| 1. |
- Seyed Khoei, Nazlisadat, et al.
(författare)
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Circulating bilirubin levels and risk of colorectal cancer : serological and Mendelian randomization analyses
- 2020
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
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| 2. |
- Fedirko, Veronika, et al.
(författare)
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Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations
- 2019
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor beta (TGF beta) signaling was associated with CRC risk (P <= 0.001), with most statistically significant genes being SMAD7 (P-BH = 0.008) and SMAD3 (P-BH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.
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| 3. |
- Luczynska, Anna, et al.
(författare)
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Plasma 25-hydroxyvitamin D concentration and lymphoma risk: results of the European Prospective Investigation into Cancer and Nutrition
- 2013
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Ingår i: American Journal of Clinical Nutrition. - Rockville Pike, Bethesda, MD, USA : Elsevier BV. - 1938-3207 .- 0002-9165. ; 98:3, s. 827-838
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relation between vitamin D status and lymphoma risk is inconclusive. Objective: We examined the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] and lymphoid cancer risk. Design: We conducted a study nested within the European Prospective Investigation into Cancer and Nutrition cohort of 1127 lymphoma cases and 1127 matched controls with a mean follow-up time of 7.1 y. Conditional logistic regression was used to estimate multivariable-adjusted incidence rate ratios of lymphoma risk in relation to plasma 25(OH)D. Season-standardized and season-specific 25(OH)D quartiles were used. We also analyzed 25(OH)D as a continuous variable and used predefined cutoffs. Results: No statistically significant association between plasma 25(OH)D and overall lymphoid cancer risk was observed. A positive association for B-cell non-Hodgkin lymphoma was noted only in those with a diagnosis made during the first 2 y of follow-up (P-heterogeneity = 0.03), which suggests the possibility of reverse causality. Further analysis restricted to participants with >= 2y of follow-up time showed a significant association between 25(OH)D and chronic lymphocytic leukemia (CLL) (n = 161): adjusted incidence rate ratios were 0.40 (95% CI: 0.18, 0.90; P-trend = 0.05) and 0.31 (95% CI: 0.13, 0.76; P-trend = 0.03) for the top compared with the bottom season-standardized and season-specific quartiles, respectively. Data on dietary vitamin D intake provided further support for the observed association (incidence rate ratio: 0.33; 95% CI = 0.12, 0.89; P-trend = 0.006). Conclusions: Our findings do not support a protective role of high 25(OH)D concentration in lymphoid cancers overall. However, they suggest that higher concentrations of 25(OH)D are associated with a reduced risk of CLL.
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