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1.
Int J Cancer ; 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31037736

RESUMO

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

2.
Int J Epidemiol ; 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31038671

RESUMO

BACKGROUND: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. METHODS: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. RESULTS: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). CONCLUSIONS: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.

4.
Gastrointest Endosc ; 90(2): 254-258.e2, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30986402

RESUMO

BACKGROUND AND AIMS: The adenoma detection rate (ADR) is the most important quality metric for colonoscopy. Numerous factors are known to influence ADR. However, no data on the effect of monitor size on ADR exist. The aim of this study was to compare the ADR and polyp detection rate (PDR) achieved using 2 different-size video monitors (19-inch diagonal and 32-inch diagonal). METHODS: In a single-center, prospective, randomized clinical trial, endoscopists were randomized on a daily basis to perform routine ambulatory colonoscopies with either a 32-inch diagonal or a 19-inch diagonal video monitor. RESULTS: The study was conducted between October 2013 and April 2014 in an outpatient center of a tertiary referral hospital. Fifteen endoscopists performed 1795 outpatient colonoscopies (mean age, 55 years; 56% women; screening, 56%). There was no substantial difference in baseline patient characteristics between the 2 arms. The overall ADR (27.4% vs 27.9%; P = .80) and PDR (32.8% vs 34.4%; P = .50) were not significantly different between the 32-inch and 19-inch monitor group, respectively. The findings were not significantly altered when stratified by indication, cecal intubation, bowel preparation, operator experience, and time of endoscopy as well as in a multivariable model that included these variables as potential confounders (all P > .05). Overall, the ADR and PDR for each individual endoscopist did not appear to be influenced by monitor size. CONCLUSIONS: The results of this trial do not support the notion that larger video monitors improve ADR. Future efforts to increase ADR should focus on other aspects of colonoscopy. (Clinical trial registration number: NCT01952418.).

5.
Am J Gastroenterol ; 114(2): 315-321, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30730324

RESUMO

INTRODUCTION: Diverticulitis is a significant cause of morbidity among older women, and little attention has been paid to understanding its etiology. We have shown that menopausal hormone therapy (MHT) is associated with the risk of inflammatory bowel disease. In this study, we prospectively examined the association between MHT and the risk of incident diverticulitis. METHODS: We studied 65,367 postmenopausal women enrolled in the Nurses' Health Study who provided detailed information on hormone use and other medical and lifestyle factors biennially, and on diet every 4 years. Between 2008 and 2014, participants reported any episodes of diverticulitis that required antibiotics and the date of occurrence. We used Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over 24 years encompassing 1,297,165 person-years of follow-up, we documented 5,425 incident cases of diverticulitis. We observed an increased risk of diverticulitis among both current (HR 1.28; 95% CI 1.18-1.39) and past (HR 1.35; 95% CI 1.25-1.45) MHT users compared to never users. The increased risk was observed among participants using estrogen only (HR 1.30; 95% CI 1.20-1.41) and those using combined estrogen and progesterone (HR 1.31; 95% CI 1.21-1.42) compared to nonusers. The risk did not increase with longer duration of use (P-trend = 0.76). The association between MHT and diverticulitis was not modified by age, body mass index, past oral contraceptive use, or fiber intake (all P-interaction >0.11). CONCLUSIONS: Menopausal hormone therapy was associated with an increased risk of diverticulitis. Further studies are needed to understand the potential mechanisms that may underlie this association.

6.
Int J Epidemiol ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30476131

RESUMO

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

7.
Int J Epidemiol ; 47(6): 1938-1946, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312404

RESUMO

Objective: To investigate the association between three diet-quality scores corresponding to adherence to healthy dietary patterns [alternate Mediterranean (aMed), Alternate Healthy Eating Index (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH)] and the risk of symptomatic gallstone disease. Methods: The study comprised 43 635 men of the Health Professionals Follow-up Study-an ongoing prospective cohort study of US health professionals. Participants were free of symptomatic gallstone disease and diabetes and provided dietary information every 4 years from 1986 (baseline) until 2012. The aMed, AHEI-2010 and DASH scores were generated and associated with the risk of symptomatic gallstone disease using Cox proportional hazards regression. Results: During 716 904 person-years of follow-up, 2382 incident cases of symptomatic gallstone disease were identified. All three scores were inversely associated with risk of symptomatic gallstone disease after adjustment for potential confounders including age, smoking, physical activity, energy and coffee intake [hazard ratios (HRs) and 95% confidence intervals (CIs)] comparing the highest with the lowest quintiles: aMed: 0.66 (0.57-0.77), AHEI-2010: 0.64 (0.56-0.74) and DASH: 0.66 (0.58-0.76)]. Findings were similar after additional adjustment for body mass index and after inclusion of asymptomatic cases. Associations were stronger when analysis was restricted to cases who had undergone cholecystectomy. Conclusions: In this prospective cohort of male US health professionals, higher adherence to the aMed, AHEI-2010 and DASH diets was associated with lower risk of symptomatic gallstone disease. Dietary recommendations focusing on high-quality diets targeting symptomatic gallstone disease may lower the incidence of this prevalent disease.

8.
PLoS Med ; 15(9): e1002644, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30180161

RESUMO

BACKGROUND: No prior study to our knowledge has examined the joint contribution of a polygenic risk score (PRS), mammographic density (MD), and postmenopausal endogenous hormone levels-all well-confirmed risk factors for invasive breast cancer-to existing breast cancer risk prediction models. METHODS AND FINDINGS: We conducted a nested case-control study within the prospective Nurses' Health Study and Nurses' Health Study II including 4,006 cases and 7,874 controls ages 34-70 years up to 1 June 2010. We added a breast cancer PRS using 67 single nucleotide polymorphisms, MD, and circulating testosterone, estrone sulfate, and prolactin levels to existing risk models. We calculated area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer. We estimated the population distribution of 5-year predicted risks for models with and without biomarkers. For the Gail model, the AUC improved (p-values < 0.001) from 55.9 to 64.1 (8.2 units) in premenopausal women (Gail + PRS + MD), from 55.5 to 66.0 (10.5 units) in postmenopausal women not using hormone therapy (HT) (Gail + PRS + MD + all hormones), and from 58.0 to 64.9 (6.9 units) in postmenopausal women using HT (Gail + PRS + MD + prolactin). For the Rosner-Colditz model, the corresponding AUCs improved (p-values < 0.001) by 5.7, 6.2, and 6.5 units. For estrogen-receptor-positive tumors, among postmenopausal women not using HT, the AUCs improved (p-values < 0.001) by 14.3 units for the Gail model and 7.3 units for the Rosner-Colditz model. Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (≥2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model. Limitations of our study included the limited racial/ethnic diversity of our cohort, and that general population exposure distributions were unavailable for some risk factors. CONCLUSIONS: In this study, the addition of PRS, MD, and endogenous hormones substantially improved existing breast cancer risk prediction models. Further studies will be needed to confirm these findings and to determine whether improved risk prediction models have practical value in identifying women at higher risk who would most benefit from chemoprevention, screening, and other risk-reducing strategies.

9.
Genet Epidemiol ; 42(6): 571-586, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29968341

RESUMO

The human MC1R gene is highly polymorphic among lightly pigmented populations, and several variants in the MC1R gene have been associated with increased risk of both melanoma and nonmelanoma skin cancers. The functional consequences of MC1R gene variants have been studied in vitro and in vivo in postulated causal pathways, such as G-protein-coupled signaling transduction, pigmentation, immune response, inflammatory response, cell proliferation, and extracellular matrix adhesion. In a case-control study nested within the Nurses' Health Study, we utilized hierarchical modeling approaches, incorporating quantitative information from these functional studies, to examine the association between particular MC1R alleles and the risk of skin cancers. Different prior matrices were constructed according to the phenotypic associations in controls, cell surface expression, and enzymatic kinetics. Our results showed the parameter variance estimates of each single nucleotide polymorphism (SNP) were smaller when using a hierarchical modeling approach compared to standard multivariable regression. Estimates of second-level parameters gave information about the relative importance of MC1R effects on different pathways, and odds ratio estimates changed depending on prior models (e.g., the change ranged from -21% to 7% for melanoma risk assessment). In addition, the estimates of prior model hyperparameters in the hierarchical modeling approach allow us to determine the relevance of individual pathways on the risk of each of the skin cancer types. In conclusion, hierarchical modeling provides a useful analytic approach in addition to the widely used conventional models in genetic association studies that can incorporate measures of allelic function.


Assuntos
Predisposição Genética para Doença , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 1 de Melanocortina/genética , Neoplasias Cutâneas/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco
10.
Inflamm Bowel Dis ; 24(10): 2247-2257, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29788077

RESUMO

Background: Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized comorbidity in Crohn's disease (CD), but the mechanisms are poorly understood. Autophagy is a highly conserved process regulating innate immunity that contributes to CD susceptibility. Emerging data suggest that variants in the autophagy-governing IRGM gene may contribute to the accumulation of visceral adipose tissue (VAT) and hepatic fat. Our objective was to characterize the relationship between VAT, IRGM gene variants, and NAFLD risk in patients with CD. Methods: We included all CD patients in the Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM) without history of alcohol abuse or liver disease. Hepatic fat was quantified by liver attenuation (LA) on computed tomography, with NAFLD defined by the validated liver:spleen (L:S) ratio. NAFLD severity was estimated by the FIB-4 Index and alanine aminotransferase (ALT). Using logistic regression modeling, we examined the relationship between VAT, autophagy gene variants, and NAFLD risk. Results: Among 462 patients, 52% had NAFLD. Increasing VAT quartile was associated with reduced LA (mean change, -7.43; 95% confidence interval [CI], -10.05 to -4.81; Ptrend < 0.0001). In the fully adjusted model, patients in the highest VAT quartile had a 2.2-fold increased NAFLD risk (95% CI, 1.21 to 4.14; Ptrend = 0.032) and a 4.2-fold increased risk of ALT>upper limit of normal (ULN) (95% CI, 1.19 to 14.76; Ptrend = 0.017). The relationship between VAT and NAFLD was modified by IRGM variants rs4958847 and rs13361189 (Pinteraction = 0.005 and Pinteraction < 0.001, respectively). Conclusions: In a large CD cohort, VAT was directly associated with prevalent NAFLD, and this relationship was augmented by functionally annotated IRGM variants associated with impaired autophagy.

11.
Nat Microbiol ; 3(3): 347-355, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29335554

RESUMO

Characterizing the stability of the gut microbiome is important to exploit it as a therapeutic target and diagnostic biomarker. We metagenomically and metatranscriptomically sequenced the faecal microbiomes of 308 participants in the Health Professionals Follow-Up Study. Participants provided four stool samples-one pair collected 24-72 h apart and a second pair ~6 months later. Within-person taxonomic and functional variation was consistently lower than between-person variation over time. In contrast, metatranscriptomic profiles were comparably variable within and between subjects due to higher within-subject longitudinal variation. Metagenomic instability accounted for ~74% of corresponding metatranscriptomic instability. The rest was probably attributable to sources such as regulation. Among the pathways that were differentially regulated, most were consistently over- or under-transcribed at each time point. Together, these results suggest that a single measurement of the faecal microbiome can provide long-term information regarding organismal composition and functional potential, but repeated or short-term measures may be necessary for dynamic features identified by metatranscriptomics.

12.
Gastroenterology ; 154(5): 1290-1297.e1, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29269313

RESUMO

BACKGROUND & AIMS: Proton pump inhibitors (PPI) are among the top 10 most prescribed medications worldwide. We investigated the association between PPI use and ischemic stroke. METHODS: We collected data on 68,514 women (mean age, 65 ± 7 years) enrolled in the Nurses' Health Study since 2000 and 28,989 men (mean age, 69 ± 8 years) in the Health Professionals Follow-up Study since 2004, without a history of stroke. We used Cox proportional hazards models to examine the association between risk of incident stroke and PPI use among participants. The primary end point was first incident stroke. RESULTS: In the 2 cohorts, we documented 2599 incident strokes (2037 in women and 562 in men) over a 12-year period, encompassing 949,330 person-years. After adjustment for established risk factors for stroke, PPI use was associated with a significant increase in risk of ischemic stroke (hazard ratio, 1.18; 95% confidence interval, 1.02-1.37). The association was reduced after we adjusted for potential indications for PPI use, including history of peptic ulcer disease, gastroesophageal reflux disease, or gastrointestinal bleeding, and prior use of histamine-2 receptor antagonist therapy (hazard ratio, 1.08; 95% confidence interval, 0.91-1.27). Regular PPI use was not associated with increased risk of stroke overall or hemorrhagic stroke. CONCLUSIONS: In an analysis of data from the Nurses' Health Study and the Health Professionals Follow-up Study, we did not find a significant association between PPI use and ischemic stroke, after accounting for indications for PPI use. Prior reports of an increased risk of stroke may be due to residual confounding related to chronic conditions associated with PPI use.


Assuntos
Isquemia Encefálica/epidemiologia , Gastroenteropatias/tratamento farmacológico , Estilo de Vida , Inibidores da Bomba de Prótons/uso terapêutico , Acidente Vascular Cerebral/epidemiologia , Adulto , Idoso , Isquemia Encefálica/diagnóstico , Comorbidade , Fatores de Confusão (Epidemiologia) , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/epidemiologia , Nível de Saúde , Inquéritos Epidemiológicos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Enfermeiras e Enfermeiros , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Fatores de Tempo , Estados Unidos
13.
Gastroenterology ; 153(4): 971-979.e4, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28728964

RESUMO

BACKGROUND & AIMS: Studies have reported associations between proton pump inhibitor (PPI) use and dementia. However, data are lacking on long-term PPI use and cognitive function. We therefore examined associations between PPI use and performance in tests of cognitive function. Because of shared clinical indications, we examined associations for H2 receptor antagonists (H2RAs) as a secondary aim. METHODS: We used prospectively collected data on medication use and other potential risk factors from 13,864 participants in the Nurses' Health Study II who had completed a self-administered computerized neuropsychological test battery. Multivariable linear regression models were used to examine associations between medication use and composite scores of psychomotor speed and attention, learning and working memory, and overall cognition. RESULTS: We observed a modest association between duration of PPI use and scores for psychomotor speed and attention (mean score difference for PPI use of 9-14 years vs never users, -0.06; 95% confidence interval, -0.11 to 0.00; Ptrend = .03). After controlling for H2RA use, the magnitude of this score difference was attenuated. Among individuals who did not use PPIs regularly, duration of H2RA use was associated with poorer cognitive scores, with the strongest association apparent for learning and working memory (mean score difference for H2RA users of 9-14 years vs never users, -0.20; 95% confidence interval, -0.32 to -0.08; Ptrend < .001). CONCLUSIONS: In an analysis of data from the Nurses' Health Study II, we did not observe a convincing association between PPI use and cognitive function. Our data do not support the suggestion that PPI use increases dementia risk. Because our primary hypothesis related to PPI use, our findings for H2RAs should be interpreted with caution.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Cognição/efeitos dos fármacos , Inibidores da Bomba de Prótons/efeitos adversos , Adulto , Idoso , Atenção/efeitos dos fármacos , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Esquema de Medicação , Feminino , Antagonistas dos Receptores Histamínicos H2/administração & dosagem , Antagonistas dos Receptores Histamínicos H2/efeitos adversos , Humanos , Modelos Lineares , Memória/efeitos dos fármacos , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Enfermeiras e Enfermeiros , Prognóstico , Estudos Prospectivos , Inibidores da Bomba de Prótons/administração & dosagem , Desempenho Psicomotor/efeitos dos fármacos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Estados Unidos
14.
Int J Epidemiol ; 46(3): 894-904, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28082375

RESUMO

Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV 1 (forced expiratory volume in 1 second) or FEV 1 /FVC (FEV 1 /forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV 1 or FEV 1 /FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction ( ßint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV 1 /FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV 1 /FVC may be more susceptible to the deleterious effects of smoking.


Assuntos
Volume Expiratório Forçado/genética , Interação Gene-Ambiente , Fumar/epidemiologia , Fumar/genética , Capacidade Vital/genética , Europa (Continente) , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo de Nucleotídeo Único , Medição de Risco , Espirometria
15.
Inflamm Bowel Dis ; 23(1): 82-88, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27893544

RESUMO

INTRODUCTION: Adipose tissue in mesenteric fat plays a key role in systemic and luminal inflammation. However, little is known about the role of visceral adipose tissue (VAT) and its interaction with genetic predisposition in Crohn's disease (CD) progression. METHODS: Our study population included patients with CD enrolled in Prospective Registry in Inflammatory Bowel Disease Study at Massachusetts General Hospital (PRISM). VAT volume was measured from computed tomography using Aquarius 3D. We used logistic regression models to estimate the multivariable-adjusted odds ratio and 95% CI. We tested for effect modification by genetic predisposition using the log likelihood ratio test. RESULTS: Among 482 patients with CD with available data on VAT, 174 developed penetrating disease, 132 developed stricturing disease, 147 developed perianal disease, and 252 required surgery. Compared with individuals in the lowest quartile of VAT volume, the multivariable-adjusted odds ratio of surgery among individuals in the highest quartile was 2.02 (95% CI, 1.09-3.76; Ptrend = 0.006). Similarly, the risk of penetrating disease seemed to increase with greater VAT volume (Ptrend = 0.022) but not stricturing or perianal disease (all Ptrend > 0.23). The associations between VAT volume and CD complications were not modified by genetic predisposition (all Pinteraction > 0.12). CONCLUSIONS: Visceral adiposity as measured by VAT volume may be associated with a significant increase in the risk of penetrating disease and surgery in CD. Our data suggest that visceral adiposity as measured by VAT may negatively impact long-term progression of CD regardless of genetic predisposition.


Assuntos
Adiposidade , Doença de Crohn/genética , Doença de Crohn/fisiopatologia , Predisposição Genética para Doença , Gordura Intra-Abdominal/fisiopatologia , Adolescente , Adulto , Doença de Crohn/cirurgia , Progressão da Doença , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Modelos Logísticos , Masculino , Massachusetts , Razão de Chances , Estudos Prospectivos , Sistema de Registros , Tomografia Computadorizada por Raios X , Adulto Jovem
16.
Int J Cancer ; 139(12): 2655-2670, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27459707

RESUMO

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.


Assuntos
Variação Genética , Neoplasias/epidemiologia , Neoplasias/genética , Homeostase do Telômero/genética , Telômero/genética , Alelos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco , Telomerase/genética
17.
Int J Cancer ; 139(6): 1223-30, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27130486

RESUMO

Breast tissue is particularly susceptible to exposures between menarche and first pregnancy, and a longer interval between these reproductive events is associated with elevated breast cancer risk. Physical activity during this time period may offset breast cancer risk, particularly for those at highest risk with longer menarche-to-first-pregnancy intervals. We used data from 65,576 parous women in the Nurses' Health Study II free of cancer in 1989 (baseline) and recalled their leisure-time physical activity at ages 12-34 in 1997. Current activity was collected at baseline and over follow-up. Relative risks (RRs) were estimated using multivariable Cox proportional hazards regression models. Between 1989 and 2011, 2,069 invasive breast cancer cases were identified. Total recreational activity between menarche and first pregnancy was not significantly associated with the risk of breast cancer. However, physical activity between menarche and first pregnancy was associated with significantly lower breast cancer risk among women in the highest category of a menarche-to first-pregnancy interval (≥20 years; RR for the highest versus the lowest quartile = 0.73, 95% confidence interval = 0.55-0.97; Ptrend = 0.045; Pinteraction = 0.048). This was not observed in women with a shorter interval. Physical activity between menarche and first pregnancy was associated with a lower risk of breast cancer among women with at least 20 years between these reproductive events. This may provide a modifiable factor that women can intervene on to mitigate their breast cancer risk associated with a longer interval.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Exercício , Menarca , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Incidência , Estilo de Vida , Enfermeiras e Enfermeiros , Razão de Chances , Vigilância da População , Gravidez , Risco , Adulto Jovem
18.
JAMA Oncol ; 2(10): 1295-1302, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27228256

RESUMO

Importance: An improved model for risk stratification can be useful for guiding public health strategies of breast cancer prevention. Objective: To evaluate combined risk stratification utility of common low penetrant single nucleotide polymorphisms (SNPs) and epidemiologic risk factors. Design, Setting, and Participants: Using a total of 17 171 cases and 19 862 controls sampled from the Breast and Prostate Cancer Cohort Consortium (BPC3) and 5879 women participating in the 2010 National Health Interview Survey, a model for predicting absolute risk of breast cancer was developed combining information on individual level data on epidemiologic risk factors and 24 genotyped SNPs from prospective cohort studies, published estimate of odds ratios for 68 additional SNPs, population incidence rate from the National Cancer Institute-Surveillance, Epidemiology, and End Results Program cancer registry and data on risk factor distribution from nationally representative health survey. The model is used to project the distribution of absolute risk for the population of white women in the United States after adjustment for competing cause of mortality. Exposures: Single nucleotide polymorphisms, family history, anthropometric factors, menstrual and/or reproductive factors, and lifestyle factors. Main Outcomes and Measures: Degree of stratification of absolute risk owing to nonmodifiable (SNPs, family history, height, and some components of menstrual and/or reproductive history) and modifiable factors (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], menopausal hormone therapy [MHT], alcohol, and smoking). Results: The average absolute risk for a 30-year-old white woman in the United States developing invasive breast cancer by age 80 years is 11.3%. A model that includes all risk factors provided a range of average absolute risk from 4.4% to 23.5% for women in the bottom and top deciles of the risk distribution, respectively. For women who were at the lowest and highest deciles of nonmodifiable risks, the 5th and 95th percentile range of the risk distribution associated with 4 modifiable factors was 2.9% to 5.0% and 15.5% to 25.0%, respectively. For women in the highest decile of risk owing to nonmodifiable factors, those who had low BMI, did not drink or smoke, and did not use MHT had risks comparable to an average woman in the general population. Conclusions and Relevance: This model for absolute risk of breast cancer including SNPs can provide stratification for the population of white women in the United States. The model can also identify subsets of the population at an elevated risk that would benefit most from risk-reduction strategies based on altering modifiable factors. The effectiveness of this model for individual risk communication needs further investigation.


Assuntos
Neoplasias da Mama/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Comportamento de Redução do Risco , Estados Unidos/epidemiologia
19.
Gastroenterology ; 151(2): 351-363.e28, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27094239

RESUMO

BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.


Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Cálculos Biliares/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Afro-Americanos/genética , Idoso , Estudos de Casos e Controles , Colesterol/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Metabolismo dos Lipídeos/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único
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