Investigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction.

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health. Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts. Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters. Measurements and Main Results: The longitudinal study found that higher omega-3 fatty acid levels were associated with attenuated lung function decline in 15,063 participants, with the largest effect sizes for the most metabolically downstream omega-3 fatty acid, docosahexaenoic acid (DHA). An increase in DHA of 1% of total fatty acids was associated with attenuations of 1.4 ml/yr for FEV1 (95% confidence interval [CI], 1.1-1.8) and 2.0 ml/yr for FVC (95% CI, 1.6-2.4) and a 7% lower incidence of spirometry-defined airway obstruction (95% CI, 0.89-0.97). DHA associations persisted across sexes and smoking histories and in Black, White, and Hispanic participants, with associations of the largest magnitude in former smokers and Hispanic participants. The MR study showed similar trends toward positive associations of genetically predicted downstream omega-3 fatty acids with FEV1 and FVC. Conclusions: The longitudinal and MR studies provide evidence supporting beneficial effects of higher levels of downstream omega-3 fatty acids, especially DHA, on lung health.

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study.

AIMS: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). METHODS AND RESULTS: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. CONCLUSION: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors.

A systematic analysis of protein-altering exonic variants in chronic obstructive pulmonary disease.

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant (P < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B (GSDMB) splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, P = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 (CCHCR1), a gene involved in regulating cell proliferation, were associated with COPD (both P < 0.0001). The SERPINA1 Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults.

BACKGROUND: Arsenic is a common environmental toxin. Exposure to arsenic (particularly its inorganic form) through contaminated food and drinking water is an important public health burden worldwide, and is associated with increased risk of neurotoxicity, congenital anomalies, cancer, and adverse neurodevelopment in children. Arsenic is excreted following methylation reactions, which are mediated by folate. Provision of folate through folic acid supplements could facilitate arsenic methylation and excretion, thereby reducing arsenic toxicity. OBJECTIVES: To assess the effects of provision of folic acid (through fortified foods or supplements), alone or in combination with other nutrients, in lessening the burden of arsenic-related health outcomes and reducing arsenic toxicity in arsenic-exposed populations. SEARCH METHODS: In September 2020, we searched CENTRAL, MEDLINE, Embase, 10 other international databases, nine regional databases, and two trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing the provision of folic acid (at any dose or duration), alone or in combination with other nutrients or nutrient supplements, with no intervention, placebo, unfortified food, or the same nutrient or supplements without folic acid, in arsenic-exposed populations of all ages and genders. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included two RCTs with 822 adults exposed to arsenic-contaminated drinking water in Bangladesh. The RCTs compared 400 µg/d (FA400) or 800 µg/d (FA800) folic acid supplements, given for 12 or 24 weeks, with placebo. One RCT, a multi-armed trial, compared FA400 plus creatine (3 g/d) to creatine alone. We judged both RCTs at low risk of bias in all domains. Due to differences in co-intervention, arsenic exposure, and participants' nutritional status, we could not conduct meta-analyses, and therefore, provide a narrative description of the data. Neither RCT reported on cancer, all-cause mortality, neurocognitive function, or congenital anomalies. Folic acid supplements alone versus placebo Blood arsenic. In arsenic-exposed individuals, FA likely reduces blood arsenic concentrations compared to placebo (2 studies, 536 participants; moderate-certainty evidence). For folate-deficient and folate-replete participants who received arsenic-removal water filters as a co-intervention, FA800 reduced blood arsenic levels more than placebo (percentage change (%change) in geometric mean (GM) FA800 -17.8%, 95% confidence intervals (CI) -25.0 to -9.8; placebo GM -9.5%, 95% CI -16.5 to -1.8; 1 study, 406 participants). In one study with 130 participants with low baseline plasma folate, FA400 reduced total blood arsenic (%change FA400 mean (M) -13.62%, standard error (SE) ± 2.87; placebo M -2.49%, SE ± 3.25), and monomethylarsonic acid (MMA) concentrations (%change FA400 M -22.24%, SE ± 2.86; placebo M -1.24%, SE ± 3.59) more than placebo. Inorganic arsenic (InAs) concentrations reduced in both groups (%change FA400 M -18.54%, SE ± 3.60; placebo M -10.61%, SE ± 3.38). There was little to no change in dimethylarsinic acid (DMA) in either group. Urinary arsenic. In arsenic-exposed individuals, FA likely reduces the proportion of total urinary arsenic excreted as InAs (%InAs) and MMA (%MMA) and increases the proportion excreted as DMA (%DMA) to a greater extent than placebo (2 studies, 546 participants; moderate-certainty evidence), suggesting that FA enhances arsenic methylation. In a mixed folate-deficient and folate-replete population (1 study, 352 participants) receiving arsenic-removal water filters as a co-intervention, groups receiving FA had a greater decrease in %InAs (within-person change FA400 M -0.09%, 95% CI -0.17 to -0.01; FA800 M -0.14%, 95% CI -0.21 to -0.06; placebo M 0.05%, 95% CI 0.00 to 0.10), a greater decrease in %MMA (within-person change FA400 M -1.80%, 95% CI -2.53 to -1.07; FA800 M -2.60%, 95% CI -3.35 to -1.85; placebo M 0.15%, 95% CI -0.37 to 0.68), and a greater increase in %DMA (within-person change FA400 M 3.25%, 95% CI 1.81 to 4.68; FA800 M 4.57%, 95% CI 3.20 to 5.95; placebo M -1.17%, 95% CI -2.18 to -0.17), compared to placebo. In 194 participants with low baseline plasma folate, FA reduced %InAs (%change FA400 M -0.31%, SE ± 0.04; placebo M -0.13%, SE ± 0.04) and %MMA (%change FA400 M -2.6%, SE ± 0.37; placebo M -0.71%, SE ± 0.43), and increased %DMA (%change FA400 M 5.9%, SE ± 0.82; placebo M 2.14%, SE ± 0.71), more than placebo. Plasma homocysteine: In arsenic-exposed individuals, FA400 likely reduces homocysteine concentrations to a greater extent than placebo (2 studies, 448 participants; moderate-certainty evidence), in the mixed folate-deficient and folate-replete population receiving arsenic-removal water filters as a co-intervention (%change in GM FA400 -23.4%, 95% CI -27.1 to -19.5; placebo -1.3%, 95% CI -5.3 to 3.1; 1 study, 254 participants), and participants with low baseline plasma folate (within-person change FA400 M -3.06 µmol/L, SE ± 3.51; placebo M -0.05 µmol/L, SE ± 4.31; 1 study, 194 participants). FA supplements plus other nutrient supplements versus nutrient supplements alone In arsenic-exposed individuals who received arsenic-removal water filters as a co-intervention, FA400 plus creatine may reduce blood arsenic concentrations more than creatine alone (%change in GM FA400 + creatine -14%, 95% CI -22.2 to -5.0; creatine -7.0%, 95% CI -14.8 to 1.5; 1 study, 204 participants; low-certainty evidence); may not change urinary arsenic methylation indices (FA400 + creatine: %InAs M 13.2%, SE ± 7.0; %MMA M 10.8, SE ± 4.1; %DMA M 76, SE ± 7.8; creatine: %InAs M 14.8, SE ± 5.5; %MMA M 12.8, SE ± 4.0; %DMA M 72.4, SE ±7.6; 1 study, 190 participants; low-certainty evidence); and may reduce homocysteine concentrations to a greater extent (%change in GM FA400 + creatinine -21%, 95% CI -25.2 to -16.4; creatine -4.3%, 95% CI -9.0 to 0.7; 1 study, 204 participants; low-certainty evidence) than creatine alone. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that FA supplements may benefit blood arsenic concentration, urinary arsenic methylation profiles, and plasma homocysteine concentration versus placebo. There is low-certainty evidence that FA supplements plus other nutrients may benefit blood arsenic and plasma homocysteine concentrations versus nutrients alone. No studies reported on cancer, all-cause mortality, neurocognitive function, or congenital anomalies. Given the limited number of RCTs, more studies conducted in diverse settings are needed to assess the effects of FA on arsenic-related health outcomes and arsenic toxicity in arsenic-exposed adults and children.

Associations of diet, physical activity and polycystic ovary syndrome in the Coronary Artery Risk Development in Young Adults Women's Study.

BACKGROUND: Current evidence supports the adoption of healthy diet and physical activity (PA) behaviors in patients with polycystic ovary syndrome (PCOS), given the positive effects of those behaviors on physical well-being. An improved understanding of the associations between diet and PA with PCOS is needed to ascertain whether tailored dietary and PA recommendations are needed for this population. Thus, we investigated the associations of diet and PA with PCOS and its isolated features. METHODS: Cross-sectional study. Of the 748 women who were included in this study from the Coronary Artery Risk Development in Young Adults (CARDIA) Women's Study, 40 were classified as having PCOS, 104 had isolated hyperandrogenism (HA) and 75 had isolated oligomenorrhea (OA). Dietary intake was measured using the CARDIA diet history questionnaire and diet quality was scored using the Alternative Healthy Eating Index 2010; a higher score indicated a better quality diet. Self-reported PA was measured using a validated interviewer-administered questionnaire. Polytomous logistic regression analyses examined the associations between diet and PA with PCOS, HA, and OA status (outcomes), adjusting for age, race, total energy intake, education, and/or body mass index. The threshold for statistical significance was set at p < 0.05. RESULTS: Mean age of the participants was 25.4 years (SD 3.6) and 46.8% of participants were Black women. There was little to no association of total energy intake, nutrients, diet quality, and PA with PCOS, HA or OA status. CONCLUSION: Energy intake, nutrient composition, diet quality, and PA were not associated with PCOS, supporting recent PCOS guidelines of using national recommendations for the general population to encourage health-promoting behaviors among women with PCOS. However, longitudinal studies evaluating changes in diet and physical activity in relation to the development and/or the progression of PCOS are needed to establish a causal association.

Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults.

Importance: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. Objective: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). Exposures: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. Main Outcomes and Measures: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)-related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. Results: Among all participants (mean [SD] age, 53.2 [15.8] years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio [PR], 1.68 [95% CI, 1.55-1.82]), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 [95% CI, 1.72-2.82]), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 [95% CI, 1.01-1.13]), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 [95% CI, 1.22-1.45]). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years [95% CI, 10.0-13.1]; adjusted hazard ratio [HR], 1.50 [95% CI, 1.42-1.59]), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years [95% CI, 0.7-1.6]; adjusted HR, 1.95 [95% CI, 1.54-2.48]), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years [95% CI, 2.1-3.4]; adjusted HR, 1.55 [95% CI, 1.36-1.77]), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years [95% CI, 4.9-7.5]; adjusted HR, 1.90 [95% CI, 1.69-2.14]), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years [95% CI, 3.7-5.8]; adjusted HR, 1.30 [95% CI, 1.18-1.42]). Conclusions and Relevance: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.

A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline.

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

Albuminuria, Lung Function Decline, and Risk of Incident Chronic Obstructive Pulmonary Disease. The NHLBI Pooled Cohorts Study.

RATIONALE: Chronic lower respiratory diseases (CLRDs), including chronic obstructive pulmonary disease (COPD) and asthma, are the fourth leading cause of death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in patients with COPD. OBJECTIVES: To test whether albuminuria was associated with lung function decline and incident CLRDs. METHODS: Six U.S. population-based cohorts were harmonized and pooled. Participants with prevalent clinical lung disease were excluded. Albuminuria (urine albumin-to-creatinine ratio) was measured in spot samples. Lung function was assessed by spirometry. Incident CLRD-related hospitalizations and deaths were classified via adjudication and/or administrative criteria. Mixed and proportional hazards models were used to test individual-level associations adjusted for age, height, weight, sex, race/ethnicity, education, birth year, cohort, smoking status, pack-years of smoking, renal function, hypertension, diabetes, and medications. MEASUREMENTS AND MAIN RESULTS: Among 10,961 participants with preserved lung function, mean age at albuminuria measurement was 60 years, 51% were never-smokers, median albuminuria was 5.6 mg/g, and mean FEV1 decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV1 decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV1/FVC decline (95% CI, 4.43-17.62%; P = 0.0011), and 15% increased hazard of incident spirometry-defined moderate-to-severe COPD (95% CI, 2-31%, P = 0.0021). Each SD log-transformed albuminuria increased hazards of incident COPD-related hospitalization/mortality by 26% (95% CI, 18-34%, P < 0.0001) among 14,213 participants followed for events. Asthma events were not significantly associated. Associations persisted in participants without current smoking, diabetes, hypertension, or cardiovascular disease. CONCLUSIONS: Albuminuria was associated with greater lung function decline, incident spirometry-defined COPD, and incident COPD-related events in a U.S. population-based sample.

Omega-3 Fatty Acids and Genome-Wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.

RATIONALE: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. METHODS: Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs. RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; ßSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; ßSNP×DHA interaction = 36.2 ml). CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults.

Metabolomic markers associated with incident central adiposity gain were investigated in young adults. In a 9-mo prospective study of university freshmen (n = 264). Blood samples and anthropometry measurements were collected in the first 3 d on campus and at the end of the year. Plasma from individuals was pooled by phenotype [incident central adiposity, stable adiposity, baseline hemoglobin A1c (HbA1c) > 5.05%, HbA1c < 4.92%] and assayed using GC-MS, chromatograms were analyzed using MetaboliteDetector software, and normalized metabolite levels were compared using Welch's t test. Assays were repeated using freshly prepared pools, and statistically significant metabolites were quantified in a targeted GC-MS approach. Isotope tracer studies were performed to determine if the potential marker was an endogenous human metabolite in men and in whole blood. Participants with incident central adiposity gain had statistically significantly higher blood erythritol [P < 0.001, false discovery rate (FDR) = 0.0435], and the targeted assay revealed 15-fold [95% confidence interval (CI): 13.27, 16.25] higher blood erythritol compared with participants with stable adiposity. Participants with baseline HbA1c > 5.05% had 21-fold (95% CI: 19.84, 21.41) higher blood erythritol compared with participants with lower HbA1c (P < 0.001, FDR = 0.00016). Erythritol was shown to be synthesized endogenously from glucose via the pentose-phosphate pathway (PPP) in stable isotope-assisted ex vivo blood incubation experiments and through in vivo conversion of erythritol to erythronate in stable isotope-assisted dried blood spot experiments. Therefore, endogenous production of erythritol from glucose may contribute to the association between erythritol and obesity observed in young adults.

Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality.

Importance: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial. Objective: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality. Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016. Exposures: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN). Main Outcomes and Measures: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach. Results: Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54%] women; 16 794 [69%] non-Hispanic white; 15 181 [63%] ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models. Conclusions and Relevance: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study.

Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD.

Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

Stress and psychological constructs related to eating behavior are associated with anthropometry and body composition in young adults.

BACKGROUND: The transition to college is associated with weight gain, but the relation between eating behavior indicators and anthropometric outcomes during this period remains unclear. OBJECTIVE: We aimed to evaluate sex differences in stress, emotional eating, tendency to overeat, and restrained eating behavior, and determine whether the psycho-behavioral constructs assessed immediately prior to starting college are associated with anthropometry and adiposity at the start of college, and with first-semester weight gain. METHODS: A prospective study administered the Three Factor Eating Questionnaire (TFEQ), Satter Eating Competence Inventory, and Perceived Stress Scale (PSS) to 264 participants one month before college. Body composition was assessed via dual energy X-ray absorptiometry (DXA) at the start of college, and anthropometry (weight, height, waist circumference [WC]) was collected at the beginning and end of the first semester. Ordinary least squares regression tested the cross-sectional association of baseline psychological and behavioral scales with baseline DXA and anthropometry, and the longitudinal association with change in anthropometry. RESULTS: Among 264 participants, 91% (241) had baseline data, and 66% (173) completed follow-up. In sex-adjusted linear regression models, baseline TFEQ disinhibited and emotional (DE; EE) eating sub-scales were positively associated with baseline weight (P = 0.003; DE, P = 0.014; EE), body mass index (BMI, P = 0.002; DE, P = 0.001; EE), WC (P = 0.004; DE, P = 0.006; EE) and DXA fat mass index (P = 0.023; DE, P = 0.014; EE). Baseline PSS was positively associated with subsequent changes in weight and WC among males only (Pinteraction = 0.0268 and 0.0017 for weight and WC, respectively). CONCLUSION: College freshmen with questionnaire scores indicating a greater tendency to overeat in response to external cues and emotions tended to have greater weight, BMI, and WC at the start of college. Males with higher perceived stress at college entrance subsequently gained significantly more weight in the first semester, but no such relation was evident in females.

Integrative pathway genomics of lung function and airflow obstruction.

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

College-Aged Males Experience Attenuated Sweet and Salty Taste with Modest Weight Gain.

Background: Human and animal studies report a blunted sense of taste in people who are overweight or obese, with heightened sensitivity also reported after weight loss. However, it is unknown if taste changes concurrently with weight gain.Objective: This study investigated the association of weight gain with changes in suprathreshold taste intensity perception in a free-living population of young adults.Methods: Taste response, anthropometric measures, and diet changes were assessed with a longitudinal study design in first-year college students 3 times throughout the academic year. At baseline, 93 participants (30 males, 63 females) were an average of 18 y old, with a body mass index (in kg/m2) of 21.9. Sweet, umami, salty, sour, and bitter taste intensities were evaluated at 3 concentrations by using the general Labeled Magnitude Scale. Ordinary least-squares regression models assessed the association of weight gain and within-person taste change, adjusting for sex, race, and diet changes.Results: Participants gained an average of 3.9% in weight, ranging from -5.7% to +13.8%. With each 1% increase in body weight, males perceived sweet and salty as less intense, with taste responses decreasing by 11.0% (95% CI: -18.9%, -2.3%; P = 0.015) and 7.5% (95% CI: -13.1%, -1.5%; P = 0.015) from baseline, respectively. Meanwhile, females did not experience this decrement, and even perceived a 6.5% increase (95% CI: 2.6%, 10.5%; P = 0.007) in sour taste with similar amounts of weight gain. Changes in the consumption of meat and other umami-rich foods also negatively correlated with umami taste response (-39.1%; 95% CI: -56.3%, -15.0%; P = 0.004).Conclusions: A modest weight gain is associated with concurrent taste changes in the first year of college, especially in males who experience a decrement in sweet and salty taste. This suggests that young-adult males may be susceptible to taste loss when gaining weight.

Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study.

BACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults. METHODS: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts. RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09). CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

A randomized controlled trial of vitamin E and selenium on rate of decline in lung function.

BACKGROUND: The intake of nutrients with antioxidant properties is hypothesized to augment antioxidant defenses, decrease oxidant damage to tissues, and attenuate age-related rate of decline in lung function. The objective was to determine whether long-term intervention with selenium and/or vitamin E supplements attenuates the annual rate of decline in lung function, particularly in cigarette smokers. METHODS: The Respiratory Ancillary Study (RAS) tested the single and joint effects of selenium (200 µg/d L-selenomethionine) and vitamin E (400 IU/day all rac-α-tocopheryl acetate) in a randomized double-blind placebo-controlled trial. At the end of the intervention, 1,641 men had repeated pulmonary function tests separated by an average of 3 years. Linear mixed-effects regression models estimated the effect of intervention on annual rate of decline in lung function. RESULTS: Compared to placebo, intervention had no main effect on either forced expiratory volume in the first second (FEV1) or forced expiratory flow (FEF25-75). There was no evidence for a smoking by treatment interaction for FEV1, but selenium attenuated rate of decline in FEF25-75 in current smokers (P = 0.0219). For current smokers randomized to selenium, annual rate of decline in FEF25-75 was similar to the annual decline experienced by never smokers randomized to placebo, with consistent effects for selenium alone and combined with vitamin E. CONCLUSIONS: Among all men, there was no effect of selenium and/or vitamin E supplementation on rate of lung function decline. However, current smokers randomized to selenium had an attenuated rate of decline in FEF25-75, a marker of airflow. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00241865 .

Genetic and environmental factors are associated with serum 25-hydroxyvitamin D concentrations in older African Americans.

BACKGROUND: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. OBJECTIVE: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. METHODS: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. RESULTS: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-µg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. CONCLUSIONS: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.

Exploiting meta-analysis of genome-wide interaction with serum 25-hydroxyvitamin D to identify novel genetic loci associated with pulmonary function.

BACKGROUND: Higher 25-hydroxyvitamin D (25(OH)D) concentrations in serum has a positive association with pulmonary function. Investigating genome-wide interactions with 25(OH)D may reveal new biological insights into pulmonary function. OBJECTIVES: We aimed to identify novel genetic variants associated with pulmonary function by accounting for 25(OH)D interactions. METHODS: We included 211,264 participants from the observational United Kingdom Biobank study with pulmonary function tests (PFTs), genome-wide genotypes, and 25(OH)D concentrations from 4 ancestral backgrounds-European, African, East Asian, and South Asian. Among PFTs, we focused on forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) because both were previously associated with 25(OH)D. We performed genome-wide association study (GWAS) analyses that accounted for variant×25(OH)D interaction using the joint 2 degree-of-freedom (2df) method, stratified by participants' smoking history and ancestry, and meta-analyzed results. We evaluated interaction effects to determine how variant-PFT associations were modified by 25(OH)D concentrations and conducted pathway enrichment analysis to examine the biological relevance of our findings. RESULTS: Our GWAS meta-analyses, accounting for interaction with 25(OH)D, revealed 30 genetic variants significantly associated with FEV1 or FVC (P2df <5.00×10-8) that were not previously reported for PFT-related traits. These novel variant signals were enriched in lung function-relevant pathways, including the p38 MAPK pathway. Among variants with genome-wide-significant 2df results, smoking-stratified meta-analyses identified 5 variants with 25(OH)D interactions that influenced FEV1 in both smoking groups (never smokers P1df interaction<2.65×10-4; ever smokers P1df interaction<1.71×10-5); rs3130553, rs2894186, rs79277477, and rs3130929 associations were only evident in never smokers, and the rs4678408 association was only found in ever smokers. CONCLUSION: Genetic variant associations with lung function can be modified by 25(OH)D, and smoking history can further modify variant×25(OH)D interactions. These results expand the known genetic architecture of pulmonary function and add evidence that gene-environment interactions, including with 25(OH)D and smoking, influence lung function.