Dataset Information

Circulating vitamin C and digestive system cancers: Mendelian randomization study.

ABSTRACT:

Background & aims

Vitamin C is an antioxidant with a potential role in the prevention of digestive system cancers, but there is yet no consensus whether vitamin C has a causal role in these cancers. The aim of this study was to utilize Mendelian randomization to decipher the potential causal associations of vitamin C with risk of digestive system cancers.

Methods

Ten genetic variants previously found to be significantly associated with circulating vitamin C were used as instrumental variables. Effect size estimates for the genetic associations of the vitamin C-associated genetic variants with six major malignancies of digestive system were obtained from the FinnGen (N = 309 154) and UK Biobank (N = 367 542) studies. Results from the two studies were combined using meta-analysis.

Results

Genetically predicted higher circulating vitamin C showed a suggestive association with lower risk of small intestine and colorectal cancer after accounting for multiple testing. The odds ratio per 1 standard deviation increment in circulating vitamin C was 0.55 (95% confidence interval 0.32-0.94; P = 0.029) for small intestine cancer and 0.84 (95% confidence interval 0.73-0.96; P = 0.013) for colorectal cancer. There was a suggestive association between genetically predicted higher circulating vitamin C with lower risk of liver cancer in FinnGen but no association in the meta-analysis (odds ratio 0.69; 95% CI 0.36-1.32; P = 0.265). Genetically predicted circulating vitamin C was not associated with cancers of the esophagus, stomach, or pancreas.

Conclusion

This Mendelian randomization study indicates that vitamin C might play a role in the prevention of small intestine and colorectal cancer.

SUBMITTER: Larsson SC

PROVIDER: S-EPMC7613472 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Circulating vitamin C and digestive system cancers: Mendelian randomization study.

Larsson Susanna C SC Mason Amy M AM Vithayathil Mathew M Carter Paul P Kar Siddhartha S Zheng Ju-Sheng JS Burgess Stephen S

Clinical nutrition (Edinburgh, Scotland) 20220807 9

<h4>Background & aims</h4>Vitamin C is an antioxidant with a potential role in the prevention of digestive system cancers, but there is yet no consensus whether vitamin C has a causal role in these cancers. The aim of this study was to utilize Mendelian randomization to decipher the potential causal associations of vitamin C with risk of digestive system cancers.<h4>Methods</h4>Ten genetic variants previously found to be significantly associated with circulating vitamin C were used as instrument ...[more]

PMID: 35986965

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Project description:BackgroundCirculating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe.MethodsWe used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes.ResultsThe MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99).ConclusionsThese findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.

Project description:Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, β-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank-the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608-0.985, p = 0.037), which was consistent with the results in FinnGen, and the combined OR was 0.764 (95% CI 0.623-0.936, p = 0.010). Likewise, higher absolute retinol levels suggestively reduced the pancreatic cancer risk in FinnGen-the OR per 10% unit increase in ln-transformed retinol was 0.705 (95% CI 0.529-0.940, p = 0.017), which was consistent with the results in UK Biobank and the combined OR was 0.747 (95% CI, 0.584-0.955, p = 0.020). Sensitivity analyses verified the above suggestive evidence. Our findings suggest that higher levels of antioxidants are unlikely to be a causal protective factor for most digestive system cancers, except for the suggestive protective effects of ascorbate on colon cancer and of retinol on pancreatic cancer.

Project description:Backgrounds: There is growing evidence linking glutamine levels to the risk of gastrointestinal diseases, yet the presence of a causal relationship remains uncertain. In this study, we employed a Mendelian randomization (MR) approach to investigate potential causal associations between glutamine and colitis, inflammatory bowel disease (IBD), and digestive tumors. Methods: Genetic instrumental variables for glutamine exposure were identified from a genome-wide association study (GWAS) involving 114,751 participants. We pooled statistics from GWAS of gastrointestinal diseases in European populations, encompassing colitis (cases=1193, controls=461,740), IBD (cases=31,665, controls=33,977), Crohn's disease (cases=17,897, controls=33,977), ulcerative colitis (cases=1,239, controls=990), oesophageal cancer (cases=740, controls=372,016), gastric cancer (cases=6,563, controls=195,745), liver cell carcinoma (cases=168, controls=372,016), hepatic bile duct cancer (cases=418, controls=159,201), pancreatic cancer (cases=1,196, controls=475,049), and colon cancer (cases=1,494, controls=461,439). To ensure the validity of our findings, we utilized several analytical approaches including inverse variance weighted, weighted median, weighted mode, MR-Egger, and simple mode method. Results: Using the IVW method, we found that glutamine levels were inversely associated with colon cancer (OR = 0.998; 95% CI: 0.997-1.000; P = 0.027), colitis (OR = 0.998; 95% CI: 0.997-1.000; P = 0.020), and IBD (OR = 0.551; 95% CI: 0.343-0.886; P = 0.014). Subgroup analysis revealed a negative association between glutamine and Crohn's disease (OR = 0.375; 95% CI: 0.253-0.557; P = 1.11E-06), but not with ulcerative colitis (OR = 0.508; 95% CI: 0.163-1.586; P = 0.244). Glutamine levels showed no significant correlation with oesophageal cancer (OR = 1.000; 95% CI: 0.999-1.001; P = 0.566), gastric cancer (OR = 0.966; 95% CI: 0.832-1.121; P = 0.648), liver cell carcinoma (OR = 1.000; 95% CI: 0.999-1.000; P = 0.397), hepatic bile duct cancer (OR = 0.819; 95% CI: 0.499-1.344; P = 0.430), and pancreatic cancer (OR = 1.130; 95% CI: 0.897-1.423; P = 0.301). Sensitivity analyses also supports this finding, affirming the reliability and robustness of our study. Conclusions: This study suggests that blood glutamine levels in European populations may lower the risk of colon cancer, colitis, and IBD, particularly Crohn's disease. Nevertheless, additional research involving a diverse range of ancestries is imperative to corroborate this causal relationship.

Project description:BackgroundPrevious observational studies have shown conflicting results of vitamins supplementation for thyroid diseases. The causal relationships between vitamins and thyroid diseases are unclear. Therefore, we conducted a two-sample bidirectional Mendelian randomization (MR) study to explore association of circulating vitamin levels with thyroid diseases.MethodsWe performed a bidirectional MR analysis using genome-wide association study (GWAS) data. Genetic tool variables for circulating vitamin levels include vitamins A, B9, B12, C, D, and E, Genetic tool variables of thyroid diseases include autoimmune hyperthyroidism, autoimmune hypothyroidism, thyroid nodules (TNs), and Thyroid cancer (TC). Inverse-variance weighted multiplicative random effects (IVW-RE) was mainly used for MR Analysis, weighted median (WM) and MR Egger were used as supplementary methods to evaluate the relationships between circulating vitamin levels and thyroid diseases. Sensitivity and pluripotency were evaluated by Cochran's Q test, MR-PRESSO, Radial MR, MR-Egger regression and leave-one-out analysis.ResultsPositive MR evidence suggested that circulating vitamin C level is a protective factor in autoimmune hypothyroidism (ORIVW-RE=0.69, 95%CI: 0.58-0.83, p = 1.05E-04). Reverse MR Evidence showed that genetic susceptibility to autoimmune hyperthyroidism is associated with reduced level of circulating vitamin A(ORIVW-RE = 0.97, 95% CI: 0.95-1.00, p = 4.38E-02), genetic susceptibility of TNs was associated with an increased level of circulating vitamin D (ORIVW-RE = 1.02, 95% CI: 1.00-1.03, p = 6.86E-03). No causal and reverse causal relationship was detected between other circulating vitamin levels and thyroid diseases.ConclusionOur findings provide genetic evidence supporting a bi-directional causal relationship between circulating vitamin levels and thyroid diseases. These findings provide information for the clinical application of vitamins prevention and treatment of thyroid diseases.

Project description: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.

Project description:Background Previous observational studies suggested inconsistent insights on the associations between meat intake and the risk of digestive tract cancers (DCTs). The causal effect of meat intake on DCTs is unclear. Methods Two-sample Mendelian randomization (MR) was performed based on genome-wide association studies (GWAS) summary data from UK Biobank and FinnGen to evaluate the causal effect of meat intake [processed meat, red meat (pork, beef, and lamb), and white meat (poultry)] on DCTs (esophageal, stomach, liver, biliary tract, pancreatic, and colorectal cancers). The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. MR-PRESSO and Radial MR were performed to identify and remove outliers. To demonstrate direct causal effects, multivariable MR (MVMR) was applied. In addition, risk factors were introduced to explore potential mediators of the relationship between exposure and outcome. Results The results of the univariable MR analysis indicated that genetically proxied processed meat intake was associated with an increased risk of colorectal cancer [IVW: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.07–4.19; P = 0.031]. The causal effect is consistent in MVMR (OR = 3.85, 95% CI 1.14–13.04; P = 0.030) after controlling for the influence of other types of exposure. The body mass index and total cholesterol did not mediate the causal effects described above. There was no evidence to support the causal effects of processed meat intake on other cancers, except for colorectal cancer. Similarly, there is no causal association between red meat, white meat intake, and DCTs. Conclusions Our study reported that processed meat intake increases the risk of colorectal cancer rather than other DCTs. No causal relationship was observed between red and white meat intake and DCTs.

Dataset Information

Circulating vitamin C and digestive system cancers: Mendelian randomization study.

Background & aims

Methods

Results

Conclusion

Publications

Circulating vitamin C and digestive system cancers: Mendelian randomization study.

Similar Datasets

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