Patricia A. Cassano

Body fat distribution, blood pressure, and hypertension: A prospective cohort study of men in the normative aging study☆

The relation between the abdominal accumulation of body fat, blood pressure, and hypertension was assessed prospectively among 1972 male participants in the Veterans Administration Normative Aging Study. Body mass index (BMI = weight [kg]/height [m]2) and the ratio of abdominal circumference to hip breadth (AC/HB), measured at regular exams, were used as indices of total adiposity and body fat distribution, respectively. Considering blood pressure as a continuous outcome variable (in models that allowed for intraclass correlation), the AC/HB ratio was significantly positively associated with both diastolic and systolic blood pressure (P < 0.001), adjusting for age and BMI. Blood pressure was dichotomized and hypertension risk was assessed using the proportional hazards model, adjusting for age and BMI. Seven hundred cases of hypertension were recorded by study physicians during 35,496 person-years of follow-up. The risk of hypertension increased approximately three-fold (95% confidence interval, 1.7 to 5.2) with a change of one unit in the AC/HB ratio. These estimates were little changed when the effects of smoking and alcohol intake were considered. Thus, the abdominal accumulation of body fat, apart from overall level of adiposity, was associated with both increased blood pressure and an increased risk of hypertension.

Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction

RATIONALE Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. OBJECTIVES Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. METHODS Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations. MEASUREMENTS AND MAIN RESULTS The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis. CONCLUSIONS These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

Antioxidants, oxidative stress, and pulmonary function in individuals diagnosed with asthma or COPD.

Objective:The objective of this study was to investigate the association between antioxidant nutrients and markers of oxidative stress with pulmonary function in persons with chronic airflow limitation.Design:Cross-sectional study exploring the association of antioxidant nutrients and markers of oxidative stress with forced expiratory volume in the first second (FEV1%) and forced vital capacity (FVC%).Setting/Subjects:The study data included 218 persons with chronic airflow limitation recruited randomly from the general population of Erie and Niagara counties, New York State, USA.Results:After adjustment for covariates, multiple linear regression analysis showed that serum β-cryptoxanthin, lutein/zeaxanthin, and retinol, and dietary β-carotene, β-cryptoxanthin, lutein/zeaxanthin, vitamin C, and lycopene were positively associated with FEV1% (P<0.05, all associations). Serum vitamins β-cryptoxanthin, lutein/zeaxanthin, and lycopene, and dietary β-cryptoxanthin, β-carotene, vitamin C, and lutein/zeaxanthin were positively associated with FVC% (P<0.05, all associations). Erythrocytic glutathione was negatively associated with FEV1%, while plasma thiobarbituric acid-reactive substances (TBARS) were negatively associated with FVC% (P<0.05).Conclusion:These results support the hypothesis that an imbalance in antioxidant/oxidant status is associated with chronic airflow limitation, and that dietary habits and/or oxidative stress play contributing roles.

Cardiac autonomic dysfunction: effects from particulate air pollution and protection by dietary methyl nutrients and metabolic polymorphisms.

Background— Particulate air pollution is associated with cardiovascular mortality and morbidity. To help identify mechanisms of action and protective/susceptibility factors, we evaluated whether the effect of particulate matter <2.5 &mgr;m in aerodynamic diameter (PM2.5) on heart rate variability was modified by dietary intakes of methyl nutrients (folate, vitamins B6 and B12, methionine) and related gene polymorphisms (C677T methylenetetrahydrofolate reductase [MTHFR] and C1420T cytoplasmic serine hydroxymethyltransferase [cSHMT]). Methods and Results— Heart rate variability and dietary data were obtained between 2000 and 2005 from 549 elderly men from the Normative Aging Study. In carriers of [CT/TT] MTHFR genotypes, the SD of normal-to-normal intervals was 17.1% (95% CI, 6.5 to 26.4; P=0.002) lower than in CC MTHFR subjects. In the same [CT/TT] MTHFR subjects, each 10-&mgr;g/m3 increase in PM2.5 in the 48 hours before the examination was associated with a further 8.8% (95% CI, 0.2 to 16.7; P=0.047) decrease in the SDNN. In [CC] cSHMT carriers, PM2.5 was associated with an 11.8% (95% CI, 1.8 to 20.8; P=0.02) decrease in SDNN. No PM2.5-SSDN association was found in subjects with either [CC] MTHFR or [CT/TT] cSHMT genotypes. The negative effects of PM2.5 were abrogated in subjects with higher intakes (above median levels) of B6, B12, or methionine. PM2.5 was negatively associated with heart rate variability in subjects with lower intakes, but no PM2.5 effect was found in the higher intake groups. Conclusion— Genetic and nutritional variations in the methionine cycle affect heart rate variability either independently or by modifying the effects of PM2.5.

A multivariate analysis of serum nutrient levels and lung function

BackgroundThere is mounting evidence that estimates of intakes of a range of dietary nutrients are related to both lung function level and rate of decline, but far less evidence on the relation between lung function and objective measures of serum levels of individual nutrients. The aim of this study was to conduct a comprehensive examination of the independent associations of a wide range of serum markers of nutritional status with lung function, measured as the one-second forced expiratory volume (FEV1).MethodsUsing data from the Third National Health and Nutrition Examination Survey, a US population-based cross-sectional study, we investigated the relation between 21 serum markers of potentially relevant nutrients and FEV1, with adjustment for potential confounding factors. Systematic approaches were used to guide the analysis.ResultsIn a mutually adjusted model, higher serum levels of antioxidant vitamins (vitamin A, beta-cryptoxanthin, vitamin C, vitamin E), selenium, normalized calcium, chloride, and iron were independently associated with higher levels of FEV1. Higher concentrations of potassium and sodium were associated with lower FEV1.ConclusionMaintaining higher serum concentrations of dietary antioxidant vitamins and selenium is potentially beneficial to lung health. In addition other novel associations found in this study merit further investigation.

The relation between dietary intake of individual fatty acids, FEV1 and respiratory disease in Dutch adults

Background: A reduced dietary intake of n-3 fatty acids, in association with increased n-6 fatty acid intake, has been proposed as a potential aetiological factor for chronic obstructive pulmonary disease (COPD) and asthma. However, the relative importance of individual fatty acids within the n-3 and n-6 categories on this effect has not been widely investigated. We have studied the relation between individual fatty acid intakes, lung function and self-reported respiratory symptoms and diagnoses in a representative sample of more than 13 000 Dutch adults. Methods: Intake of individual fatty acids was estimated by a food frequency questionnaire and analysed in relation to measures of forced expiratory volume in 1 s (FEV1) and to questionnaire reported wheeze, asthma and COPD symptoms. Results: After adjusting for confounding, we found no protective association between individual n-3 fatty acid intakes and FEV1. Higher intakes of some n-6 fatty acids were associated with lower FEV1, this effect being most marked for c22:4 n-6 docosatetraenoic acid (reduction in FEV1 between the highest and lowest quintile of intake 54.5 ml (95% CI −81.6 to −27.4)). Most of the n-6 fatty acid effects interacted significantly with smoking, their effects being strongest in current smokers. Individual n-3 fatty acid intakes were generally associated with a higher risk of wheeze in the past year, but otherwise there was little or no association between fatty acid intake and wheeze, doctor diagnosed asthma or other respiratory symptoms. Conclusions: A high intake of n-3 fatty acids does not appear to protect against COPD or asthma, but a high intake of several n-6 fatty acids is associated with a significant reduction in FEV1, particularly in smokers. These findings indicate that high dietary intake of n-6 fatty acids, rather than reduced n-3 intake, may have an adverse effect on lung health.

Genetic variation and gene expression in antioxidant related enzymes and risk of COPD: a systematic review

Background: Observational epidemiological studies of dietary antioxidant intake, serum antioxidant concentration and lung outcomes suggest that lower levels of antioxidant defences are associated with decreased lung function. Another approach to understanding the role of oxidant/antioxidant imbalance in the risk of chronic obstructive pulmonary disease (COPD) is to investigate the role of genetic variation in antioxidant enzymes, and indeed family based studies suggest a heritable component to lung disease. Many studies of the genes encoding antioxidant enzymes have considered COPD or COPD related outcomes, and a systematic review is needed to summarise the evidence to date, and to provide insights for further research. Methods: Genetic association studies of antioxidant enzymes and COPD/COPD related traits, and comparative gene expression studies with disease or smoking as the exposure were systematically identified and reviewed. Antioxidant enzymes considered included enzymes involved in glutathione metabolism, in the thioredoxin system, superoxide dismutases (SOD) and catalase. Results: A total of 29 genetic association and 15 comparative gene expression studies met the inclusion criteria. The strongest and most consistent effects were in the genes GCL, GSTM1, GSTP1 and SOD3. This review also highlights the lack of studies for genes of interest, particularly GSR, GGT and those related to TXN. There were limited opportunities to evaluate the contribution of a gene to disease risk through synthesis of results from different study designs, as the majority of studies considered either association of sequence variants with disease or effect of disease on gene expression. Conclusion: Network driven approaches that consider potential interaction between and among genes, smoke exposure and antioxidant intake are needed to fully characterise the role of oxidant/antioxidant balance in pathogenesis.

Patterns of dietary intake and relation to respiratory disease, forced expiratory volume in 1 s, and decline in 5-y forced expiratory volume

BACKGROUND The independent effect of individual foods on the risk of respiratory disease is difficult to establish because intakes of specific foods are generally strongly correlated. To date, few studies have examined the relation between dietary food patterns and forced expiratory volume in 1 s (FEV(1)) or respiratory symptoms. OBJECTIVE The objective was to investigate the relation between dietary patterns and FEV(1), FEV(1) decline, and respiratory health in a general population sample. DESIGN Data were collected from the cross-sectional study in 12,648 adults from the Netherlands [MORGEN-EPIC (Monitoring Project on Risk Factors and Chronic Diseases in the Netherlands-European Prospective Investigation into Cancer and Nutrition)]. Principal components analysis was used to derive dietary patterns, and multivariate regression analyses were conducted to investigate these patterns with FEV(1) or respiratory health. We also investigated these dietary patterns in relation to lung function decline over 5 y in a subpopulation. RESULTS A more traditional diet (high intake of meat and potatoes and lower intake of soy and cereal) was associated with a lower FEV(1) (fifth compared with first quintile: -94.4 mL; 95% CI: -123.4, -65.5 mL; P for trend < 0.001) and a higher prevalence of chronic obstructive pulmonary disease. An increased trend through quintiles was seen with a cosmopolitan diet (higher intakes of vegetables, fish, and chicken) for asthma and wheeze. CONCLUSIONS The results suggest that a traditional diet has adverse effects on lung function and chronic obstructive pulmonary disease and that a more cosmopolitan diet was associated with increased risk of wheeze and asthma. However, none of the dietary patterns appear to be related to lung function decline.

Evaluating brief measures of fruit and vegetable consumption frequency and variety : Cognition, interpretation, and other measurement issues

To evaluate whether items from 3 brief measures of fruit and vegetable consumption were understood and interpreted as intended, cognitive testing was conducted in a purposive sample of 31 white, African-American and Hispanic persons. The measurement instruments tested were the fruit and vegetable module from the Behavioral Risk Factor Surveillance System (to measure frequency), and 1 fruit and 1 vegetable variety measurement instrument developed by the investigators. The cognitive testing interviews were analyzed qualitatively to identify interpretation difficulties and other measurement issues. The testing identified a number of measurement issues, including issues related to time frame, wording, interpretation, grouping of items, and serving size. Recommendations based on the findings were incorporated into revised versions of each instrument, which were further tested in a small sample. As revised and presented in this article, these instruments for assessing fruit and vegetable frequency and variety appear to be understood and interpreted as intended across different racial and ethnic groups, and may be useful in situations requiring brief dietary assessment, although further testing is needed.

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Background Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.