| 1. |
- Larsson, Susanna C., et al.
(författare)
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Genetically predicted plasma phospholipid arachidonic acid concentrations and 10 site-specific cancers in UK biobank and genetic consortia participants : A mendelian randomization study
- 2021
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Ingår i: Clinical Nutrition. - : Elsevier. - 0261-5614 .- 1532-1983. ; 40:5, s. 3332-3337
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Arachidonic acid (AA) is metabolized by cyclooxygenases and lipoxygenases to pro-inflammatory eicosanoids, which according to experimental research modulate tumor cell proliferation, differentiation, and apoptosis. We employed the Mendelian randomization design to test the hypothesis that higher plasma phospholipid AA concentrations are associated with increased risk of 10 site-specific cancers.METHODS: Two genetic variants associated with plasma phospholipid concentrations of AA (rs174547 in FADS1 [P = 3.0 × 10-971] and rs16966952 in PDXDC1 [P = 2.4 × 10-10]) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium were used as genetic instruments. The associations of those variants with cancer were taken from the UK Biobank (n = 367,643), FinnGen consortium (n = 135,638), International Lung Cancer Consortium (n = 27,209), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254), Breast Cancer Association Consortium (n = 228,951), Ovarian Cancer Association Consortium (n = 66,450), and BioBank Japan (n = 212,453).RESULTS: Higher genetically predicted plasma phospholipid AA concentrations were associated with increased risk of colorectal and lung cancer. Results were consistent across data sources and variants. The combined odds ratios per standard deviation increase of AA concentrations were 1.08 (95% CI 1.05-1.11; P = 6.3 × 10-8) for colorectal cancer and 1.07 (95%CI 1.05-1.10; P = 3.5 × 10-7) for lung cancer. Genetically predicted AA concentrations had a suggestive positive association with esophageal cancer (odds ratio 1.09; 95% CI 1.02-1.17; P = 0.016) but were not associated with cancers of the stomach, pancreas, bladder, prostate, breast, uterus, or ovary.CONCLUSION: These results indicate that AA may be implicated in the development of colorectal and lung cancer and possibly esophageal cancer. Treatments with plasma AA-lowering properties should be evaluated for clinical benefit.
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| 2. |
- Larsson, Susanna C., et al.
(författare)
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Serum Estradiol and 20 Site-Specific Cancers in Women : Mendelian Randomization Study.
- 2021
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Endocrine Society. - 0021-972X .- 1945-7197. ; 107:2, s. e467-e474
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The causal role of endogenous estradiol in cancers other than breast and endometrial cancer remains unclear.OBJECTIVE: To assess the causal associations of endogenous 17β-estradiol (E2), the most potent estrogen, with cancer risk in women through Mendelian randomization.METHODS: As primary genetic instrument, we used a genetic variant in the CYP19A1 gene that is strongly associated with serum E2 levels. Summary statistics genetic data for the association of the E2 variant with breast, endometrial, and ovarian cancer were obtained from large-scale consortia. We additionally estimated the associations of the E2 variant with any and 20 site-specific cancers in 198 825 women of European descent in UK Biobank. Odds ratios (OR) of cancer per 0.01 unit increase in log-transformed serum E2 levels in pmol/L were estimated using the Wald ratio.RESULTS: Genetic predisposition to higher serum E2 levels was associated with increased risk of estrogen receptor positive breast cancer (OR 1.02; 95% confidence interval [CI] 1.01-1.03; P=2.5×10 -3), endometrial cancer overall (OR 1.09; 95% CI 1.06-1.11; P=7.3×10 -13), and endometrial cancer of the endometrioid histology subtype (OR 1.10; 95% CI 1.07-1.13; P=2.1×10 -11). There were suggestive associations with breast cancer overall (OR 1.01; 95% CI 1.00-1.02; P=0.02), ovarian cancer of the endometrioid subtype (OR 1.05; 95% CI 1.01-1.10; P=0.02), and stomach cancer (OR 1.12; 95% CI 1.00-1.26; P=0.05), but no significant association with other cancers.CONCLUSION: This study supports a role of E2 in the development of estrogen receptor positive breast cancer and endometrioid endometrial cancer, but found no strong association with other cancers in women.
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| 3. |
- Titova, Olga E, et al.
(författare)
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Sleep duration and risk of overall and 22 site-specific cancers : A Mendelian randomization study
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 148:4, s. 914-920
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Tidskriftsartikel (refereegranskat)abstract
- Studies of sleep duration in relation to the risk of site-specific cancers other than breast cancer are scarce. Furthermore, the available results are inconclusive and the causality remains unclear. We aimed to investigate the potential causal associations of sleep duration with overall and site-specific cancers using the Mendelian randomization (MR) design. Single-nucleotide polymorphisms associated with the sleep traits identified from a genome-wide association study were used as instrumental variables to estimate the association with overall cancer and 22 site-specific cancers among 367 586 UK Biobank participants. A replication analysis was performed using data from the FinnGen consortium (up to 121 579 individuals). There was suggestive evidence that genetic liability to short-sleep duration was associated with higher odds of cancers of the stomach (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.15-4.30;P= .018), pancreas (OR, 2.18; 95% CI, 1.32-3.62;P= .002) and colorectum (OR, 1.48; 95% CI, 1.12-1.95;P= .006), but with lower odds of multiple myeloma (OR, 0.47; 95% CI, 0.22-0.99;P= .047). Suggestive evidence of association of genetic liability to long-sleep duration with lower odds of pancreatic cancer (OR, 0.44; 95% CI, 0.25-0.79;P= .005) and kidney cancer (OR, 0.44; 95% CI, 0.21-0.90;P= .025) was observed. However, none of these associations passed the multiple comparison threshold and two-sample MR analysis using FinnGen data did not confirm these findings. In conclusion, this MR study does not provide strong evidence to support causal associations of sleep duration with risk of overall and site-specific cancers. Further MR studies are required.
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| 4. |
- Vithayathil, Mathew, et al.
(författare)
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Body size and composition and risk of site-specific cancers in the UK Biobank and large international consortia : A mendelian randomisation study
- 2021
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 18:7
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Tidskriftsartikel (refereegranskat)abstract
- Author summary Why was this study done? The causal relevance of body size and composition as risk factors for specific cancers is unclear based on traditional observational studies. By considering the relationships between genetically predicted values of body size and composition with cancer risk, our estimates are less influenced by confounding variables, and, hence, more reliably reflect the underlying causal relationships between these measures and cancer risk. What did the researchers do and find? We assessed the associations between genetically predicted body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with 22 specific cancers in the UK Biobank (UKBB), a population-based sample of the United Kingdom residents. Although genetically predicted height was consistently associated with increased risk of site-specific cancers, genetically predicted BMI was associated with an increased risk of certain digestive system cancers (esophageal, stomach, liver, and pancreas), plus lung and uterine cancer, but a decreased risk of breast and prostate cancer. When dividing cancers into digestive system cancers versus non-digestive system cancers, genetically predicted BMI was associated with increased risk of digestive system cancers, but not associated with non-digestive system cancers. What do these findings mean? Our findings suggest that BMI is a causal risk factor for some cancers, but is not a generic risk factor for all cancers. Body fat may play a role in development of specific cancers and should be studied further to identify future targets to prevent cancer. Public health strategies should focus on reducing obesity as a risk factor for cancer, but should be clear that benefit may be limited to certain cancers. Background Evidence for the impact of body size and composition on cancer risk is limited. This mendelian randomisation (MR) study investigates evidence supporting causal relationships of body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), and height with cancer risk. Methods and findings Single nucleotide polymorphisms (SNPs) were used as instrumental variables for BMI (312 SNPs), FMI (577 SNPs), FFMI (577 SNPs), and height (293 SNPs). Associations of the genetic variants with 22 site-specific cancers and overall cancer were estimated in 367,561 individuals from the UK Biobank (UKBB) and with lung, breast, ovarian, uterine, and prostate cancer in large international consortia. In the UKBB, genetically predicted BMI was positively associated with overall cancer (odds ratio [OR] per 1 kg/m(2) increase 1.01, 95% confidence interval [CI] 1.00-1.02; p = 0.043); several digestive system cancers: stomach (OR 1.13, 95% CI 1.06-1.21; p < 0.001), esophagus (OR 1.10, 95% CI 1.03, 1.17; p = 0.003), liver (OR 1.13, 95% CI 1.03-1.25; p = 0.012), and pancreas (OR 1.06, 95% CI 1.01-1.12; p = 0.016); and lung cancer (OR 1.08, 95% CI 1.04-1.12; p < 0.001). For sex-specific cancers, genetically predicted elevated BMI was associated with an increased risk of uterine cancer (OR 1.10, 95% CI 1.05-1.15; p < 0.001) and with a lower risk of prostate cancer (OR 0.97, 95% CI 0.94-0.99; p = 0.009). When dividing cancers into digestive system versus non-digestive system, genetically predicted BMI was positively associated with digestive system cancers (OR 1.04, 95% CI 1.02-1.06; p < 0.001) but not with non-digestive system cancers (OR 1.01, 95% CI 0.99-1.02; p = 0.369). Genetically predicted FMI was positively associated with liver, pancreatic, and lung cancer and inversely associated with melanoma and prostate cancer. Genetically predicted FFMI was positively associated with non-Hodgkin lymphoma and melanoma. Genetically predicted height was associated with increased risk of overall cancer (OR per 1 standard deviation increase 1.09; 95% CI 1.05-1.12; p < 0.001) and multiple site-specific cancers. Similar results were observed in analyses using the weighted median and MR-Egger methods. Results based on consortium data confirmed the positive associations between BMI and lung and uterine cancer risk as well as the inverse association between BMI and prostate cancer, and, additionally, showed an inverse association between genetically predicted BMI and breast cancer. The main limitations are the assumption that genetic associations with cancer outcomes are mediated via the proposed risk factors and that estimates for some lower frequency cancer types are subject to low precision. Conclusions Our results show that the evidence for BMI as a causal risk factor for cancer is mixed. We find that BMI has a consistent causal role in increasing risk of digestive system cancers and a role for sex-specific cancers with inconsistent directions of effect. In contrast, increased height appears to have a consistent risk-increasing effect on overall and site-specific cancers.
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| 6. |
- Yuan, Shuai, et al.
(författare)
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Genetically predicted circulating B vitamins in relation to digestive system cancers
- 2021
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Ingår i: British Journal of Cancer. - : Springer Nature. - 0007-0920 .- 1532-1827. ; 124:12, s. 1997-2003
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Tidskriftsartikel (refereegranskat)abstract
- Background Folate, vitamin B6 and vitamin B12 have been associated with digestive system cancers. We conducted a two-sample Mendelian randomisation study to assess the causality of these associations. Methods Two, one and 14 independent single nucleotide polymorphisms associated with serum folate, vitamin B6 and vitamin B12 at the genome-wide significance threshold were selected as genetic instruments. Summary-level data for the associations of the vitamin-associated genetic variants with cancer were obtained from the UK Biobank study including 367,561 individuals and FinnGen consortium comprising up to 176,899 participants. Results Genetically predicted folate and vitamin B6 concentrations were not associated with overall cancer, overall digestive system cancer or oesophageal, gastric, colorectal or pancreatic cancer. Genetically predicted vitamin B12 concentrations were positively associated with overall digestive system cancer (ORSD, 1.12; 95% CI 1.04, 1.21, p = 0.003) and colorectal cancer (ORSD 1.16; 95% CI 1.06, 1.26, p = 0.001) in UK Biobank. Results for colorectal cancer were consistent in FinnGen and the combined ORSD was 1.16 (95% CI 1.08, 1.25, p < 0.001). There was no association of genetically predicted vitamin B12 with any other site-specific digestive system cancers or overall cancer. Conclusions These results provide evidence to suggest that elevated serum vitamin B12 concentrations are associated with colorectal cancer.
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