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1.
J Natl Cancer Inst ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31917448

RESUMO

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies (GWAS) in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study (TWAS) in Europeans using three approaches, FUSION, MetaXcan and SMulTiXcan. We integrated GWAS summary statistics from 9,040 pancreatic cancer cases and 12,496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics, LTG (n = 95) and Genotype-Tissue Expression, GTEx v7 (n = 174) datasets), and data from 48 different tissues (GTEx v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (FDR < 0.05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12:, PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at 6 known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci, and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1 and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

2.
Hepatology ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31808181

RESUMO

BACKGROUND: In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts. METHODS: Seven sex steroid hormones and SHBG were quantitated using gas chromatography-tandem mass spectrometry (GC-MS/MS) and competitive electrochemiluminescence immunoassay, respectively, from baseline serum/plasma samples of 191 post-menopausal female liver cancer cases (HCC n=83, ICC n=56) and 426 controls, matched on sex, cohort, age, race/ethnicity, and blood collection date. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between a one-unit increase in log2 hormone value (approximate doubling of circulating concentration) and liver cancer were calculated using multivariable-adjusted conditional logistic regression. RESULTS: A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while SHBG was associated with a 31% increased risk (OR=1.31,95%CI=1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR=1.40,95%CI=1.05-1.89), but not HCC (OR=1.12,95%CI=0.81-1.54). CONCLUSIONS: This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.

3.
J Am Geriatr Soc ; 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31840808

RESUMO

OBJECTIVES: Limited data suggest that a healthy diet is associated with a lower risk of frailty. We sought to assess the relationship between three measures of diet quality and frailty among male physicians. DESIGN: Cross-sectional analysis of a cohort study. SETTING: Physicians' Health Study. PARTICIPANTS: A total of 9861 initially healthy US men, aged 60 years or older, who provided data on frailty status and dietary habits. MEASUREMENTS: A cumulative deficit frailty index (FI) was calculated using 33 variables encompassing domains of comorbidity, functional status, mood, general health, social isolation, and change in weight. Diet quality was measured using the Alternative Healthy Eating Index (aHEI), Mediterranean Diet Score (MDS), and Dietary Approaches to Stop Hypertension (DASH). RESULTS: The FI identified 38% of physicians as non-frail, 44% as pre-frail, and 18% as frail. Multinomial logistic regression models adjusted for age, smoking status, and energy intake showed that compared with the lowest aHEI quintiles, those in the highest quintiles had lower odds of frailty and pre-frailty compared with non-frailty (odds ratio [OR] for frailty = .47; 95% confidence interval [CI] = .39-.58; for pre-frailty: OR = .75; CI = .65-.87). Exercise did not modify this association (P interaction >.1). Similar relationships were observed for DASH and MDS quintiles with frailty and pre-frailty. Restricted cubic splines showed an inverse dose-response relationship of diet quality scores with odds of frailty and pre-frailty. CONCLUSION: Cross-sectional data show an inverse dose-response relationship of diet quality with pre-frailty and frailty. Future longitudinal studies are needed to investigate whether healthier diet is a modifiable risk factor for frailty. ClinicalTrials.gov identifier: NCT00000500.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31872970

RESUMO

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

5.
Circulation ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31709816

RESUMO

Among older adults, heart failure (HF) is the leading cause of hospitalization in the US and is associated with high costs and mortality1. Vitamin D and marine omega-3 (n-3) fatty acids have each been associated with reduced risks of HF in observational studies, but randomized trial evidence is limited. The current ancillary study sought to investigate the effects of vitamin D and n-3 supplements on the incidence of HF hospitalization in a large multi-ethnic cohort. VITAL-HF is an ancillary study of the parent VITAL trial, which is a completed randomized trial with a two-by-two factorial design to examine the efficacy of vitamin D3 (2000 IU/d) and n-3 fatty acids (1 gram per day, including eicosapentaenoic acid [EPA, 460 mg] + docosahexaenoic acid [DHA, 380 mg]) for the prevention of cardiovascular disease and cancer in 25, 871 adults from 2011 to 2017. Detailed description of the VITAL design and main results has been published2. We excluded 36 participants with prevalent HF for current analyses. Each participant signed informed consent and the study protocol was approved by the Institutional Review Board of Brigham and Women's Hospital.

6.
Nat Protoc ; 14(12): 3426-3444, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748751

RESUMO

Phenotypes are the foundation for clinical and genetic studies of disease risk and outcomes. The growth of biobanks linked to electronic medical record (EMR) data has both facilitated and increased the demand for efficient, accurate, and robust approaches for phenotyping millions of patients. Challenges to phenotyping with EMR data include variation in the accuracy of codes, as well as the high level of manual input required to identify features for the algorithm and to obtain gold standard labels. To address these challenges, we developed PheCAP, a high-throughput semi-supervised phenotyping pipeline. PheCAP begins with data from the EMR, including structured data and information extracted from the narrative notes using natural language processing (NLP). The standardized steps integrate automated procedures, which reduce the level of manual input, and machine learning approaches for algorithm training. PheCAP itself can be executed in 1-2 d if all data are available; however, the timing is largely dependent on the chart review stage, which typically requires at least 2 weeks. The final products of PheCAP include a phenotype algorithm, the probability of the phenotype for all patients, and a phenotype classification (yes or no).

7.
Nat Genet ; 51(11): 1574-1579, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.

8.
Int J Cancer ; 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31677159

RESUMO

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type - hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that includes data from 1,167,244 individuals (PLC n=2,208, HCC n=1,154, ICC n=335). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR=1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR=1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5-<25 kg/m2 ; HR=1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR=1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR=0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements. This article is protected by copyright. All rights reserved.

9.
J Am Coll Cardiol ; 74(21): 2623-2634, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31727422

RESUMO

BACKGROUND: Sudden cardiac death occurs in ∼220,000 U.S. adults annually, the majority of whom have no prior symptoms or cardiovascular diagnosis. Rare pathogenic DNA variants in any of 49 genes can pre-dispose to 4 important causes of sudden cardiac death: cardiomyopathy, coronary artery disease, inherited arrhythmia syndrome, and aortopathy or aortic dissection. OBJECTIVES: This study assessed the prevalence of rare pathogenic variants in sudden cardiac death cases versus controls, and the prevalence and clinical importance of such mutations in an asymptomatic adult population. METHODS: The authors performed whole-exome sequencing in a case-control cohort of 600 adult-onset sudden cardiac death cases and 600 matched controls from 106,098 participants of 6 prospective cohort studies. Observed DNA sequence variants in any of 49 genes with known association to cardiovascular disease were classified as pathogenic or likely pathogenic by a clinical laboratory geneticist blinded to case status. In an independent population of 4,525 asymptomatic adult participants of a prospective cohort study, the authors performed whole-genome sequencing and determined the prevalence of pathogenic or likely pathogenic variants and prospective association with cardiovascular death. RESULTS: Among the 1,200 sudden cardiac death cases and controls, the authors identified 5,178 genetic variants and classified 14 as pathogenic or likely pathogenic. These 14 variants were present in 15 individuals, all of whom had experienced sudden cardiac death-corresponding to a pathogenic variant prevalence of 2.5% in cases and 0% in controls (p < 0.0001). Among the 4,525 participants of the prospective cohort study, 41 (0.9%) carried a pathogenic or likely pathogenic variant and these individuals had 3.24-fold higher risk of cardiovascular death over a median follow-up of 14.3 years (p = 0.02). CONCLUSIONS: Gene sequencing identifies a pathogenic or likely pathogenic variant in a small but potentially important subset of adults experiencing sudden cardiac death; these variants are present in ∼1% of asymptomatic adults.

10.
J Am Med Inform Assoc ; 26(11): 1255-1262, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613361

RESUMO

OBJECTIVE: Electronic health records linked with biorepositories are a powerful platform for translational studies. A major bottleneck exists in the ability to phenotype patients accurately and efficiently. The objective of this study was to develop an automated high-throughput phenotyping method integrating International Classification of Diseases (ICD) codes and narrative data extracted using natural language processing (NLP). MATERIALS AND METHODS: We developed a mapping method for automatically identifying relevant ICD and NLP concepts for a specific phenotype leveraging the Unified Medical Language System. Along with health care utilization, aggregated ICD and NLP counts were jointly analyzed by fitting an ensemble of latent mixture models. The multimodal automated phenotyping (MAP) algorithm yields a predicted probability of phenotype for each patient and a threshold for classifying participants with phenotype yes/no. The algorithm was validated using labeled data for 16 phenotypes from a biorepository and further tested in an independent cohort phenome-wide association studies (PheWAS) for 2 single nucleotide polymorphisms with known associations. RESULTS: The MAP algorithm achieved higher or similar AUC and F-scores compared to the ICD code across all 16 phenotypes. The features assembled via the automated approach had comparable accuracy to those assembled via manual curation (AUCMAP 0.943, AUCmanual 0.941). The PheWAS results suggest that the MAP approach detected previously validated associations with higher power when compared to the standard PheWAS method based on ICD codes. CONCLUSION: The MAP approach increased the accuracy of phenotype definition while maintaining scalability, thereby facilitating use in studies requiring large-scale phenotyping, such as PheWAS.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31660540

RESUMO

Aims: While some but not all trial data have suggested an elevated risk of type 2 diabetes with statin use, limited data are available on the relation of statin treatment with glycaemia and risk of type 2 diabetes among Veterans. We examined whether statin use was associated with a higher incidence of type 2 diabetes and secondarily, if statin use was associated with high plasma glucose. Methods: Prospective analysis based on electronic health records of 3,390,799 US Veterans from 2000 to 2012. We used the Veteran Administration Corporate Data Warehouse to obtain information on random plasma glucose. Statin use was captured using the pharmacy database. type 2 diabetes was defined as having at least one inpatient diagnosis or at least two outpatient diagnoses of type 2 diabetes using International Classification of Disease version 9 codes 250.xx, or the use of hypoglycemic agents. We used multi-level derived propensity score and inverse probability weighting to address confounding by indication and Cox regression to estimate relative risk of type 2 diabetes. Results: The mean age was 62±11.9 years; 93.3% were men and 82.7% were white. During a median follow-up of 3.0 years, 443,104 new cases of type 2 diabetes occurred. Compared to no statin use, multivariable adjusted hazard ratio (95% CI) for type 2 diabetes was 1.21 (1.19-1.24) for low statin potency, 1.22 (1.21-1.23) for medium statin potency, and 1.34 (1.32-1.36) for high statin potency (p linear trend <0.0001). In secondary analysis, statin use was not associated with higher plasma glucose. Conclusions: Our data show a positive association between statin use and incidence of type 2 diabetes among US Veterans.

12.
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.

13.
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.

14.
Cancer Epidemiol Biomarkers Prev ; 28(11): 1868-1875, 2019 Nov.
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.

15.
Atherosclerosis ; 289: 51-56, 2019 Oct.
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.

16.
Nat Commun ; 10(1): 3842, 2019 08 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.

17.
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.

18.
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.

19.
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.

20.
Nat Med ; 25(8): 1274-1279, 2019 08.
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.


Assuntos
Estudo de Associação Genômica Ampla , Doença Arterial Periférica/genética , Idoso , LDL-Colesterol/genética , Fator V/genética , Inibidores do Fator Xa/uso terapêutico , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Receptores de LDL/genética , Veteranos
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