| 1. |
- Klein, Alison P., et al.
(författare)
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Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
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| 2. |
- Luo, Juhua, et al.
(författare)
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Personality traits and diabetes incidence among postmenopausal women.
- 2019
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Ingår i: Menopause (New York, N.Y.). - 1530-0374. ; 26:6, s. 629-636
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Tidskriftsartikel (refereegranskat)abstract
- We examined whether personality traits, including optimism, ambivalence over emotional expressiveness, negative emotional expressiveness, and hostility, were associated with risk of developing type 2 diabetes (hereafter diabetes) among postmenopausal women.A total of 139,924 postmenopausal women without diabetes at baseline (between 1993 and 1998) aged 50 to 79 years from the Women's Health Initiative were prospectively followed for a mean of 14 (range 0.1-23) years. Multivariable Cox proportional hazards regression models were used to assess associations between personality traits and diabetes incidence adjusting for common demographic factors, health behaviors, and depressive symptoms. Personality traits were gathered at baseline using questionnaires. Diabetes during follow-up was assessed via self-report of physician-diagnosed treated diabetes.There were 19,240 cases of diabetes during follow-up. Compared with women in the lowest quartile of optimism (least optimistic), women in the highest quartile (most optimistic) had 12% (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.84-0.92) lower risk of incident diabetes. Compared with women in the lowest quartile for negative emotional expressiveness or hostility, women in the highest quartile had 9% (HR, 1.09; 95% CI: 1.05-1.14) and 17% (HR, 1.17; 95% CI: 1.12-1.23) higher risk of diabetes, respectively. The association of hostility with risk of diabetes was stronger among nonobese than obese women.Low optimism and high NEE and hostility were associated with increased risk of incident diabetes among postmenopausal women independent of major health behaviors and depressive symptoms. In addition to efforts to promote healthy behaviors, women's personality traits should be considered to guide clinical or programmatic intervention strategies in diabetes prevention.
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| 3. |
- Reeves, Katherine W., et al.
(författare)
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Predictors of urinary phthalate biomarker concentrations in postmenopausal women
- 2019
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Ingår i: Environmental Research. - : Academic Press. - 0013-9351 .- 1096-0953. ; 169, s. 122-130
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear.OBJECTIVES: We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI).MATERIALS AND METHODS: We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993-2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics.RESULTS: Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (ΣDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (ΣDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (ΣDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and ΣDBP, while current smokers had higher ΣDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, ΣDiBP, and ΣDEHP.CONCLUSION: Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non-Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations.
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| 4. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 5. |
- Sharma, Sonia, et al.
(författare)
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Incident injury is strongly associated with subsequent incident temporomandibular disorder : results from the OPPERA study.
- 2019
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Ingår i: Pain. - : Lippincott Williams & Wilkins Ltd.. - 0304-3959 .- 1872-6623. ; 160:7, s. 1551-1561
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Tidskriftsartikel (refereegranskat)abstract
- Cross-sectional studies confirm, as expected, a positive association between jaw injury and painful temporomandibular disorders (TMDs), but prospective evaluations are lacking. We prospectively assessed incident jaw injury, injury type, and development of TMD in adults aged 18 to 44 years. Data were collected from 3258 individuals from communities surrounding 4 US academic institutes between 2006 and 2008. At enrollment, participants reported no TMD history and no facial injuries in the previous 6 months. Quarterly, follow-up questionnaires assessed incident jaw injury, which was classified as intrinsic (attributed to yawning or prolonged mouth opening) or extrinsic (attributed to other causes). Examiners classified incident TMD during a median follow-up period of 2.8 years (range 0.2-5.2 years). Cox regression models used jaw injury as a time-dependent covariate to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association with incident TMD. Among 1729 participants with complete data, 175 developed TMD. Eighty percent of injuries were intrinsic. Temporomandibular disorder annual incidence was nearly twice as high in those experiencing jaw injury (5.37%) compared with those who did not (3.44%). In the Cox model that accounted for timing of injury, the corresponding HR was 3.94 (95% CI = 2.82-5.50) after adjusting for study site, age, race, and sex. Hazard ratios did not differ (P = 0.91) for extrinsic injuries (HR = 4.03, 95% CI = 2.00-8.12) and intrinsic injuries (HR = 3.85, 95% CI = 2.70-5.49). Jaw injury was strongly associated with incident TMD. If surveillance and intervention after jaw injury is to be effective in preventing TMD, they should focus on both intrinsic and extrinsic injuries.
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| 6. |
- Walsh, Naomi, et al.
(författare)
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Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 111:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes.Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.
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| 7. |
- Zhang, Mingfeng, et al.
(författare)
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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:41, s. 66328-66343
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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