randomization Study

Qiu

Jin

et al. 2021

Front. Genet.

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Significant genetic association exists between rheumatoid arthritis (RA) and cardiovascular disease. The associated mechanisms include common inflammatory mediators, changes in lipoprotein composition and function, immune responses, etc. However, the causality of RA and vascular/heart problems remains unknown. Herein, we performed Mendelian randomization (MR) analysis using a large-scale RA genome-wide association study (GWAS) dataset (462,933 cases and 457,732 controls) and six cardio-cerebrovascular disease GWAS datasets, including age angina (461,880 cases and 447,052 controls), hypertension (461,880 cases and 337,653 controls), age heart attack (10,693 cases and 451,187 controls), abnormalities of heartbeat (461,880 cases and 361,194 controls), stroke (7,055 cases and 454,825 controls), and coronary heart disease (361,194 cases and 351,037 controls) from United Kingdom biobank. We further carried out heterogeneity and sensitivity analyses. We confirmed the causality of RA with age angina (OR = 1.17, 95% CI: 1.04–1.33, p = 1.07E−02), hypertension (OR = 1.45, 95% CI: 1.20–1.75, p = 9.64E−05), age heart attack (OR = 1.15, 95% CI: 1.05–1.26, p = 3.56E−03), abnormalities of heartbeat (OR = 1.07, 95% CI: 1.01–1.12, p = 1.49E−02), stroke (OR = 1.06, 95% CI: 1.01–1.12, p = 2.79E−02), and coronary heart disease (OR = 1.19, 95% CI: 1.01–1.39, p = 3.33E−02), contributing to the understanding of the overlapping genetic mechanisms and therapeutic approaches between RA and cardiovascular disease.

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A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Cited by 48 publications

References 65 publications

Review of Mendelian Randomization Studies on Ovarian Cancer

Review of Mendelian Randomization Studies on Ovarian Cancer

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health

Rheumatoid Arthritis and Cardio-Cerebrovascular Disease: A Mendelian Randomization Study

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