Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 500
Filtrar
1.
Int J Cancer ; 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35579976

RESUMO

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14,944 cases and 36,752 controls, including 1,870 aggressive prostate cancers). In Mendelian randomization (MR) analyses, using instruments identified using UK Biobank (up to 194,453 men) and outcome data from PRACTICAL (up to 79,148 cases and 61,106 controls, including 15,167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD=1.23, 95% CI=1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI=1.02-1.28; Phet =0.0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR:1.20,1.08-1.34; blood-based:1.03,1.01-1.05) and early-onset prostate cancer (MR:1.37,1.09-1.73; blood-based:1.08,0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.

2.
Eur J Epidemiol ; 2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35460393

RESUMO

Chocolate is a rich dietary source of various bioactive flavonoid compounds. Despite being one of the most popular foods worldwide, the association between chocolate consumption and long-term mortality remains unclear. The objective of this study is to determine the associations between chocolate consumption and long-term overall and cause-specific mortality, to evaluate dose-response and potential mediators, and to conduct an updated meta-analysis based on prospective cohort studies. We performed a prospective analysis in the Alpha-Tocopherol, Beta-Carotene cancer prevention (ATBC) Study with a total of 27,111 men who were recruited between 1985 and 1988 and followed through 2015. Exposure data of daily chocolate consumption was obtained from validated baseline food frequency questionnaire. Hazard ratios (HRs) and 30-year absolute risk differences (ARDs) including 95% confidence intervals (CI) for overall and cause-specific mortality were estimated using multivariable-adjusted Cox proportional hazards regression models. An updated meta-analysis of cohort studies was also conducted. During 482,807 person-years of follow-up, a total of 22,064 men died. The multivariable analyses showed a statistically significant inverse association between chocolate consumption and risk of overall mortality, with HRs of 0.91, 0.89, 0.89, and 0.88 for the increasing categories 2-5 as compared with those in the lowest category (Ptrend < 0.0001, and P for nonlinearity < 0.0001). We observed significantly lower mortality from cardiovascular disease (CVD), heart disease and cancer, representing 13%, 16% and 12% risk reductions for the highest compared to lowest chocolate category, respectively (all Ptrend ≤ 0.002; all P for nonlinearity < 0.0001). The inverse associations of chocolate consumption with risk of overall, CVD and heart disease mortality were generally consistent across cohort subgroups (e.g., body mass index and serum cholesterol). Mediation analysis showed that 4.3% of the inverse association of chocolate and overall mortality was mediated through reducing blood pressure. Within the updated meta-analysis of cohort studies (21 risk estimates, 908,390 participants and 65,407 events), greater consumption of chocolate (per 5 g/day) was associated with a lower risk of CVD incidence and mortality (pooled relative risk = 0.98, P value < 0.001; P for nonlinearity < 0.001). The predefined subgroup analyses generally revealed consistent inverse chocolate-CVD risk associations. In this prospective study, calorie-balanced greater consumption of chocolate was inversely associated with lower overall, CVD, heart disease and cancer mortality. The systematic review and meta-analysis provide support for the inverse chocolate-CVD association. Our findings may provide evidence to partially allay concerns regarding adverse health outcomes from low-to-moderate chocolate consumption.

3.
Cancer Epidemiol Biomarkers Prev ; 31(5): 1077-1089, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35438744

RESUMO

BACKGROUND: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. METHODS: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. RESULTS: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. CONCLUSIONS: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. IMPACT: The study identifies multifaceted evidence of a possible functional effect for rs1318920.


Assuntos
Neoplasias Colorretais , Estudo de Associação Genômica Ampla , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/genética , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Circulation ; 145(20): 1506-1520, 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35360933

RESUMO

BACKGROUND: Despite substantial research highlighting the importance of exogenous dietary cholesterol intake and endogenous serum cholesterol level in human health, a thorough evaluation of the associations is lacking. Our study objective was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption, and conduct an updated meta-regression analysis of cohort studies. METHODS: We conducted a prospective analysis of 27 078 men in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). Multivariable-controlled cause-specific Cox proportional hazards regression models were used to calculate hazard ratios and 31-year absolute mortality risk differences. A systematic review and meta-analysis of cohort studies was also performed (PROSPERO [URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42021272756]). RESULTS: Based on 482 316 person-years of follow-up, we identified 22 035 deaths, including 9110 deaths from cardiovascular disease (CVD). Greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Hazard ratios for each additional 300 mg cholesterol intake per day were 1.10 and 1.13 for overall and CVD-related mortality, respectively; for each additional 50-g egg consumed daily, hazard ratios were 1.06 and 1.09, respectively, for overall and CVD-related mortality (all P values<0.0001). After multivariable adjustment, higher serum total cholesterol concentrations were associated with increased risk of CVD-related mortality (hazard ratios per 1 SD increment, 1.14; P<0.0001). The observed associations were generally similar across cohort subgroups. The updated meta-analysis of cohort studies on the basis of 49 risk estimates, 3 601 401 participants, and 255 479 events showed consumption of 1 additional 50-g egg daily was associated with significantly increased CVD risk (pooled relative risk, 1.04 [95% CI, 1.00-1.08]; I2=80.1%). In the subgroup analysis of geographic regions (Pinteraction=0.02), an increase of 50-g egg consumed daily was associated with a higher risk of CVD in US cohorts (pooled relative risk, 1.08 [95% CI, 1.02-1.14]) and appeared related to a higher CVD risk in European cohorts with borderline significance (pooled relative risk, 1.05), but was not associated with CVD risk in Asian cohorts. CONCLUSIONS: In this prospective cohort study and updated meta-analysis, greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Our findings support restricted consumption of dietary cholesterol as a means to improve long-term health and longevity.

5.
Eur J Clin Nutr ; 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35322169

RESUMO

BACKGROUND/OBJECTIVES: The role of vitamin E in chronic disease risk remains incompletely understood, particularly in an un-supplemented state, and evidence is sparse regarding the biological actions and pathways involved in its influence on health outcomes. Identifying vitamin-E-associated metabolites through agnostic metabolomics analyses can contribute to elucidating the specific associations and disease etiology. This study aims to investigate the association between circulating metabolites and serum α-tocopherol concentration in an un-supplemented state. SUBJECTS/METHODS: Metabolomic analysis of 4,294 male participants was conducted based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The associations between 1,791 known metabolites measured by ultra-high-performance LC-MS/GC-MS and HPLC-determined α-tocopherol concentration were estimated using multivariable linear regression. Differences in metabolite levels per unit difference in α-tocopherol concentration were calculated as standardized ß-coefficients and standard errors. RESULTS: A total of 252 metabolites were associated with serum α-tocopherol at the Bonferroni-corrected p value (p < 2.79 × 10-5). Most of these metabolites were of lipid and amino acid origin, with the respective subclasses of dicarboxylic fatty acids, and valine, leucine, and isoleucine metabolism, being highly represented. Among lipids, the strongest signals were observed for linoleoyl-arachidonoyl-glycerol (18:2/20:4)[2](ß = 0.149; p = 8.65 × 10-146) and sphingomyelin (D18:2/18:1) (ß = 0.035; p = 1.36 × 10-30). For amino acids, the strongest signals were aminoadipic acid (ß = 0.021; p = 5.01 × 10-13) and l-leucine (ß = 0.007; p = 1.05 × 10-12). CONCLUSIONS: The large number of metabolites, particularly lipid and amino acid compounds associated with serum α-tocopherol provide leads regarding potential mechanisms through which vitamin E influences human health, including its role in cardiovascular disease and cancer.

6.
PLoS Med ; 19(2): e1003897, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35113855

RESUMO

BACKGROUND: Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS: We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), ß-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. CONCLUSIONS: In this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications.


Assuntos
Anti-Hipertensivos/efeitos adversos , Análise da Randomização Mendeliana/métodos , Neoplasias/genética , Peptidil Dipeptidase A/genética , Receptores Adrenérgicos beta 1/genética , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Neoplasias/induzido quimicamente , Neoplasias/epidemiologia , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Membro 3 da Família 12 de Carreador de Soluto/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-35152271

RESUMO

BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

8.
Artigo em Inglês | MEDLINE | ID: mdl-35197557

RESUMO

OBJECTIVE: Investigate the relationship between serum α-tocopherol concentration and long-term risk of prostate cancer, and evaluate the interaction with vitamin E-related genetic variants and their polygenic risk score (PRS). METHODS: We conducted a biochemical analysis of 29,102 male Finnish smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and 2724 prostate cancer cases were identified during 28 years of follow-up. Cox proportional hazards models examined whether serum α-tocopherol concentrations were associated with prostate cancer risk. Among 8383 participants, three SNPs related to vitamin E status (rs964184, rs2108622, and rs11057830) were examined to determine whether they modified the relationship between serum α-tocopherol concentrations and prostate cancer risk, both individually and as a PRS using logistic regression models. RESULTS: No association was observed between serum α-tocopherol and prostate cancer risk (fifth quintile (Q5) vs. Q1 hazard ratio (HR) = 0.87, 95% confidence interval (95% CI) 0.75, 1.02; P-trend = 0.57). Though no interactions were seen by population characteristics, high α-tocopherol concentration was associated with reduced prostate cancer risk among the trial α-tocopherol supplementation group (Q5 quintile vs. Q1 HR = 0.79, 95% CI 0.64, 0.99). Finally, no associated interaction between the three SNPs or their PRS and prostate cancer risk was observed. CONCLUSION: Although there was a weak inverse association between α-tocopherol concentration and prostate cancer risk over nearly three decades, our findings suggest that men receiving the trial α-tocopherol supplementation who had higher baseline serum α-tocopherol concentration experienced reduced prostate cancer risk. Vitamin E-related genotypes did not modify the serum α-tocopherol-prostate cancer risk association.

9.
J Nutr ; 152(1): 211-216, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34590122

RESUMO

BACKGROUND: Multivitamins are among the most commonly used supplements in the United States, but their effectiveness in preventing cancer remains unclear. OBJECTIVES: We prospectively examined the association between multivitamin use and risks of overall and site-specific cancer in a large, well-characterized cohort to ascertain potential preventive or harmful relationships. METHODS: We examined 489,640 participants ages 50-71 in the NIH-American Association of Retired Persons (AARP) Diet and Health Study who were enrolled from 1995 to 1998. We linked to 11 state cancer registries in order to identify incident cancers. Multivitamin use was assessed by a baseline questionnaire. Cox proportional hazards regression models of multivitamin use were used to estimate HRs and 95% CIs for cancer risks in men and women, adjusted for potential confounders, including age, BMI, smoking, physical activity, the Healthy Eating Index 2015 score, and use of single-vitamin/-mineral supplements. RESULTS: A slightly higher overall cancer risk was observed in men (but not women) who consumed 1 or more multivitamins daily compared to nonusers [HRs, 1.02 (95% CI: 1.01-1.04) and 1.03 (95% CI: 1.00-1.07), respectively; P-trend = 0.002]. The latter reflected higher risks for prostate cancer (HR, 1.04; 95% CI: 0.98-1.10; P-trend = 0.005), lung cancer (HR, 1.07; 95% CI: 0.96-1.20; P-trend = 0.003), and leukemia (HR, 1.26; 95% CI: 1.02-1.57; P-trend = 0.003). Taking more than 1 multivitamin daily was also strongly positively associated with the risk of oropharyngeal cancer in women (HR, 1.53, 95% CI: 1.04-2.24; P-trend < 0.0001). By contrast, daily multivitamin use was inversely associated with the colon cancer risk in both sexes (HR, 0.82; 95% CI: 0.73-0.93; P-trend = 0.0003). CONCLUSIONS: We found little evidence to support a cancer-preventive role for multivitamin use, with the exception of colon cancer, in both sexes in the NIH-AARP Diet and Health Study. In addition, slightly higher risks of overall, prostate, and lung cancer, as well as leukemia, were observed for greater multivitamin use in men, with a higher oropharyngeal cancer risk in women.


Assuntos
Neoplasias da Próstata , Vitaminas , Idoso , Dieta , Humanos , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia
10.
Cancer Causes Control ; 33(1): 91-99, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34652593

RESUMO

PURPOSE: To determine whether higher coffee intake may reduce the risk of renal cell cancer (RCC) associated with lead (Pb) and other heavy metals with known renal toxicity. METHODS: We conducted a nested case-control study of male smokers (136 RCC cases and 304 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cases diagnosed with RCC at 5 or more years following cohort enrollment were matched to controls on age (± 7 years) and whole blood draw date (± 30 days). Conditional logistic regression (using two-sided tests) was used to test for main effects and additive models of effect modification. RESULTS: After a mean follow-up of 16.3 years, coffee consumption was not significantly associated with renal cell cancer risk, when adjusting for blood concentrations of Cd, Hg, and Pb and RCC risk factors (age, smoking, BMI, and systolic blood pressure) (p-trend, 0.134). The association with above median blood Pb and RCC (HR = 1.69, 95% CI 1.06, 2.85) appeared to be modified by coffee consumption, such that RCC risk among individuals with both increased coffee intake and higher blood lead concentration were more than threefold higher RCC risk (HR = 3.40, 95% CI 1.62, 7.13; p-trend, 0.003). CONCLUSION: Contrary to our initial hypothesis, this study suggests that heavy coffee consumption may increase the previously identified association between higher circulating lead (Pb) concentrations and increased RCC risk. Improved assessment of exposure, including potential trace element contaminants in coffee, is needed.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Oligoelementos , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/etiologia , Estudos de Casos e Controles , Café/efeitos adversos , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/etiologia , Masculino , Fatores de Risco , Fumantes
12.
Cancer ; 128(6): 1260-1266, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34797564

RESUMO

BACKGROUND: According to the International Agency for Research on Cancer, some hair dye chemicals are considered mutagenic and carcinogenic in humans. One hospital-based study reported a positive association between hair dye use and prostate cancer risk, but no prospective analyses have been conducted. METHODS: This study investigated the association between hair dye use and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort, a large, well-characterized cohort of 29,133 male Finnish smokers. Participants completed questionnaires regarding lifestyle, medical, and risk factor information, including the use of hair dye, which was available for 98.8% of the cohort (28,795 men). Prostate cancer cases were identified through linkage with the Finnish Cancer Registry and the Finnish Mortality Register. Hazard ratios (HRs) and confidence intervals (CIs) were estimated via multivariable Cox proportional hazards regression. RESULTS: During a 28-year period of observation, 2703 incident prostate cancer cases were diagnosed. As reported at the baseline, 75 men used hair dye, and 13 of these men were subsequently diagnosed with prostate cancer. After adjustments for potential confounders, men who used hair dyes experienced substantially higher prostate cancer risk than men who did not (HR, 1.77; 95% CI, 1.03-3.05). CONCLUSIONS: This first prospective investigation of hair dye use and prostate cancer suggests that personal hair dye use may be related to increased risk. The findings warrant re-examination in other prospective cohorts along with studies evaluating specific hair dyes and possible underlying biological mechanisms.


Assuntos
Tinturas para Cabelo , Neoplasias da Próstata , Estudos de Coortes , Tinturas para Cabelo/efeitos adversos , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/prevenção & controle , Fatores de Risco , alfa-Tocoferol , beta Caroteno
13.
JAMA Oncol ; 8(2): 268-274, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34913949

RESUMO

IMPORTANCE: Autoimmune gastritis is an alternative cause of gastric carcinogenesis. This cause may be gaining importance with declining prevalence of chronic Helicobacter pylori infection. OBJECTIVE: To determine the association of prediagnostic autoantibodies to gastric mucosa with gastric cancer (GC) risk. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used nested GC case-control analyses within separate Finnish cohorts of women of reproductive age (Finnish Maternity Cohort [FMC]; born 1938-1989) and older men (Alpha-Tocopherol, Beta-Carotene Cancer Prevention [ATBC] Study; born 1916-1939). There were 529 and 457 matched pairs from the FMC and ATBC Study, respectively, with mean participant ages of 30.5 and 57.5 years and medians of 17 and 11 years from baseline to cancer diagnosis. Data analyses were performed between August 2019 and November 2020. EXPOSURES: Antiparietal cell antibodies (APCAs), anti-intrinsic factor antibodies, and anti-H pylori antibodies were measured in baseline serum using immunoassays. MAIN OUTCOMES AND MEASURES: Autoantibody associations were estimated by odds ratios (ORs) and 95% CIs. RESULTS: Of the 529 control participants in the FMC and 457 control participants in the ATBC Study, 53 (10%) women and 35 (7.7%) men were APCA seropositive, respectively, whereas 146 (28%) women and 329 (72%) men were H pylori seropositive. In the FMC, APCA seropositivity was statistically significantly associated with GC risk among H pylori-seronegative women (OR, 5.52; 95% CI, 3.16-9.64) but not H pylori-seropositive women (OR, 1.29; 95% CI, 0.64-2.60; P for interaction = .002). The APCA association with H pylori seronegativity was strongest for tumors in the fundus and corpus (OR, 24.84; 95% CI, 8.49-72.72). In the ATBC Study, APCA seropositivity was not associated with GC among either H pylori-seronegative men (OR, 0.99; 95% CI, 0.32-3.04) or H pylori-seropositive men (OR, 1.06; 95% CI, 0.60-1.88). In both cohorts, anti-intrinsic factor antibody seroprevalence was less than 2% among cases as well as controls and not statistically associated with GC risk. CONCLUSIONS AND RELEVANCE: Results of this cohort study demonstrate that autoantibody positivity may reflect subclinical autoimmune gastritis in younger women. The findings among young females and corpus subsite align with increasing cancer incidence trends for these groups. Stronger autoimmune associations in H pylori-seronegative individuals support a model of autoimmune gastritis replacing H pylori as the driving factor.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Adulto , Idoso , Autoanticorpos , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Soroepidemiológicos , Neoplasias Gástricas/epidemiologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-34964002

RESUMO

PURPOSE: Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete. MATERIALS AND METHODS: We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases. RESULTS: In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair (MLH1 and MSH2) and cellular metabolism (IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls (P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis (P = .001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant. CONCLUSION: These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology.


Assuntos
Neoplasias da Bexiga Urinária/genética , Idoso , Feminino , Predisposição Genética para Doença/epidemiologia , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias da Bexiga Urinária/epidemiologia , Sequenciamento Completo do Exoma/métodos , Sequenciamento Completo do Exoma/estatística & dados numéricos
15.
Nat Commun ; 12(1): 6418, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34741009

RESUMO

How retinol as a clinical indicator of vitamin A status is related to long-term mortality is unknown. Here we report the results of a prospective analysis examining associations between serum retinol and risk of overall and cause-specific mortality. During a 30-year cohort follow-up, 23,797 deaths were identified among 29,104 men. Participants with higher serum retinol experienced significantly lower overall, CVD, heart disease, and respiratory disease mortality compared to men with the lowest retinol concentrations, reflecting 17-32% lower mortality risk (Ptrend < 0.0001). The retinol-overall mortality association is similar across subgroups of smoking intensity, alcohol consumption, body mass index, trial supplementation, serum alpha-tocopherol and beta-carotene concentrations, and follow-up time. Mediation analysis indicated that <3% of the effects of smoking duration and diabetes mellitus on mortality were mediated through retinol concentration. These findings indicate higher serum retinol is associated with lower overall mortality, including death from cardiovascular, heart, and respiratory diseases.


Assuntos
alfa-Tocoferol/sangue , beta Caroteno/sangue , Consumo de Bebidas Alcoólicas , Índice de Massa Corporal , Causas de Morte , Cardiopatias/sangue , Humanos , Estudos Prospectivos , Vitamina A
16.
Nutrients ; 13(11)2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34836419

RESUMO

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.


Assuntos
Aspirina/uso terapêutico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Ácido Salicílico/sangue , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Neoplasias Colorretais/prevenção & controle , Dieta , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Ácido Salicílico/administração & dosagem
17.
J Transl Genet Genom ; 5: 200-217, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34622145

RESUMO

AIM: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. METHODS: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. RESULTS: We discovered positive associations between FROH and CLL (ß = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (ß = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (ß = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. CONCLUSION: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

18.
Am J Clin Nutr ; 114(5): 1802-1813, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34477829

RESUMO

BACKGROUND: A growing body of literature suggests chronically higher bile acid (BA) concentrations may be associated with multiple health conditions. Diet may affect BA metabolism and signaling; however, evidence from human populations is lacking. OBJECTIVES: We systematically investigated cross-sectional associations of a priori-selected dietary components (fiber, alcohol, coffee, fat) with circulating BA concentrations. METHODS: We used targeted, quantitative LC-MS/MS panels to measure 15 circulating BAs in a subset of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC; n = 2224) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; n = 986) comprising Finnish male smokers and United States men and women, respectively. We used multivariable linear regression to estimate associations of each dietary component with log-transformed BAs; exponentiated coefficients estimate proportional differences. We included the median of the dietary component quartile in linear regression models to test for trend. RESULTS: In ATBC, fiber was inversely associated with multiple circulating BAs. The proportional difference was -10.09% (95% CI: -19.29 to 0.16; P-trend = 0.04) when comparing total BAs among those in the highest relative to the lowest fiber quartile. Alcohol, trans fat, and polyunsaturated fat were positively associated with BAs in ATBC. The proportional difference comparing total BAs among those in the highest relative to the lowest alcohol quartile was 8.76% (95% CI: -3.10 to 22.06; P-trend = 0.03). Coffee and monounsaturated fat were inversely associated with BAs. The proportional difference comparing total BAs among those in the highest relative to the lowest coffee quartile was -24.03% (95% CI: -31.57 to -15.66; P-trend < 0.0001). In PLCO, no dietary components were associated with BAs except fiber, which was inversely associated with tauroursodeoxycholic acid. CONCLUSIONS: Alcohol, coffee, certain fat subtypes, and fiber were associated with circulating concentrations of multiple BAs among Finnish male smokers. Given the potential role of BAs in disease risk, further investigation of the effects of diet on BAs in humans is warranted.


Assuntos
Ácidos e Sais Biliares/sangue , Dieta , Idoso , Consumo de Bebidas Alcoólicas , Café , Estudos Transversais , Gorduras na Dieta/administração & dosagem , Fibras na Dieta/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade
19.
Am J Clin Nutr ; 114(4): 1408-1417, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34258619

RESUMO

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.


Assuntos
Adenocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Hepcidinas/metabolismo , Ferro/metabolismo , Neoplasias Pancreáticas/metabolismo , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Hepcidinas/genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
20.
Sci Rep ; 11(1): 13805, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226613

RESUMO

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.


Assuntos
Biomarcadores/sangue , Carbono/metabolismo , Inflamação/genética , Rim/metabolismo , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Proteína C-Reativa/genética , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Inflamação/patologia , Cinurenina/sangue , Masculino , Pessoa de Meia-Idade , Fumar/genética , Abandono do Hábito de Fumar , Vitaminas/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...