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1.
Circ Genom Precis Med ; 14(4): e003300, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34319147

RESUMO

BACKGROUND: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

2.
Am J Epidemiol ; 190(11): 2461-2473, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34142699

RESUMO

Dietary guidance emphasizes healthy dietary patterns, but supporting evidence comes from self-reported dietary data, which are prone to measurement error. We explored whether nutritional biomarkers from the Women's Health Initiative Nutrition and Physical Activity Assessment Study Feeding Study (NPAAS-FS) (n = 153; 2010-2014) and the Women's Health Initiative Nutrition and Physical Activity Assessment Study Observational Study (NPAAS-OS) (n = 450; 2006-2009) could identify biomarker signatures of dietary patterns for development of corresponding regression calibration equations to help mitigate measurement error. Fasting blood samples were assayed for a specific panel of vitamins, carotenoids, and phospholipid fatty acids; 24-hour urine samples were assayed for nitrogen, sodium, and potassium levels. Intake records from the NPAAS-FS were used to calculate Healthy Eating Index 2010 (HEI-2010), Alternative Healthy Eating Index 2010 (AHEI-2010), alternative Mediterranean diet (aMED), and Dietary Approaches to Stop Hypertension (DASH) scores. Scores were regressed on blood and urine nutritional measures for discovery of dietary pattern biomarkers using a cross-validated model R2 ≥ 36% criterion (stage 1). Next, stepwise models (P ≤ 0.10 for entry/removal) using NPAAS-OS data were used to regress stage 1 dietary pattern biomarkers on NPAAS-OS self-reported dietary pattern scores using a food frequency questionnaire, a 4-day food record, and a 24-hour recall (stage 2). HEI-2010 and aMED analyses met the cross-validated R2 ≥ 36% criterion in stage 1, while AHEI-2010 and DASH analyses did not. The R2 values for HEI-2010 stage 2 calibration equations were as follows: food frequency questionnaire, 63.5%; 4-day food record, 83.1%; and 24-hour recall, 77.8%. Stage 2 aMED R2 values were 34.9%-46.8%. Dietary pattern biomarkers have potential for calibrating self-reports to enhance studies of diet-disease associations.


Assuntos
Biomarcadores/sangue , Dieta Saudável , Estado Nutricional , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/urina , Dieta Mediterrânea , Abordagens Dietéticas para Conter a Hipertensão , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/sangue , Pós-Menopausa/urina
3.
J Nutr ; 151(8): 2330-2341, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-33880504

RESUMO

BACKGROUND: Knowledge about macronutrient intake and chronic disease risk has been limited by the absence of objective macronutrient measures. Recently, we proposed novel biomarkers for protein, protein density, carbohydrate, and carbohydrate density, using established biomarkers and serum and urine metabolomics profiles in a human feeding study. OBJECTIVES: We aimed to use these biomarkers to develop calibration equations for macronutrient variables using dietary self-reports and personal characteristics and to study the association between biomarker-calibrated intake estimates and cardiovascular disease, cancer, and diabetes risk in Women's Health Initiative (WHI) cohorts. METHODS: Prospective disease association analyses are based on WHI cohorts of postmenopausal US women aged 50-79 y when enrolled at 40 US clinical centers (n = 81,954). We used biomarker intake values in a WHI nutritional biomarker study (n = 436) to develop calibration equations for each macronutrient variable, leading to calibrated macronutrient intake estimates throughout WHI cohorts. We then examined the association of these intakes with chronic disease incidence over a 20-y (median) follow-up period using HR regression methods. RESULTS: In analyses that included doubly labeled water-calibrated total energy, HRs for cardiovascular diseases and cancers were mostly unrelated to calibrated protein density. However, many were inversely related to carbohydrate density, with HRs (95% CIs) for a 20% increment in carbohydrate density of 0.81 (0.69, 0.95) and 0.83 (0.74, 0.93), respectively, for primary outcomes of coronary heart disease and breast cancer, as well as 0.74 (0.60, 0.91) and 0.87 (0.81, 0.93) for secondary outcomes of heart failure and total invasive cancer. Corresponding HRs (95% CIs) for type 2 diabetes incidence in relation to protein density and carbohydrate density were 1.17 (1.09, 1.75) and 0.73 (0.66, 0.80), respectively. CONCLUSIONS: At specific energy intake, a diet high in carbohydrate density is associated with substantially reduced risk of major chronic diseases in a population of US postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.

4.
Am J Clin Nutr ; 113(5): 1083-1092, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33876183

RESUMO

The dietary modification (DM) clinical trial, within the Women's Health Initiative (WHI), studied a low-fat dietary pattern intervention that included guidance to increase vegetables, fruit, and grains. This study was motivated in part from uncertainty about the reliability of observational studies examining the association between dietary fat and chronic disease risk by using self-reported dietary data. In addition to this large trial, which had breast and colorectal cancer as its primary outcomes, a substantial biomarker research effort was initiated midway in the WHI program to contribute to nutritional epidemiology research more broadly. Here we review and update findings from the DM trial and from the WHI nutritional biomarker studies and examine implications for future nutritional epidemiology research. The WHI included the randomized controlled DM trial (n = 48,835) and a prospective cohort observational (OS) study (n = 93,676), both among postmenopausal US women, aged 50-79 y when enrolled during 1993-1998. Also reviewed is a nutrition and physical activity assessment study in a subset of 450 OS participants (2007-2009) and a related controlled feeding study among 153 WHI participants (2010-2014). Long-term follow-up in the DM trial provides evidence for intervention-related reductions in breast cancer mortality, diabetes requiring insulin, and coronary artery disease in the subset of normotensive healthy women, without observed adverse effects or changes in all-cause mortality. Studies of intake biomarkers, and of biomarker-calibrated intake, suggest important associations of total energy intake and macronutrient dietary composition with the risk for major chronic diseases among postmenopausal women. Collectively these studies argue for a nutrition epidemiology research agenda that includes major efforts in nutritional biomarker development, and in the application of biomarkers combined with self-reported dietary data in disease association analyses. We expect such efforts to yield novel disease association findings and to inform disease prevention approaches for potential testing in dietary intervention trials. This trial was registered at clinicaltrials.gov as NCT00000611.


Assuntos
Dieta , Fenômenos Fisiológicos da Nutrição , Saúde da Mulher , Feminino , Humanos , Estado Nutricional
5.
J Vasc Surg ; 73(4): 1245-1252.e3, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32882349

RESUMO

OBJECTIVE: Few studies have prospectively examined the associations of lipoprotein(a) [Lp(a)] levels with the risk of abdominal aortic aneurysm (AAA), especially in women. Accounting for commonly recognized risk factors, we investigated the baseline Lp(a) levels and the risk of AAA among postmenopausal women participating in the ongoing national Women's Health Initiative. METHODS: Women's Health Initiative participants with baseline Lp(a) levels available who were beneficiaries of Medicare parts A and B fee-for-service at study enrollment or who had aged into Medicare at any point were included. Participants with missing covariate data or known AAA at baseline were excluded. Thoracic aneurysms were excluded owing to the different pathophysiology. The AAA cases and interventions were identified using the International Classification of Diseases, 9th and 10th revision, codes and Current Procedural Terminology codes from claims data. Hazard ratios were computed using Cox proportional hazard models according to the quintiles of Lp(a). RESULTS: The mean age of the 6615 participants included in the analysis was 65.3 years. Of the 6615 participants, 66.6% were non-Hispanic white, 18.9% were black, 7% were Hispanic and 4.7% were Asian/Pacific Islander. Compared with the participants in the lowest Lp(a) quintile, those in higher quintiles were more likely to be overweight, black, and former or current smokers, to have hypertension, hyperlipidemia, and a history of cardiovascular disease, and to use menopausal hormone therapy and statins. During 65,476 person-years of follow-up, with a median of 10.4 years, 415 women had been diagnosed with an AAA and 36 had required intervention. More than one half had required intervention for a ruptured AAA. We failed to find a statistically significant association between Lp(a) levels and incident AAA. Additional sensitivity analyses stratified by race, with exclusion of statin users and alternative categorizations of Lp(a) using log-transformed levels, tertiles, and a cutoff of >50 mg/dL, were conducted, which did not reveal any significant associations. CONCLUSIONS: We found no statistically significant association between Lp(a) levels and the risk of AAA in a large and well-phenotyped sample of postmenopausal women. Women with high Lp(a) levels were more likely to be overweight, black, and former or current smokers, and to have hypertension, hyperlipidemia, and a history of cardiovascular disease, or to use hormone therapy and statins compared with those with lower Lp(a) levels. These findings differ from previous prospective, case-control, and meta-analysis studies that had supported a significant relationship between higher Lp(a) levels and an increased risk of AAA. Differences in the association could have resulted from study limitations or sex differences.


Assuntos
Aneurisma da Aorta Abdominal/epidemiologia , Ruptura Aórtica/epidemiologia , Dislipidemias/sangue , Lipoproteína(a)/sangue , Saúde da Mulher , Idoso , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/cirurgia , Biomarcadores/sangue , Comorbidade , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Humanos , Incidência , Medicare , Pessoa de Meia-Idade , Pós-Menopausa , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Estados Unidos/epidemiologia
6.
Am J Clin Nutr ; 113(3): 706-715, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33381804

RESUMO

BACKGROUND: Metabolic syndrome (MetS) is associated with increased mortality independent of BMI, resulting in discordant metabolic phenotypes, such as metabolically healthy obese and metabolically unhealthy normal-weight individuals. Studies investigating dietary intake in MetS have reported mixed results, due in part to the limitations of self-reported measures. OBJECTIVES: To investigate the role of biomarker-calibrated estimates of energy and protein in MetS and metabolic phenotypes. METHODS: Postmenopausal participants from the Women's Health Initiative (WHI) study who were free of MetS at baseline, had available data from FFQs at baseline, and had components of MetS at Year 3 (n = 3963) were included. Dietary energy and protein intakes were estimated using biomarker calibration methods. MetS was defined as 3 or more of the following: elevated serum triglycerides (≥150 mg/dL), low HDL cholesterol (<50 mg/dL), hypertension [systolic blood pressure (BP) ≥130 or diastolic BP ≥85 mmHg], elevated serum glucose (>100 mg/dL), and abdominal adiposity (waist circumference > 89 cm). Models were adjusted for age, WHI study component, race/ethnicity, education, income, smoking, recreational physical activity, disease history, and parity. RESULTS: For every 10% increment in total calibrated energy intake, women were at a 1.37-fold elevated risk of MetS (95% CI, 1.15-1.63); a 10% increment in calibrated total protein intake was associated with a 1.21-fold elevated risk of MetS (95% CI, 1.00-1.47). Specifically, animal protein intake was associated with MetS (OR, 1.08; 95% CI, 1.02-1.14), whereas vegetable protein intake was not (OR, 0.99; 95% CI, 0.95-1.03). No differences were seen when examining metabolic phenotypes. CONCLUSIONS: We found that higher calibrated total energy, total protein, and total animal protein intakes were strongly associated with MetS. If replicated in clinical trials, these results will have implications for the promotion of energy and animal protein restrictions for the reduction of MetS risks.


Assuntos
Proteínas na Dieta/administração & dosagem , Proteínas na Dieta/efeitos adversos , Ingestão de Energia/fisiologia , Síndrome Metabólica/etiologia , Idoso , Biomarcadores/sangue , Feminino , Humanos , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade
7.
Ann Surg ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33156064

RESUMO

OBJECTIVE: To determine if premature menopause and early menarche are associated with increased risk of AAA, and to explore potential effect modification by smoking history. SUMMARY OF BACKGROUND DATA: Despite worse outcomes for women with AAA, no studies have prospectively examined sex-specific risk factors, such as premature menopause and early menarche, with risk of AAA in a large, ethnically diverse cohort of women. METHODS: This was a post-hoc analysis of Women's Health Initiative participants who were beneficiaries of Medicare Parts A&B fee-for-service. AAA cases and interventions were identified from claims data. Follow-up period included Medicare coverage until death, end of follow-up or end of coverage inclusive of 2017. RESULTS: Of 101,119 participants included in the analysis, the mean age was 63 years and median follow-up was 11.3 years. Just under 10,000 (9.4%) women experienced premature menopause and 22,240 (22%) experienced early menarche. Women with premature menopause were more likely to be overweight, Black, have ≥20 pack years of smoking, history of cardiovascular disease, hypertension, and early menarche. During 1,091,840 person-years of follow-up, 1125 women were diagnosed with AAA, 134 had premature menopause (11.9%), 93 underwent surgical intervention and 45 (48%) required intervention for ruptured AAA. Premature menopause was associated with increased risk of AAA [hazard ratio 1.37 (1.14, 1.66)], but the association was no longer significant after multivariable adjustment for demographics and cardiovascular disease risk factors. Amongst women with ≥20 pack year smoking history (n = 19,286), 2148 (11.1%) had premature menopause, which was associated with greater risk of AAA in all models [hazard ratio 1.63 (1.24, 2.23)]. Early menarche was not associated with increased risk of AAA. CONCLUSIONS: This study finds that premature menopause may be an important risk factor for AAA in women with significant smoking history. There was no significant association between premature menopause and risk of AAA amongst women who have never smoked. These results suggest an opportunity to develop strategies for better screening, risk reduction and stratification, and outcome improvement in the comprehensive vascular care of women.

8.
Am J Clin Nutr ; 112(1): 168-179, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32133498

RESUMO

BACKGROUND: We recently presented associations between serum-based biomarkers of carotenoid and tocopherol intake and chronic disease risk in a Women's Health Initiative (WHI) Measurement Precision subcohort (n = 5488). Questions remain as to whether self-reported dietary data can usefully augment such biomarkers or can be calibrated using biomarkers for reliable disease association estimation in larger WHI cohorts. OBJECTIVES: The aims were to examine the potential of FFQ data to explain intake variation in a WHI Feeding Study and to compare association parameter estimates and their precision from studies based on biomarker-calibrated FFQ intake in larger WHI cohorts, with those previously presented. METHODS: Serum-based intake measures were augmented by using FFQ data in a WHI Feeding Study (n = 153). Corresponding calibration equations were generated, both in a companion Nutritional Biomarker Study (n = 436) and in the previously mentioned subcohort (n = 5488), by regressing these intake measures on dietary data and participant characteristics, for α- and ß-carotene, lutein plus zeaxanthin, and α-tocopherol. The supplemental value of FFQ data was considered by examining the fraction of feeding study intake variation explained by these regression models. Calibrated intake and disease association analyses were evaluated by comparisons with previously reported subcohort results. RESULTS: The inclusion of FFQ data led to some increases in feeding study intake variation explained (total R2 of ∼50%). Calibrated intake estimates explained 25-75% of serum-based intake variation, whether developed using either of the 2 cohort subsamples. Related disease associations for micronutrients were precisely estimated in larger WHI cohorts (n = 76,691) but were often closer to the null compared with previously reported associations. CONCLUSIONS: FFQ data may usefully augment blood concentrations in estimating the intake of carotenoids and tocopherols. Calibrated intake estimates using FFQ, dietary supplement, and participant characteristics only may require further justification to ensure reliable estimation of related disease associations.


Assuntos
Micronutrientes/sangue , Idoso , Biomarcadores/sangue , Carotenoides/sangue , Doença Crônica , Estudos de Coortes , Feminino , Humanos , Micronutrientes/metabolismo , Pessoa de Meia-Idade , Estado Nutricional , Saúde da Mulher , alfa-Tocoferol/sangue , beta Caroteno/sangue
9.
Int J Cancer ; 146(9): 2394-2405, 2020 05 01.
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.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/sangue , Carcinoma de Células Grandes/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Inflamação/complicações , Neoplasias Pulmonares/diagnóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Adenocarcinoma de Pulmão/sangue , Adenocarcinoma de Pulmão/etiologia , Adulto , Idoso , Carcinoma de Células Grandes/sangue , Carcinoma de Células Grandes/etiologia , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/imunologia , Cinurenina/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Neopterina/sangue , Prognóstico , Estudos Prospectivos , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/etiologia , Triptofano/sangue
10.
Medicine (Baltimore) ; 98(24): e15869, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192918

RESUMO

Higher trait optimism and/or lower cynical hostility are associated with healthier behaviors and lower risk of morbidity and mortality, yet their association with health care utilization has been understudied. Whether these psychological attitudes are associated with breast cancer screening behavior is unknown. To assess the association of optimism and cynical hostility with screening mammography in older women and whether sociodemographic factors acted as mediators of these relationships, we used Women's Health Initiative (WHI) observational cohort survey data linked to Medicare claims. The sample includes WHI participants without history of breast cancer who were enrolled in Medicare Parts A and B for ≥2 years from 2005-2010, and who completed WHI baseline attitudinal questionnaires (n = 48,291). We used survival modeling to examine whether screening frequency varied by psychological attitudes (measured at study baseline) after adjusting for sociodemographic characteristics, health conditions, and healthcare-related variables. Psychological attitudes included trait optimism (Life Orientation Test-Revised) and cynical hostility (Cook Medley subscale), which were self-reported at study baseline. Sociodemographic, health conditions, and healthcare variables were self-reported at baseline and updated through 2005 as available. Contrary to our hypotheses, repeated events survival models showed that women with the lowest optimism scores (i.e., more pessimistic tendencies) received 5% more frequent screenings after complete covariate adjustment (p < .01) compared to the most optimistic group, and showed no association between cynical hostility and frequency of screening mammograms. Sociodemographic factors did not appear to mediate the relationship between optimism and screenings. However, higher levels of education and higher levels of income were associated with more frequent screenings (both p < .01). We also found that results for optimism were primarily driven by women who were aged 75 or older after January 2009, when changes to clinical guidelines lead to uncertainty about risks and benefits of screening in this age group. The study demonstrated that lower optimism, higher education, and higher income were all associated with more frequent screening mammograms in this sample after repeated events survival modeling and covariate adjustment.


Assuntos
Mamografia/estatística & dados numéricos , Otimismo/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Idoso , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Revisão da Utilização de Seguros , Estudos Longitudinais , Medicare , Fatores Socioeconômicos , Estados Unidos , Saúde da Mulher
11.
Am J Clin Nutr ; 109(4): 1189-1196, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30915444

RESUMO

BACKGROUND: Biomarkers provide potential to objectively measure the intake of nutrients and foods, and thereby to strengthen nutritional epidemiology association studies. However, there are only a few established intake biomarkers, mostly based on recovery of nutrients or their metabolites in urine. Blood concentration measures provide a potential biomarker source for many additional nutritional variables, but their use in disease-association studies requires further development. OBJECTIVE: The aim of this study was to apply recently proposed serum-based carotenoid and tocopherol intake biomarkers and to examine their association with the incidence of major cardiovascular diseases, cancers, and diabetes in a subset of Women's Health Initiative (WHI) cohorts. METHODS: Serum concentrations of α- and ß-carotene, lutein plus zeaxanthin (L + Z), and α-tocopherol were routinely measured at baseline in a subset of 5488 enrollees in WHI cohorts. Intake biomarkers for these 4 micronutrients, obtained by combining serum concentrations with participant characteristics, were recently proposed using a 153-woman feeding study within WHI. These biomarker equations are augmented here to include pertinent disease risk factors and are associated with subsequent chronic disease incidence in this WHI subset. RESULTS: HRs for a doubling of micronutrient intake differed only moderately from the null for the outcomes considered. However, somewhat lower risks of specific cardiovascular outcomes, breast cancer, and diabetes were associated with a higher intake of α- and ß-carotene, lower risk of diabetes was associated with higher L + Z intake, and elevated risks of certain cardiovascular outcomes were associated with a higher intake of α-tocopherol. These patterns remained following the exclusion of baseline users of dietary supplements. CONCLUSIONS: Concentration biomarkers can be calculated from blood specimens obtained in large epidemiologic cohorts and applied directly in disease-association analyses, without relying on self-reported dietary data. Observed associations between carotenoid and tocopherol biomarkers and chronic disease risk could be usefully evaluated further using stored serum specimens on the entire WHI cohort. This study was registered at www.clinicaltrials.gov as NCT00000611.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Carotenoides/sangue , Diabetes Mellitus/prevenção & controle , Neoplasias/prevenção & controle , Tocoferóis/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doença Crônica/prevenção & controle , Estudos de Coortes , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Suplementos Nutricionais/análise , Feminino , Humanos , Luteína/sangue , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/epidemiologia , Estado Nutricional , Fatores de Risco , Estados Unidos/epidemiologia , Zeaxantinas/sangue
12.
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
13.
Int J Cancer ; 145(6): 1499-1503, 2019 09 15.
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 etiology 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 5183 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.


Assuntos
Neoplasias Pulmonares/etiologia , Vitamina B 12/sangue , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fumar
14.
J Clin Rheumatol ; 25(3): 127-132, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29794514

RESUMO

OBJECTIVE: The aim of this study was to evaluate whether tea or coffee consumption is associated with an increased risk of older-onset rheumatoid arthritis (RA) using the Women's Health Initiative Observational Study. METHODS: The Women's Health Initiative Observational Study is a longitudinal prospective cohort study conducted from 1993 to 1998. There were 76,853 women who completed a self-administered questionnaire about their daily consumption of tea and coffee. One hundred eighty-five women self-reported and validated incident cases of RA were observed after 3 years of observation. Multivariable Cox proportional hazards models were performed to assess the relationship between consumption habits and disease incidence. Trend tests were calculated using categorical variables modeled as a continuous variable without collapsing. RESULTS: There was no increase in the hazard ratio for incident RA in those participants who drank coffee compared with those who did not. The amount of coffee consumed and the method of preparation (caffeinated/decaffeinated; filtered/unfiltered) also did not alter the risk of incident RA. There was a positive association of incident RA and caffeinated tea consumption in the trend test (p = 0.03). When assessing any caffeinated tea consumption versus no tea consumption, the hazard ratio for incident RA was 1.40 (confidence interval, 1.01-1.93; p = 0.04). CONCLUSIONS: In a large prospective cohort of older women, there was no association between coffee consumption and incident RA. A small association between daily caffeinated, nonherbal tea consumption and incident RA was found.


Assuntos
Artrite Reumatoide , Café , Comportamento de Ingestão de Líquido , Chá , Idoso , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/psicologia , Estudos de Coortes , Correlação de Dados , Feminino , Humanos , Incidência , Estudos Longitudinais , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia , Saúde da Mulher
15.
PLoS One ; 13(12): e0207509, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30513095

RESUMO

IMPORTANCE: Carpal tunnel syndrome (CTS) is a common and debilitating condition that commonly affects postmenopausal women. OBJECTIVE: To determine the effect of menopausal hormone therapy (HT) in healthy postmenopausal women on CTS risk. DESIGN: We conducted a secondary analysis of the Women's Health Initiative's (WHI) HT trials linked to Medicare claims data. Separate intention-to-treat analyses were performed for the two trials; the conjugated equine estrogens alone (CEE alone) and the trial of CEE plus medroxyprogesterone acetate (MPA) trial. (ClinicalTrials.gov, NCT number): NCT00000611. SETTING: Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers. PARTICIPANTS: The sample size included in the analysis was 16,053 community-dwelling women aged ≥65 years at study entry or those who later aged into Medicare eligibility, and who were enrolled in Medicare (including Part A and/or Part B coverage). INTERVENTION: Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E+P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14203). MAIN OUTCOME(S): The primary outcome was incident CTS and the secondary outcome was therapeutic CTS procedure occurring during the intervention phases of the trials. RESULTS: A total of 16,053 women were randomized in both trials. During mean follow up of 4.5 ± 2.8 years in the CEE trial (n = 6,833), there were 203 incident CTS cases in the intervention and 262 incident CTS cases in the placebo group (HR, 0.78; 95% CI, 0.65-0.94; P = 0.009). The CEE+MPA trial (n = 9,220) followed participants for a mean of 3.7 ± 2.3 years. There were 173 incident CTS cases in the intervention compared to 203 cases in the placebo group (HR, 0.80, 95% CI, 0.65-0.97; P = 0.027). CONCLUSIONS: These findings suggest a protective effect of menopausal HT on the incidence of CTS among postmenopausal women. A potential therapeutic role for other forms of estrogen therapy in the management of CTS warrants future research.


Assuntos
Síndrome do Túnel Carpal/epidemiologia , Terapia de Reposição Hormonal/estatística & dados numéricos , Pós-Menopausa/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Síndrome do Túnel Carpal/terapia , Método Duplo-Cego , Feminino , Humanos , Incidência , Pessoa de Meia-Idade
16.
Menopause ; 25(11): 1313-1320, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30358728

RESUMO

OBJECTIVE: Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen's influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women's Health Initiative randomized, placebo-controlled, clinical trial. METHODS: A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms. RESULTS: At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen's association with reduced joint pain but attenuate estrogen's association with increased joint swelling. CONCLUSIONS: The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.


Assuntos
Artralgia/tratamento farmacológico , Terapia de Reposição de Estrogênios , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios/administração & dosagem , Pós-Menopausa/fisiologia , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Histerectomia/efeitos adversos , Modelos Logísticos , Pessoa de Meia-Idade , Inquéritos e Questionários , Resultado do Tratamento , Saúde da Mulher
17.
Am J Epidemiol ; 187(10): 2126-2135, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29868784

RESUMO

The inconsistent findings from epidemiologic studies relating total sugars (TS) consumption to cardiovascular disease (CVD) or type 2 diabetes (T2D) risk may be partly due to measurement error in self-reported intake. Using regression calibration equations developed based on the predictive biomarker for TS and recovery biomarker for energy, we examined the association of TS with T2D and CVD risk, before and after dietary calibration, in 82,254 postmenopausal women participating in the Women's Health Initiative Observational Study. After up to 16 years of follow-up (1993-2010), 6,621 T2D and 5,802 CVD incident cases were identified. The hazard ratio for T2D per 20% increase in calibrated TS was 0.94 (95% confidence interval (CI): 0.77, 1.15) in multivariable energy substitution, and 1.00 (95% CI: 0.85, 1.18) in energy partition models. Multivariable hazard ratios for total CVD were 0.97 (95% CI: 0.87, 1.09) from energy substitution, and 0.91 (95% CI: 0.80, 1.04) from energy partition models. Uncalibrated TS generated a statistically significant inverse association with T2D and total CVD risk in multivariable energy substitution and energy partition models. The lack of conclusive findings from our calibrated analyses may be due to the low explanatory power of the calibration equations for TS, which could have led to incomplete deattenuation of the risk estimates.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Inquéritos sobre Dietas/estatística & dados numéricos , Dieta/efeitos adversos , Açúcares da Dieta/análise , Idoso , Biomarcadores/análise , Calibragem , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Inquéritos sobre Dietas/métodos , Ingestão de Energia , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Análise Multivariada , Pós-Menopausa , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Regressão , Medição de Risco , Estados Unidos/epidemiologia , Saúde da Mulher
18.
Int J Epidemiol ; 47(6): 1760-1771, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29901778

RESUMO

Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine-a nicotine metabolite and biomarker of recent tobacco exposure-provides additional information on lung cancer risk. Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis. Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32-1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68-0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64-0.68) (P = 1.5x10-9). Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.


Assuntos
Cotinina/sangue , Neoplasias Pulmonares/sangue , Fumar Tabaco/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Autorrelato
19.
Menopause ; 25(9): 985-991, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29738414

RESUMO

OBJECTIVE: Research on the relationships between different hormone therapy doses, formulation and routes of delivery, and subsequent breast cancer incidence has been limited. This study directly compared different estrogen doses, formulations, and route of delivery of estrogen alone among women with a hysterectomy in relation to invasive breast cancer incidence. METHODS: The Women's Health Initiative Observational Study is a large multicenter prospective cohort study conducted at 40 US sites. Analyses included 26,525 postmenopausal women with a hysterectomy, aged 50 to 79 years, at study entry, recruited between September, 1993 and December, 1998, with annual follow-up through September 12, 2005. RESULTS: Average follow-up was 8.2 years. For conjugated equine estrogen (CEE) users, no difference was observed between low-dose CEE (<0.625 mg) compared with conventional-dose CEE (0.625 mg) for breast cancer (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.65, 1.48)]. Compared with conventional-dose CEE, transdermal estrogen was associated with a nonsignificant lower risk of invasive breast cancer (HR 0.75, 95% CI 0.47, 1.19). The low prevalence of transdermal use likely limited power for this comparison, and for a comparison of oral estradiol to conventional-dose CEE (HR 1.20, 95% CI 0.84, 1.39). CONCLUSION: Our results indicate that invasive breast cancer risk did not differ appreciably in women with a hysterectomy using estrogen-alone when directly comparing different doses, formulations, and routes of delivery to the conventional oral CEE. These findings suggest that the lower breast cancer risk found in the WHI estrogen-alone trial may extend to lower doses of CEE. Additional research is needed to confirm these hypotheses.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios Conjugados (USP)/administração & dosagem , Estrogênios Conjugados (USP)/uso terapêutico , Estrogênios/administração & dosagem , Estrogênios/uso terapêutico , Administração Cutânea , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Histerectomia/efeitos adversos , Incidência , Pessoa de Meia-Idade , Invasividade Neoplásica , Pós-Menopausa , Modelos de Riscos Proporcionais , Estudos Prospectivos , Inquéritos e Questionários , Estados Unidos/epidemiologia
20.
J Natl Cancer Inst ; 110(1)2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922778

RESUMO

Background: Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown. Methods: Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models. Results: Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups. Conclusions: Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.


Assuntos
Ácido Fólico/sangue , Neoplasias Pulmonares/epidemiologia , Metionina/sangue , Vitamina B 6/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia/epidemiologia , Austrália/epidemiologia , Estudos de Casos e Controles , Cotinina/sangue , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Fumar/sangue , Fumar/epidemiologia , Estados Unidos/epidemiologia
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