The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis

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Abstract

Background:

Vitamin D has been linked with improved cancer outcome. This systematic review and meta-analysis investigates the relationship between cancer outcomes and both vitamin D-related genetic variation and circulating 25-hydroxyvitamin D (25OHD) concentration.

Methods:

A systematic review and meta-analysis of papers until November 2016 on PubMed, EMBASE and Web of Science pertaining to association between circulating vitamin D level, functionally relevant vitamin D receptor genetic variants and variants within vitamin D pathway genes and cancer survival or disease progression was performed.

Results:

A total of 44 165 cases from 64 studies were included in meta-analyses. Higher 25OHD was associated with better overall survival (hazard ratio (HR=0.74, 95% CI: 0.66–0.82) and progression-free survival (HR=0.84, 95% CI: 0.77–0.91). The rs1544410 (BsmI) variant was associated with overall survival (HR=1.40, 95% CI: 1.05–1.75) and rs7975232 (ApaI) with progression-free survival (HR=1.29, 95% CI: 1.02–1.56). The rs2228570 (FokI) variant was associated with overall survival in lung cancer patients (HR=1.29, 95% CI: 1.0–1.57), with a suggestive association across all cancers (HR=1.26, 95% CI: 0.96–1.56).

Conclusions:

Higher 25OHD concentration is associated with better cancer outcome, and the observed association of functional variants in vitamin D pathway genes with outcome supports a causal link. This analysis provides powerful background rationale to instigate clinical trials to investigate the potential beneficial effect of vitamin D in the context of stratification by genotype.

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Most cited references 115

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Genetics and biology of vitamin D receptor polymorphisms.

André G. Uitterlinden, Yue Fang, Joyce B J van Meurs … (2004)

The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.

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Hazard rate ratio and prospective epidemiological studies.

M.J. Symons, D.T. Moore (2002)

Analysis of prospective follow-up data usually includes a Cox regression model. When a hazard rate ratio, obtained as the exponential of an estimated regression coefficient from the Cox model, is greater than 1.0, it consistently exceeds relative risk, and is exceeded by the odds ratio. The divergence of these distinct epidemiologic measures increases with the product of three factors: (1) the length of follow-up, (2) the average rate of the end point occurence over the follow-up period, and (3) the magnitude of risk, either above or below 1. Cornfield's rare disease assumption is basically the product of the first two of these factors. However, risks in excess of 2.5 have a powerful effect on the divergence of these measures, and this point has received less emphasis. Conversely, and as seen frequently in applications, relative risk, hazard rate ratio, and odds ratio numerically approximate one another with shorter follow-up, rarer end points, and risks closer to 1. Although the hazard rate ratio is not always distinguished from relative risk, it is commonly close to, and is always between, relative risk and the odds ratio. Consistent and accurate terminology would have us use hazard rate ratio with Cox regression and odds ratio with logistic regression. The term "relative risk" seems to be a default choice, regardless of the model being used. However, when relative risk is the object of the model chosen, as in a Poisson regression approximation of two binomial proportions or an equivalent weighted least squares, then for us, relative risk is the accurate terminology.

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Genetically low vitamin D concentrations and increased mortality: mendelian randomisation analysis in three large cohorts

Shoaib Afzal, Peter Brøndum-Jacobsen, Stig Bojesen … (2014)

Objective To test the hypothesis that genetically low 25-hydroxyvitamin D concentrations are associated with increased mortality. Design Mendelian randomisation analysis. Setting Copenhagen City Heart Study, Copenhagen General Population Study, and Copenhagen Ischemic Heart Disease Study. Participants 95 766 white participants of Danish descent from three cohorts, with median follow-up times of 19.1, 5.8, and 7.9 years, genotyped for genetic variants in DHCR7 and CYP2R1 affecting plasma 25-hydroxyvitamin D concentrations; 35 334 also had plasma 25-hydroxyvitamin D measurements. Participants were followed from study entry through 2013, during which time 10 349 died. Main outcome measures All cause mortality and cause specific mortality, adjusted for common risk factors for all cause mortality based on the World Health Organization’s global health status. Results The multivariable adjusted hazard ratios for a 20 nmol/L lower plasma 25-hydroxyvitamin D concentration were 1.19 (95% confidence interval 1.14 to 1.25) for all cause mortality, 1.18 (1.09 to 1.28) for cardiovascular mortality, 1.12 (1.03 to 1.22) for cancer mortality, and 1.27 (1.15 to 1.40) for other mortality. Each increase in DHCR7/CYP2R1 allele score was associated with a 1.9 nmol/L lower plasma 25-hydroxyvitamin D concentration and with increased all cause, cancer, and other mortality but not with cardiovascular mortality. The odds ratio for a genetically determined 20 nmol/L lower plasma 25-hydroxyvitamin D concentration was 1.30 (1.05 to 1.61) for all cause mortality, with a corresponding observational multivariable adjusted odds ratio of 1.21 (1.11 to 1.31). Corresponding genetic and observational odds ratios were 0.77 (0.55 to 1.08) and 1.13 (1.03 to 1.24) for cardiovascular mortality, 1.43 (1.02 to 1.99) and 1.10 (1.02 to 1.19) for cancer mortality, and 1.44 (1.01 to 2.04) and 1.17 (1.06 to 1.29) for other mortality. The results were robust in sensitivity analyses. Conclusions Genetically low 25-hydroxyvitamin D concentrations were associated with increased all cause mortality, cancer mortality, and other mortality but not with increased cardiovascular mortality. These findings are compatible with the notion that genetically low 25-hydroxyvitamin D concentrations may be causally associated with cancer and other mortality but also suggest that the observational association with cardiovascular mortality could be the result of confounding.

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Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Print): 11 April 2017

Publication date (Electronic): 16 March 2017

Publication date PMC-release: 11 April 2017

Volume: 116

Issue: 8

Pages: 1092-1110

Affiliations

[1 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh , Edinburgh EH42XU, UK

[2 ]Department of Public Health and Primary Care, Trinity College Dublin , Dublin 24, Republic of Ireland

[3 ]Centre for Population Health Sciences, University of Edinburgh , Edinburgh EH164UX, UK

Author notes

[* ]E-mail: zgagal@ 123456tcd.ie

Article

Publisher Item ID: bjc201744

DOI: 10.1038/bjc.2017.44

PMC ID: 5396104

PubMed ID: 28301870

SO-VID: 79e79045-8555-469f-9f7c-379f675c62e8

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

History

Date received : 29 November 2016

Date revision received : 20 January 2017

Date accepted : 26 January 2017

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The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis

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Most cited references 115

Genetics and biology of vitamin D receptor polymorphisms.

Hazard rate ratio and prospective epidemiological studies.

Genetically low vitamin D concentrations and increased mortality: mendelian randomisation analysis in three large cohorts

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