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1.
Am J Hum Genet ; 105(4): 763-772, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564439

RESUMO

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31427306

RESUMO

BACKGROUND: Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival. METHODS: We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival (OS) time among 423 participants diagnosed with pancreatic adenocarcinoma between 1984 and 2008 within the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, and Women's Health Initiative. We measured prediagnostic leukocyte telomere length in banked blood samples using quantitative PCR. Cox proportional hazards models were used to estimate HRs for OS with adjustment for potential confounders. We also evaluated 10 SNPs at the telomerase reverse transcriptase locus. RESULTS: Shorter prediagnostic leukocyte telomere length was associated with reduced OS among patients with pancreatic cancer (P trend = 0.04). The multivariable-adjusted HR for OS comparing the lowest with highest quintiles of leukocyte telomere length was 1.39 (95% confidence interval, 1.01-1.93), corresponding to a 3-month difference in median OS time. In an analysis excluding cases with blood collected within 2 years of cancer diagnosis, the association was moderately stronger (HR, 1.55; 95% confidence interval, 1.09-2.21; comparing the lowest with highest quintiles; P trend = 0.01). No prognostic association or effect modification for the prognostic association of prediagnostic leukocyte telomere length was noted in relation to the studied SNPs. CONCLUSIONS: Prediagnostic leukocyte telomere length was associated with pancreatic cancer survival. IMPACT: Prediagnostic leukocyte telomere length can be a prognostic biomarker in pancreatic cancer.

3.
Atherosclerosis ; 289: 51-56, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31450014

RESUMO

BACKGROUND: Walking pace is increasingly being used to assess functional status in ambulatory settings. METHODS: We conducted a prospective analysis within the Physicians' Health Study to examine whether walking pace is associated with mortality and incident cardiovascular disease (fatal or nonfatal myocardial infarction, coronary artery bypass grafting and percutaneous transluminal coronary angioplasty). Participants included 21,919 male physicians with a mean age of 67.8 ±â€¯9.0 years. RESULTS: After a median follow-up of 9.4 years (IQR: 7.9-10.3), 3906 deaths and 2487 incident CVD events occurred. In a multivariable Cox proportional hazards model adjusting for age, body mass index, smoking, exercise frequency, and prevalent hypertension, diabetes mellitus, heart failure, peripheral vascular disease, cancer, and total weekly walking time, hazard ratios for mortality were 0.72 (95% CI: 0.64-0.81) for walking pace of 2-2.9mph, 0.63 (95% CI: 0.55-0.73) for walking pace of 3-3.9mph and 0.63 (95% CI: 0.48-0.83) for walking pace of ≥4mph compared to the group that reported not walking regularly (p trend <0.0001). Similar findings were observed for incident CVD: HRs were 0.88 (95% CI: 0.75-1.03) for a walking pace of 2-2.9mph, 0.75 (95% CI: 0.63-0.89) for a walking pace of 3-3.9mph and 0.70 (0.53-0.94) for a walking pace of ≥4mph compared to the group that reported not walking regularly (p trend 0.0001). These associations persisted after excluding those who exercised regularly. CONCLUSION: We found that walking pace is inversely associated with risk of mortality and CVD among US male physicians.

4.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

5.
J Am Heart Assoc ; 8(15): e011346, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31378120

RESUMO

Background Although coffee consumption is often reported as a trigger for atrial fibrillation (AF) among patients with paroxysmal AF, prospective studies on the relation of coffee consumption with AF risk have been inconsistent. Hence, we sought to assess the association between coffee consumption and risk of AF in men. Methods and Results We prospectively studied men who participated in the Physicians' Health Study (N=18 960). Coffee consumption was assessed through self-reported food frequency questionnaires. The incidence of AF was assessed through annual questionnaires and validated through review of medical records in a subsample. Cox proportional hazard models were used to calculate hazard ratios and 95% CIs of AF. The average age was 66.1 years. A total of 2098 new cases of AF occurred during a mean follow-up of 9 years. Hazard ratios (95% CI) of AF were 1.0 (reference), 0.85 (0.71-1.02), 1.07 (0.88-1.30), 0.93 (0.74-1.17), 0.85 (0.74-0.98), 0.86 (0.76-0.97), and 0.96 (0.80-1.14) for coffee consumption of rarely/never, ≤1 cup/week, 2 to 4 cups/week, 5 to 6 cups/week, 1 cup/day, 2 to 3 cups/day, and 4+ cups/day, respectively; adjusting for age, smoking, alcohol intake, and exercise (P for nonlinear trend=0.01). In a secondary analysis the multivariable adjusted hazard ratio (95% CI) of AF per standard deviation (149-mg) change in caffeine intake was 0.97 (0.92-1.02). Conclusions Our data suggest a lower risk of AF among men who reported coffee consumption of 1 to 3 cups/day.

6.
Int J Cancer ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

7.
Clin Nutr ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31279615

RESUMO

INTRODUCTION: Previous studies of the relationship between fried food consumption and coronary artery disease (CAD) have yielded conflicting results. We tested the hypothesis that frequent fried food consumption is associated with a higher risk of incident CAD events in Million Veteran Program (MVP) participants. METHODS: Veterans Health Administration electronic health record data were linked to questionnaires completed at MVP enrollment. Self-reported fried food consumption at baseline was categorized: (<1, 1-3, 4-6 times per week or daily). The outcome of interest was non-fatal myocardial infarction or CAD events. We fitted a Cox regression model adjusting for age, sex, race, education, exercise, smoking and alcohol consumption. RESULTS: Of 154,663 MVP enrollees with survey data, mean age was 64 years and 90% were men. During a mean follow-up of approximately 3 years, there were 6,725 CAD events. There was a positive linear relationship between frequency of fried food consumption and risk of CAD (p for trend 0.0015). Multivariable adjusted hazard ratios (95% CI) were 1.0 (ref), 1.07 (1.01-1.13), 1.08 (1.01-1.16), and 1.14 (1.03-1.27) across consecutive increasing categories of fried food intake. CONCLUSIONS: In a large national cohort of U.S. Veterans, fried food consumption has a positive, dose-dependent association with CAD.

8.
Nat Neurosci ; 22(9): 1394-1401, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358989

RESUMO

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10-10: CAMKV; chromosome 17 closest to KANSL1, but within a large high linkage disequilibrium region that also includes CRHR1; and TCF4. Associations were enriched with respect to the transcriptomic profiles of striatal medium spiny neurons. No significant associations were observed in the African American cohort of the sample. Results in European Americans were replicated in the UK Biobank data. These results provide new insights into the biology of PTSD in a well-powered genome-wide association study.

9.
Nat Med ; 25(8): 1274-1279, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31285632

RESUMO

Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.

10.
Circulation ; 140(12): 1031-1040, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

11.
Biol Psychiatry ; 86(5): 365-376, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31151762

RESUMO

BACKGROUND: Habitual alcohol use can be an indicator of alcohol dependence, which is associated with a wide range of serious health problems. METHODS: We completed a genome-wide association study in 126,936 European American and 17,029 African American subjects in the Veterans Affairs Million Veteran Program for a quantitative phenotype based on maximum habitual alcohol consumption. RESULTS: ADH1B, on chromosome 4, was the lead locus for both populations: for the European American sample, rs1229984 (p = 4.9 × 10-47); for African American, rs2066702 (p = 2.3 × 10-12). In the European American sample, we identified three additional genome-wide-significant maximum habitual alcohol consumption loci: on chromosome 17, rs77804065 (p = 1.5 × 10-12), at CRHR1 (corticotropin-releasing hormone receptor 1); the protein product of this gene is involved in stress and immune responses; and on chromosomes 8 and 10. European American and African American samples were then meta-analyzed; the associated region at CRHR1 increased in significance to 1.02 × 10-13, and we identified two additional genome-wide significant loci, FGF14 (p = 9.86 × 10-9) (chromosome 13) and a locus on chromosome 11. Besides ADH1B, none of the five loci have prior genome-wide significant support. Post-genome-wide association study analysis identified genetic correlation to other alcohol-related traits, smoking-related traits, and many others. Replications were observed in UK Biobank data. Genetic correlation between maximum habitual alcohol consumption and alcohol dependence was 0.87 (p = 4.78 × 10-9). Enrichment for cell types included dopaminergic and gamma-aminobutyric acidergic neurons in midbrain, and pancreatic delta cells. CONCLUSIONS: The present study supports five novel alcohol-use risk loci, with particularly strong statistical support for CRHR1. Additionally, we provide novel insight regarding the biology of harmful alcohol use.

12.
J Natl Cancer Inst ; 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127946

RESUMO

BACKGROUND: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS: Over a period of 38,369,156 person-years of follow-up, 1,391 gallbladder, 758 intrahepatic bile duct, 1,208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (e.g., current versus never smokers hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.34 to 2.13 and 2.22, 95%CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<0.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (e.g., >40 cigarettes/day versus never smokers HR = 2.15, 95%CI: 1.15 to 4.00; P-trend=0.001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming ≥5 versus 0 drinks/day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend=0.04). There was evidence of statistical heterogeneity between several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.

13.
Cancer Res ; 79(15): 3973-3982, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31113819

RESUMO

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

14.
Int J Cardiol ; 290: 119-124, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30929975

RESUMO

OBJECTIVE: The purpose of our study is to examine whether serial measurements of serum sodium values after diagnosis identify a higher-risk subset of patients with heart failure with preserved ejection fraction. METHODS: We identified 50,932 subjects with HFpEF with 759,577 recorded sNa measurements (mean age 72 ±â€¯11 years) using a validated algorithm in the VA national database from 2002 to 2012. We examined the association of repeated measures of sNa with mortality using a multivariable Cox proportional hazards model. RESULTS: After a median follow-up of 2.9 years (IQR: 1.2-5.4), 19,011 deaths occurred. After adjusting for age, sex, race, BMI, glomerular filtration rate, potassium, coronary artery disease, hypertension, hyperlipidemia, atrial fibrillation, pulmonary disease, diabetes, anemia, and medications, we found J-shaped associations of serum sodium with mortality. HRs for all-cause mortality were 2.48 (95% CI: 2.38-2.60) for the sNA 115.00-133.99 category; and 1.40 (95% CI: 1.35-1.46) for the sNA 143.00-175.00 category compared to the 137.01-140.99 category (ref). We used generalized estimating equation-based negative binomial regression to compute the incidence density ratios (IDR) to examine days hospitalized for heart failure and for all causes. There were a total of 1,275,614 days of all-cause hospitalization and 104,006 days of heart-failure hospitalization. The IDRs for the lowest sNA group were 2.03 (95% CI: 1.90-2.18) for all-cause hospitalization and 1.73 (95% CI: 1.39-2.16) for heart-failure hospitalization. CONCLUSIONS: Our findings suggest that monitoring of serum sodium values during longitudinal follow-up can identify HFpEF patients at risk of adverse outcomes.

15.
J Hypertens ; 37(6): 1223-1229, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30882595

RESUMO

BACKGROUND: Experimental studies suggest that omega-3 fatty acid have favorable effects on blood pressure (BP). However, data on the association of long-term dietary intake of omega-3 fatty acid or fish with risk of hypertension in healthy subjects are sparse. We examined whether fish or omega-3 fatty acid consumption was associated with incident hypertension in the Physicians' Health Study (PHS). METHODS: In a prospective cohort study, we analyzed data on 12 279 PHS participants (mean age: 53.0 ±â€Š8.7 years) free of hypertension at baseline. Fish and omega-3 fatty acid consumption were assessed from a baseline semiquantitative food-frequency questionnaire. Incident hypertension was ascertained via self-reports on annual follow-up questionnaires. RESULTS: During a mean follow-up of 15.8 years, 6299 men (51.3%) developed hypertension. In a multivariable model controlling for established risk factors for hypertension, fish and omega-3 fatty acid consumption was not significantly associated with incident hypertension. The hazard ratio (95% CI) of hypertension was 1.10 (0.93-1.30) for men who consumed at least five servings per week of fish compared with those who did not consume any fish (P for trend = 0.29). For the highest versus lowest quintile of omega-3 fatty acid intake, the hazard ratio of hypertension was 1.02 (0.94-1.11) (P for trend = 0.34). The associations did not vary by type of fish. There was also no evidence of effect modification by baseline BP, BMI, or history of hypercholesterolemia. CONCLUSION: Overall, long-term dietary intake of fish and omega-3 fatty acid was not associated with incident hypertension in a cohort of middle-aged and older US men.

16.
Clin Nutr ; 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30914216

RESUMO

BACKGROUND & AIMS: Observational and clinical trial evidence suggests an inverse association of omega-3 polyunsaturated fatty acids with coronary artery disease (CAD) mortality, although relationships with non-fatal CAD and stroke are less clear. We investigated whether omega-3 fatty acid supplement use and fish intake were associated with incident non-fatal CAD and ischemic stroke among US Veterans. METHODS: The Million Veteran Program (MVP) is an ongoing nation-wide longitudinal cohort study of US Veterans with self-reported survey, biospecimen, and electronic health record data. Regular use of omega-3 supplements (yes/no) and frequency of fish intake within the past year were assessed using a food frequency questionnaire. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations of omega-3 supplement use and fish intake with incident non-fatal CAD and ischemic stroke, defined from electronic health records using validated algorithms. Multivariable models included demographics, body mass index, education, smoking status, alcohol intake, and exercise frequency. RESULTS: Among 197,761 participants with food frequency data (mean age: 66 ± 12 years, 92% men), 21% regularly took omega-3 supplements and median fish intake was 1 (3-5 ounce) serving/week. Over a median follow-up of 2.9 years for non-fatal CAD and 3.3 years for non-fatal ischemic stroke, we observed 6265 and 4042 incident cases of non-fatal CAD and non-fatal ischemic stroke, respectively. Omega-3 fatty acid supplement use was independently associated with a lower risk of non-fatal ischemic stroke [HR (95% CI): 0.88 (0.81, 0.95)] but not non-fatal CAD [0.99 (0.93, 1.06)]. Fish intake was not independently associated with non-fatal CAD [1.01 (0.94, 1.09) for 1-3 servings/month, 1.03 (0.98, 1.11) for 1 serving/week, 1.02 (0.93, 1.11) for 2-4 servings/week, and 1.15 (0.98, 1.35) for ≥5 servings/week, reference = <1 serving/month, linear p-trend = 0.09] or non-fatal ischemic stroke [0.92 (0.84, 1.00) for 1-3 servings/month, 0.93 (0.85, 1.02) for 1 serving/week, 0.96 (0.86, 1.07) for 2-4 servings/week, and 1.13 (0.93-1.38) for ≥5 servings/week, linear p-trend = 0.16]. CONCLUSIONS: Neither omega-3 supplement use, nor fish intake, was associated with non-fatal CAD among US Veterans. While omega-3 supplement use was associated with lower risk of non-fatal ischemic stroke, fish intake was not. Randomized controlled trials are needed to confirm whether omega-3 supplementation is protective against ischemic stroke in a US population.

17.
JAMA ; 321(3): 253-255, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30667488
18.
BMJ ; 364: k4981, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606716

RESUMO

OBJECTIVES: To conduct a comprehensive analysis of prospectively measured circulating high sensitivity C reactive protein (hsCRP) concentration and risk of lung cancer overall, by smoking status (never, former, and current smokers), and histological sub-type. DESIGN: Nested case-control study. SETTING: 20 population based cohort studies in Asia, Europe, Australia, and the United States. PARTICIPANTS: 5299 patients with incident lung cancer, with individually incidence density matched controls. EXPOSURE: Circulating hsCRP concentrations in prediagnostic serum or plasma samples. MAIN OUTCOME MEASURE: Incident lung cancer diagnosis. RESULTS: A positive association between circulating hsCRP concentration and the risk of lung cancer for current (odds ratio associated with a doubling in hsCRP concentration 1.09, 95% confidence interval 1.05 to 1.13) and former smokers (1.09, 1.04 to 1.14) was observed, but not for never smokers (P<0.01 for interaction). This association was strong and consistent across all histological subtypes, except for adenocarcinoma, which was not strongly associated with hsCRP concentration regardless of smoking status (odds ratio for adenocarcinoma overall 0.97, 95% confidence interval 0.94 to 1.01). The association between circulating hsCRP concentration and the risk of lung cancer was strongest in the first two years of follow-up for former and current smokers. Including hsCRP concentration in a risk model, in addition to smoking based variables, did not improve risk discrimination overall, but slightly improved discrimination for cancers diagnosed in the first two years of follow-up. CONCLUSIONS: Former and current smokers with higher circulating hsCRP concentrations had a higher risk of lung cancer overall. Circulating hsCRP concentration was not associated with the risk of lung adenocarcinoma. Circulating hsCRP concentration could be a prediagnostic marker of lung cancer rather than a causal risk factor.


Assuntos
Proteína C-Reativa/metabolismo , Carcinoma de Células Grandes/sangue , Carcinoma de Células Pequenas/sangue , Carcinoma de Células Escamosas/sangue , Neoplasias Pulmonares/sangue , Fumar/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Grandes/epidemiologia , Carcinoma de Células Pequenas/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Estudos de Casos e Controles , Ex-Fumantes/estatística & dados numéricos , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , não Fumantes/estatística & dados numéricos , Razão de Chances , Estudos Prospectivos , Medição de Risco , Sensibilidade e Especificidade , Fumantes/estatística & dados numéricos , Fumar/epidemiologia , Adulto Jovem
19.
Int J Cancer ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499135

RESUMO

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer aetiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5,183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ]= 1.08, 95%CI= 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer. This article is protected by copyright. All rights reserved.

20.
Clin Epidemiol ; 10: 1509-1521, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425582

RESUMO

Background: Large databases provide an efficient way to analyze patient data. A challenge with these databases is the inconsistency of ICD codes and a potential for inaccurate ascertainment of cases. The purpose of this study was to develop and validate a reliable protocol to identify cases of acute ischemic stroke (AIS) from a large national database. Methods: Using the national Veterans Affairs electronic health-record system, Center for Medicare and Medicaid Services, and National Death Index data, we developed an algorithm to identify cases of AIS. Using a combination of inpatient and outpatient ICD9 codes, we selected cases of AIS and controls from 1992 to 2014. Diagnoses determined after medical-chart review were considered the gold standard. We used a machine-learning algorithm and a neural network approach to identify AIS from ICD9 codes and electronic health-record information and compared it with a previous rule-based stroke-classification algorithm. Results: We reviewed administrative hospital data, ICD9 codes, and medical records of 268 patients in detail. Compared with the gold standard, this AIS algorithm had a sensitivity of 91%, specificity of 95%, and positive predictive value of 88%. A total of 80,508 highly likely cases of AIS were identified using the algorithm in the Veterans Affairs national cardiovascular disease-risk cohort (n=2,114,458). Conclusion: Our algorithm had high specificity for identifying AIS in a nationwide electronic health-record system. This approach may be utilized in other electronic health databases to accurately identify patients with AIS.

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