Interplay between vitamin D and metabolic factors in colorectal cancer development: a molecular epidemiology approach

Observational studies have reported that higher levels of serum vitamin D are associated with lower risk of colorectal cancer (CRC) and metabolic syndrome (MetS). Given the fact that MetS and its components are also associated with CRC, the potential causal pathways between vitamin D, MetS and its components, and CRC are not well understood. At the same time, observational studies have inherit limitations and can only assess association rather than causation. Alternatively, the Mendelian randomisation (MR) approach uses genetic variants as proxies for an environmental exposure and can be used to provide more robust evidence for potential causality. In this thesis I used a variety of methods to study the interlinked effects of vitamin D, MetS, and CRC. Mediation analysis was used to assess whether the association between vitamin D and CRC was mediated by MetS in the EPIC cohort. I further assessed the potential causal association between vitamin D and CRC using both individual and summary-level data in EPIC, UK Biobank, the GECCO consortium and data from the SUNLIGHT consortium. Moreover, I assessed the direction of potential causal relationship between vitamin D and MetS components using summary-level data from genetic consortia. Among the 2,300 participants in EPIC, MetS mediated ~18% of the association between vitamin D and CRC. No significant causal association between vitamin D and CRC was found for either the individual-level data in EPIC (OR: 1.03, 95%CI: 0.99 – 1.06), or for the larger studies using summary-level data in the UK Biobank (OR: 0.86, 95%CI: 0.68 – 1.08) or GECCO (OR: 0.92, 95%CI: 0.76 – 1.10). I also assessed the potential causal association between vitamin D and MetS components and found that a 1 standard deviation decrease in the natural log transformed 25-hydroxyvitamin D (25(OH)D) was associated with a 4% increase in HbA1c levels. The results also showed that high BMI and low levels of HDL cholesterol reduced the levels of 25(OH)D, and that high levels of HbA1c and SBP increased 25(OH)D levels. To conclude, no evidence for a causal association was found between vitamin D and CRC. Further research needs to be conducted to understand the inconsistency of results between observational and MR analyses of vitamin D and CRC. Moreover, evidence of causality was found between vitamin D and MetS components; however, present methods cannot reliably infer the directionality of these associations.Open Acces

Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power. METHODS: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods. RESULTS: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy. CONCLUSIONS: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency

Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention

Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

Objective: To determine if circulating concentrations of vitamin D are causally associated with risk of cancer. There is debate on whether vitamin D status is a cause of disease or just a correlate marker of overall health. Evidence from in-vitro and animal model studies supports an anti-neoplastic role of vitamin D, but epidemiological studies and randomized controlled trials have yielded mixed results. Design: To overcome potential limitations in epidemiological studies and randomized controlled trials, a Mendelian randomization (MR) approach was used. Participants and Setting: A total of 70,563 cancer cases and 84,418 controls were used from large genetic epidemiology networks, which consisted of 22,898 cases of prostate cancer, 15,748 cases of breast cancer, 12,537 cases of lung cancer, 11,488 cases of colorectal cancer, 4,369 cases of ovarian cancer, 1,896 cases of pancreatic cancer and 1,627 cases of neuroblastoma. Exposures: Four vitamin D associated single nucleotide polymorphisms (SNPs: rs2282679, rs10741657, rs12785878 and rs6013897) were used to define a multi-SNP score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Main outcomes and measures: The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung and pancreatic cancer, and neuroblastoma, which was evaluated using an inverse-variance weighted average of the SNP-specific associations and a likelihood-based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage and histology were also examined. Results: There was little evidence that the multi-SNP score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically-determined 25(OH)D concentrations were 0.92 (95% CI, 0.76-1.10) for colorectal cancer, 1.05 (95% CI, 0.89-1.24) for breast cancer, 0.89 (95% CI, 0.77-1.02) for prostate cancer, and 1.03 (95% CI, 0.87-1.23) for lung cancer. The results were consistent with the two different analytic approaches, and the study was powered to detect relative effect sizes of moderate magnitude (e.g., 1.20-1.50) per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The MR assumptions did not appear to be violated. Conclusions: Our results provide little evidence of a linear causal association between circulating vitamin D concentration and risk of colorectal, breast, prostate, ovarian, lung and pancreatic cancer, and neuroblastoma, but we cannot rule out existence of causal clinically relevant effects of low magnitude. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not be recommended at this time as a primary cancer prevention strategy.</p

Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits

Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)—a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.</p

Global Biobank Meta-analysis Initiative: Powering genetic discovery across human disease.

Funder: BiogenBiobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits