| 41. |
- King, Sontoria D., et al.
(författare)
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Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization
- 2023
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association For Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 32:9, s. 1265-1269
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer.METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes.RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample.CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk.IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.
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| 42. |
- Kitahara, Cari M., et al.
(författare)
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Association between adult height, genetic susceptibility and risk of glioma
- 2012
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 41:4, s. 1075-1085
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Tidskriftsartikel (refereegranskat)abstract
- Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub- types, and investigated effect modification by genetic susceptibility to the disease. Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. Results Among men, we found a positive association between height and glioma risk (epsilon 190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (epsilon 175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.
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| 43. |
- Kitahara, Cari M., et al.
(författare)
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Association between Class III Obesity (BMI of 40-59 kg/m(2)) and Mortality : A Pooled Analysis of 20 Prospective Studies
- 2014
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Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalence of class III obesity (body mass index [BMI]>= 40 kg/m(2)) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. Methods and Findings: In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex-and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19-83 y at baseline, classified as obese class III (BMI 40.0-59.9 kg/m(2)) compared with those classified as normal weight (BMI 18.5-24.9 kg/m(2)). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (19762009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40-44.9, 45-49.9, 50-54.9, and 55-59.9 kg/m(2) was associated with an estimated 6.5 (95% CI: 5.7-7.3), 8.9 (95% CI: 7.4-10.4), 9.8 (95% CI: 7.4-12.2), and 13.7 (95% CI: 10.5-16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Conclusions: Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight.
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| 44. |
- Leenders, Max, et al.
(författare)
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Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4
- 2013
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Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 24:3, s. 595-602
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Tidskriftsartikel (refereegranskat)abstract
- The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed. Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (< 0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition. When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers. This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
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| 45. |
- Li, Donghui, et al.
(författare)
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Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer
- 2012
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 33:7, s. 1384-1390
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Tidskriftsartikel (refereegranskat)abstract
- Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 x 10(-6), 1.6 x 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 x 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
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| 46. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 47. |
- Muller, David C., et al.
(författare)
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Circulating high sensitivity C reactive protein concentrations and risk of lung cancer : nested case-control study within Lung Cancer Cohort Consortium
- 2019
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Ingår i: The BMJ. - : BMJ Publishing Group Ltd. - 1756-1833 .- 0959-8138. ; 364
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type.Design Nested case-control study.Setting 20 population based cohort studies in Asia, Europe, Australia, and the United States.Participants 5299 patients with incident lung cancer, with individually incidence density matched controls.Exposure Circulating hsCRP concentrations in prediagnostic serum or plasma samples.Main outcome measure Incident lung cancer diagnosis.Results A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up.Conclusions Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.
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| 48. |
- Nichols, Hazel B, et al.
(författare)
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Breast Cancer Risk After Recent Childbirth : A Pooled Analysis of 15 Prospective Studies
- 2019
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Ingår i: Annals of Internal Medicine. - : American College of Physicians. - 0003-4819 .- 1539-3704. ; 170:1, s. 22-30
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Tidskriftsartikel (refereegranskat)abstract
- Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.Objective: To characterize breast cancer risk in relation to recent childbirth.Design: Pooled analysis of individual-level data from 15 prospective cohort studies.Setting: The international Premenopausal Breast Cancer Collaborative Group.Participants: Women younger than 55 years.Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.
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| 49. |
- Nichols, Hazel B., et al.
(författare)
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The Premenopausal Breast Cancer Collaboration : A Pooling Project of Studies Participating in the National Cancer Institute Cohort Consortium
- 2017
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 26:9, s. 1360-1369
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Forskningsöversikt (refereegranskat)abstract
- Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individuallevel data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations.
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| 50. |
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