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

Abstract

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.

Assessing the causal association between 25‐hydroxyvitamin D and the risk of oral and oropharyngeal cancer using Mendelian randomization

“…These findings mirror a recently published MR study of colorectal, breast, prostate, ovarian, lung and pancreatic cancer, and neuroblastoma that did not support a causal role of 25OHD in the risk of these cancers 34. Similar to the inference from this work on oral and pharyngeal cancer, the authors of the previous study state that although they are unable to rule out clinically relevant effects of small magnitude, their study combined 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’.…”

Vitamin D: And its role in breast cancer

“…A significant reduction in the postmenopausal incidence of breast cancer has been related to high levels of 25‐hydroxyvitamin D (25(OH)D) [13]. 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 [14,15].…”

CYP24A1 genetic variants in the vitamin D metabolic pathway are involved in the outcomes of hepatitis C virus infection among high-risk Chinese population

“…Moreover, our report showed that the risk effects of the rs6013897 variant were statistically significant in most subgroups, and there was no significant heterogeneity within each subgroup variable, which suggested that these variables did not modify this association. Some previous research has also reported that rs6013897 can affect the risk of Parkinson disease (PD), aggressive prostate cancer, and bone mineral density at the femoral neck (FN-BMD) by affecting the 25(OH)D 3 concentration (Dimitrakopoulou et al, 2017;Larsson et al, 2017;Larsson et al, 2018).…”