Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

He, Yazhou; Timofeeva, Maria; Farrington, Susan M.; Vaughan-Shaw, Peter G; Svinti, Victoria; Walker, Marion; Zgaga, Lina; Meng, Xiangrui; Li, Xue; Spiliopoulou, Athina; Jiang, Xia; Hyppönen, Elina; Kraft, Peter; Kiel, Douglas P.; Hayward, Caroline; Campbell, Archie; Porteous, David J.; Vučić, Katarina; Kirac, Iva; Filipović, Maša; Harris, Sarah E.; Deary, Ian J.; Houlston, Richard S.; Tomlinson, Ian; Campbell, Harry; Τheodoratou, Evropi; Dunlop, Malcolm G.

doi:10.1186/s12916-018-1119-2

Cited by 70 publications

(56 citation statements)

References 65 publications

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“…2.0–2.9 μg in non‐users. Furthermore, recent studies have examined vitamin D receptor polymorphisms and risk of colorectal diseases and found different results for different disease entities, and a large Mendelian randomization study provides no evidence for a causal relationship between vitamin D and risk of colorectal cancers, although small effect sizes and non‐linear relationships cannot be ruled out. Like our study, none of these studies had information on potential confounding factors such as smoking habits, alcohol consumption, body fatness, physical activity or family history of cancer.…”

Section: Discussionsupporting

confidence: 79%

Vitamin D levels and cancer incidence in 217,244 individuals from primary health care in Denmark

Vojdeman

Madsen

Frederiksen

et al. 2019

Intl Journal of Cancer

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Vitamin D has been linked to cancer development in both pre‐clinical and epidemiological studies. Our study examines the association between serum levels of vitamin D and cancer incidence in the Capital Region of Denmark. Individuals who had vitamin D analyzed at The Copenhagen General Practitioners Laboratory between April 2004 and January 2010 were linked to Danish registries with end of follow‐up date at Dec 31st 2014, excluding individuals with pre‐existing cancer. Cox regression models adjusted for age in one‐year intervals, sex, month of sampling, and Charlson Comorbidity Index were applied. The study population of 217,244 individuals had a median vitamin D level of 46 nmol/L (IQR 27–67 nmol/L). Non‐melanoma skin cancer was the most frequent form of cancer, followed by breast‐, lung‐, and prostate cancers. No associations were found between increments of 10 nmol/L vitamin D and incidence of breast, colorectal, urinary, ovary or corpus uteri cancer. However, higher levels of vitamin D were associated with higher incidence of non‐melanoma (HR 1.09 [1.09–1.1]) and melanoma skin cancer (HR 1.1 [1.08–1.13]) as well as prostate (HR 1.05 [1.03–1.07]) and hematological cancers (HR 1.03 [1.01–1.06]), but with lower incidence of lung cancer (HR 0.95 [0.93–0.97]). In our study, vitamin D levels are not associated with the incidence of several major cancer types, but higher levels are significantly associated with a higher incidence of skin, prostate, and hematological cancers as well as a lower incidence of lung cancer. These results do not support an overall protective effect against cancer by vitamin D.

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Section: Discussionsupporting

confidence: 79%

Vitamin D levels and cancer incidence in 217,244 individuals from primary health care in Denmark

Vojdeman

Madsen

Frederiksen

et al. 2019

Intl Journal of Cancer

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“…The renal cancer analysis used summary statistics from the Kidney Cancer GWAS Meta-Analysis Project of 10,784 cases of renal cell carcinoma and 20,406 controls 76 . Colorectal cancer summary statistics were from eight UK-based GWAS studies, totalling 22,372 colorectal cancer cases and 44,271 controls 77,78 . The summary statistics for overall lung cancer were from GWAS analyses of 29,266 lung cancer cases and 56,450 controls conducted by the International Lung Cancer Consortium 79 .…”

Section: Integration With Cancer Data and Modelling Loy As A Causal Ementioning

confidence: 99%

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

Thompson¹,

Halvardson²,

Ulirsch³

et al. 2019

Preprint

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Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Using a newly developed approach, we estimate that 20% of the UK Biobank male population (N=205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes involved in cell-cycle regulation, cancer susceptibility, somatic drivers of tumour growth and cancer therapy targets. Genetic susceptibility to LOY is associated with non-haematological health outcomes in both men and women, supporting the hypothesis that clonal haematopoiesis is a biomarker of genome instability in other tissues. Single-cell RNA sequencing identifies dysregulated autosomal gene expression in leukocytes with LOY, providing insights into how LOY may confer cellular growth advantage. Collectively, these data highlight the utility of studying clonal mosaicism to uncover fundamental mechanisms underlying cancer and other ageing-related diseases.

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“…Several studies demonstrate an inverse correlation between colorectal cancer and 25VD levels [58,59]. The findings do not correspond to the results of a larger Vitamin D Deficiency study, detecting no significant association between colorectal cancer and VD status [60]. Unfortunately, the data from interventional trails with VD supplementation also have conflicting result for the effect of VD on colorectal cancer prevention and survival improvement [44,61].…”

Section: Colorectal Cancermentioning

confidence: 89%

Vitamin D Deficiency in Renal Disease

Filipov¹,

Dimitrov²

2020

Vitamin D Deficiency

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Vitamin D deficiency is highly prevalent in patients with renal disease. The abnormal vitamin D (VD) metabolism in chronic kidney disease (CKD) is a key factor for developing CKD-related mineral bone disease (CKD-MBD), which directly influences the survival of the CKD patients. The importance of VD is perhaps of greater value due to its pleiotropic effects that span beyond calcium-phosphorus metabolism (cancer protection, diabetes prevention, and renal protection). The aim of our chapter is to depict the clinical implications of VD deficiency in the setting of CKD, including VD pleiotropy in renal disease, and to propose the most adequate treatment suggested in the literature. Keywords: vitamin D deficiency, chronic kidney disease, mineral bone disease, vitamin D pleiotropy, vitamin D supplementationVitamin D Deficiency 2 the ratio between free and total 25VD remained unchained; therefore, total 25VD is the indicator of VD status in CKD [3].Generally, 25VD level has reverse association with parathyroid hormone (PTH) levels. In addition, higher 25VD is associated with higher calcium intestinal reabsorption. However, at 25VD ≥ 75 nmol/l, no reduction in PTH levels and no increase in calcium intestinal reabsorption occurs [4, 5]. Therefore, 25VD ≥ 75 nmol/l is regarded as a cut-off value for vitamin D sufficiency.No generally accepted definition for VD deficiency exists, as authors choose cut-off value either serum 25VD of 25 nmol/L [6] or serum 25VD of 50 nmol/L [7]. However, target levels of 75 nmol/L are recommended, taking into consideration the clinical importance of mild VD insufficiency (25VD between 50 and 74.9 nmol/L) [7,8].Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for more than 3 months, with implications for health [one of the following: estimated glomerular filtration rate (eGFR) less than 60 ml/ min/1.73 m 2 ,presence of proteinuria, structural abnormalities of the kidney detected on imaging, pathological findings detected on kidney biopsy, urine sediment pathology, electrolyte abnormalities due to tubular disorders, history of kidney transplantation] [9]. CKD patients are at increased risk for VD deficiency; therefore, they require VD screening [7]. Vitamin D metabolism in health and renal disease VD metabolism in healthy subjectsVD is synthesized predominantly endogenously (approx. to 90% of the total VD in human body). In the skin, the ultraviolet light transforms 7-dehydroxycholesterol (provitamin D) to pre-vitamin D, which under the influence of body temperature spontaneously isomerizes to cholecalciferol (vitamin D3). Approximately, 10% of total body VD is taken orally (vitamin D2, ergocalciferol, and cholecalciferol). VD is transported via VD-binding protein to the liver, where it is hydroxylated to 25VD. The next step in VD activation is hydroxylation of 25VD by the enzyme 1α-hydroxylase (CYP27B1) to 1,25VD, which is the active VD metabolite. The process occurs predominantly in the renal tubules. In addition, non-renal CYP27B1 was detected...

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Exploring causality in the association between circulating 25-hydroxyvitamin D and colorectal cancer risk: a large Mendelian randomisation study

Cited by 70 publications

References 65 publications

Vitamin D levels and cancer incidence in 217,244 individuals from primary health care in Denmark

Vitamin D levels and cancer incidence in 217,244 individuals from primary health care in Denmark

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

Vitamin D Deficiency in Renal Disease

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