TY - JOUR T1 - Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study. JF - Am J Epidemiol Y1 - 2018 A1 - Oelsner, Elizabeth C A1 - Balte, Pallavi P A1 - Cassano, Patricia A A1 - Couper, David A1 - Enright, Paul L A1 - Folsom, Aaron R A1 - Hankinson, John A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kaplan, Robert A1 - Kronmal, Richard A1 - Lange, Leslie A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Navas Acien, Ana A1 - Newman, Anne B A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Smith, Lewis J A1 - Yeh, Fawn A1 - Zhang, Yiyi A1 - Moran, Andrew E A1 - Mwasongwe, Stanford A1 - White, Wendy B A1 - Yende, Sachin A1 - Barr, R Graham AB -

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.

VL - 187 IS - 11 ER - TY - JOUR T1 - 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. JF - Br J Nutr Y1 - 2018 A1 - Xu, Jiayi A1 - Bartz, Traci M A1 - Chittoor, Geetha A1 - Eiriksdottir, Gudny A1 - Manichaikul, Ani W A1 - Sun, Fangui A1 - Terzikhan, Natalie A1 - Zhou, Xia A1 - Booth, Sarah L A1 - Brusselle, Guy G A1 - de Boer, Ian H A1 - Fornage, Myriam A1 - Frazier-Wood, Alexis C A1 - Graff, Mariaelisa A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Hou, Ruixue A1 - Houston, Denise K A1 - Jacobs, David R A1 - Kritchevsky, Stephen B A1 - Latourelle, Jeanne A1 - Lemaitre, Rozenn N A1 - Lutsey, Pamela L A1 - O'Connor, George A1 - Oelsner, Elizabeth C A1 - Pankow, James S A1 - Psaty, Bruce M A1 - Rohde, Rebecca R A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Lewis J A1 - Stricker, Bruno H A1 - Voruganti, V Saroja A1 - Wang, Thomas J A1 - Zillikens, M Carola A1 - Barr, R Graham A1 - Dupuis, Josée A1 - Gharib, Sina A A1 - Lahousse, Lies A1 - London, Stephanie J A1 - North, Kari E A1 - Smith, Albert V A1 - Steffen, Lyn M A1 - Hancock, Dana B A1 - Cassano, Patricia A AB -

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.

ER - TY - JOUR T1 - Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association. JF - Am J Respir Crit Care Med Y1 - 2018 A1 - Xu, Jiayi A1 - Gaddis, Nathan C A1 - Bartz, Traci M A1 - Hou, Ruixue A1 - Manichaikul, Ani W A1 - Pankratz, Nathan A1 - Smith, Albert V A1 - Sun, Fangui A1 - Terzikhan, Natalie A1 - Markunas, Christina A A1 - Patchen, Bonnie K A1 - Schu, Matthew A1 - Beydoun, May A A1 - Brusselle, Guy G A1 - Eiriksdottir, Gudny A1 - Zhou, Xia A1 - Wood, Alexis C A1 - Graff, Mariaelisa A1 - Harris, Tamara B A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Launer, Lenore J A1 - Lemaitre, Rozenn N A1 - O'Connor, George A1 - Oelsner, Elizabeth C A1 - Psaty, Bruce M A1 - Ramachandran, Vasan S A1 - Rohde, Rebecca R A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Smith, Lewis J A1 - Tiemeier, Henning A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - Voruganti, V Saroja A1 - Xu, Hanfei A1 - Zilhão, Nuno R A1 - Fornage, Myriam A1 - Zillikens, M Carola A1 - London, Stephanie J A1 - Barr, R Graham A1 - Dupuis, Josée A1 - Gharib, Sina A A1 - Gudnason, Vilmundur A1 - Lahousse, Lies A1 - North, Kari E A1 - Steffen, Lyn M A1 - Cassano, Patricia A A1 - Hancock, Dana B AB -

RATIONALE: Omega-3 poly-unsaturated 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 (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/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 single nucleotide polymorphism (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 (P=9.4×10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80%) was associated with lower FVC (P=2.1×10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1×10; β=36.2mL).

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.

ER - TY - JOUR T1 - Albuminuria, Lung Function Decline, and Risk of Incident Chronic Obstructive Pulmonary Disease. The NHLBI Pooled Cohorts Study. JF - Am J Respir Crit Care Med Y1 - 2019 A1 - Oelsner, Elizabeth C A1 - Balte, Pallavi P A1 - Grams, Morgan E A1 - Cassano, Patricia A A1 - Jacobs, David R A1 - Barr, R Graham A1 - Burkart, Kristin M A1 - Kalhan, Ravi A1 - Kronmal, Richard A1 - Loehr, Laura R A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Shlipak, Michael A1 - Tracy, Russell P A1 - Tsai, Michael Y A1 - White, Wendy A1 - Yende, Sachin AB -

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 FEV decline was 31.5 ml/yr. For each SD increase in log-transformed albuminuria, there was 2.81% greater FEV decline (95% confidence interval [CI], 0.86-4.76%; P = 0.0047), 11.02% greater FEV/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.

VL - 199 IS - 3 ER - TY - JOUR T1 - Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality. JF - JAMA Y1 - 2019 A1 - Bhatt, Surya P A1 - Balte, Pallavi P A1 - Schwartz, Joseph E A1 - Cassano, Patricia A A1 - Couper, David A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - O'Connor, George T A1 - Yende, Sachin A1 - Sanders, Jason L A1 - Umans, Jason G A1 - Dransfield, Mark T A1 - Chaves, Paulo H A1 - White, Wendy B A1 - Oelsner, Elizabeth C KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Female KW - Forced Expiratory Volume KW - Hospitalization KW - Humans KW - Male KW - Middle Aged KW - Prognosis KW - Proportional Hazards Models KW - Pulmonary Disease, Chronic Obstructive KW - Risk Assessment KW - Vital Capacity AB -

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.

VL - 321 IS - 24 ER - TY - JOUR T1 - Association of Nonobstructive Chronic Bronchitis With Respiratory Health Outcomes in Adults. JF - JAMA Intern Med Y1 - 2020 A1 - Balte, Pallavi P A1 - Chaves, Paulo H M A1 - Couper, David J A1 - Enright, Paul A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kronmal, Richard A A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Newman, Anne B A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Smith, Benjamin M A1 - Smith, Lewis J A1 - White, Wendy B A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Asthma KW - Bronchitis, Chronic KW - Female KW - Humans KW - Lung KW - Male KW - Middle Aged KW - Prospective Studies KW - Respiratory Function Tests KW - Smokers KW - Smoking KW - Young Adult AB -

Importance: Chronic bronchitis has been associated with cigarette smoking as well as with e-cigarette use among young adults, but the association of chronic bronchitis in persons without airflow obstruction or clinical asthma, described as nonobstructive chronic bronchitis, with respiratory health outcomes remains uncertain.

Objective: To assess whether nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes in adult ever smokers and never smokers.

Design, Setting, and Participants: This prospective cohort study included 22 325 adults without initial airflow obstruction (defined as the ratio of forced expiratory volume in the first second [FEV1] to forced vital capacity [FVC] of <0.70) or clinical asthma at baseline. The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 9 US general population-based cohorts. Thus present study is based on data from 5 of these cohorts. Participants were enrolled from August 1971 through May 2007 and were followed up through December 2018.

Exposures: Nonobstructive chronic bronchitis was defined by questionnaire at baseline as both cough and phlegm for at least 3 months for at least 2 consecutive years.

Main Outcomes and Measures: Lung function was measured by prebronchodilator spirometry. Hospitalizations and deaths due to chronic lower respiratory disease and respiratory disease-related mortality were defined by events adjudication and administrative criteria. Models were stratified by smoking status and adjusted for anthropometric, sociodemographic, and smoking-related factors. The comparison group was participants without nonobstructive chronic bronchitis.

Results: Among 22 325 adults included in the analysis, mean (SD) age was 53.0 (16.3) years (range, 18.0-95.0 years), 58.2% were female, 65.9% were non-Hispanic white, and 49.6% were ever smokers. Among 11 082 ever smokers with 99 869 person-years of follow-up, participants with nonobstructive chronic bronchitis (300 [2.7%]) had accelerated decreases in FEV1 (4.1 mL/y; 95% CI, 2.1-6.1 mL/y) and FVC (4.7 mL/y; 95% CI, 2.2-7.2 mL/y), increased risks of chronic lower respiratory disease-related hospitalization or mortality (hazard ratio [HR], 2.2; 95% CI, 1.7-2.7), and greater respiratory disease-related (HR, 2.0; 95% CI, 1.1-3.8) and all-cause mortality (HR, 1.5; 95% CI, 1.3-1.8) compared with ever smokers without nonobstructive chronic bronchitis. Among 11 243 never smokers with 120 004 person-years of follow-up, participants with nonobstructive chronic bronchitis (151 [1.3%]) had greater rates of chronic lower respiratory disease-related hospitalization or mortality (HR, 3.1; 95% CI, 2.1-4.5) compared with never smokers without nonobstructive chronic bronchitis. Nonobstructive chronic bronchitis was not associated with FEV1:FVC decline or incident airflow obstruction. The presence of at least 1 of the component symptoms of nonobstructive chronic bronchitis (ie, chronic cough or phlegm), which was common in both ever smokers (11.0%) and never smokers (6.7%), was associated with adverse respiratory health outcomes.

Conclusions and Relevance: The findings suggest that nonobstructive chronic bronchitis is associated with adverse respiratory health outcomes, particularly in ever smokers, and may be a high-risk phenotype suitable for risk stratification and targeted therapies.

VL - 180 IS - 5 ER - TY - JOUR T1 - A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline. JF - Am J Epidemiol Y1 - 2020 A1 - Cornelius, Talea A1 - Schwartz, Joseph E A1 - Balte, Pallavi A1 - Bhatt, Surya P A1 - Cassano, Patricia A A1 - Currow, David A1 - Jacobs, David R A1 - Johnson, Miriam A1 - Kalhan, Ravi A1 - Kronmal, Richard A1 - Loehr, Laura A1 - O'Connor, George T A1 - Smith, Benjamin A1 - White, Wendy B A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Aged KW - Body Mass Index KW - Cohort Studies KW - Humans KW - Linear Models KW - Lung KW - Middle Aged KW - Respiratory Function Tests KW - Weight Gain AB -

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.

VL - 189 IS - 10 ER - TY - JOUR T1 - Lung function decline in former smokers and low-intensity current smokers: a secondary data analysis of the NHLBI Pooled Cohorts Study. JF - Lancet Respir Med Y1 - 2020 A1 - Oelsner, Elizabeth C A1 - Balte, Pallavi P A1 - Bhatt, Surya P A1 - Cassano, Patricia A A1 - Couper, David A1 - Folsom, Aaron R A1 - Freedman, Neal D A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Mathew, Amanda R A1 - Kronmal, Richard A A1 - Loehr, Laura R A1 - London, Stephanie J A1 - Newman, Anne B A1 - O'Connor, George T A1 - Schwartz, Joseph E A1 - Smith, Lewis J A1 - White, Wendy B A1 - Yende, Sachin KW - Adult KW - Aged KW - Case-Control Studies KW - Ex-Smokers KW - Female KW - Follow-Up Studies KW - Humans KW - Lung KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Non-Smokers KW - Respiratory Physiological Phenomena KW - Smokers KW - Smoking KW - Spirometry KW - United States KW - Young Adult AB -

BACKGROUND: Former smokers now outnumber current smokers in many developed countries, and current smokers are smoking fewer cigarettes per day. Some data suggest that lung function decline normalises with smoking cessation; however, mechanistic studies suggest that lung function decline could continue. We hypothesised that former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers, including among those without prevalent lung disease.

METHODS: We used data on six US population-based cohorts included in the NHLBI Pooled Cohort Study. We restricted the sample to participants with valid spirometry at two or more exams. Two cohorts recruited younger adults (≥17 years), two recruited middle-aged and older adults (≥45 years), and two recruited only elderly adults (≥65 years) with examinations done between 1983 and 2014. FEV decline in sustained former smokers and current smokers was compared to that of never-smokers by use of mixed models adjusted for sociodemographic and anthropometric factors. Differential FEV decline was also evaluated according to duration of smoking cessation and cumulative (number of pack-years) and current (number of cigarettes per day) cigarette consumption.

FINDINGS: 25 352 participants (ages 17-93 years) completed 70 228 valid spirometry exams. Over a median follow-up of 7 years (IQR 3-20), FEV decline at the median age (57 years) was 31·01 mL per year (95% CI 30·66-31·37) in sustained never-smokers, 34·97 mL per year (34·36-35·57) in former smokers, and 39·92 mL per year (38·92-40·92) in current smokers. With adjustment, former smokers showed an accelerated FEV decline of 1·82 mL per year (95% CI 1·24-2·40) compared to never-smokers, which was approximately 20% of the effect estimate for current smokers (9·21 mL per year; 95% CI 8·35-10·08). Compared to never-smokers, accelerated FEV decline was observed in former smokers for decades after smoking cessation and in current smokers with low cumulative cigarette consumption (<10 pack-years). With respect to current cigarette consumption, the effect estimate for FEV decline in current smokers consuming less than five cigarettes per day (7·65 mL per year; 95% CI 6·21-9·09) was 68% of that in current smokers consuming 30 or more cigarettes per day (11·24 mL per year; 9·86-12·62), and around five times greater than in former smokers (1·57 mL per year; 1·00-2·14). Among participants without prevalent lung disease, associations were attenuated but were consistent with the main results.

INTERPRETATION: Former smokers and low-intensity current smokers have accelerated lung function decline compared with never-smokers. These results suggest that all levels of smoking exposure are likely to be associated with lasting and progressive lung damage.

FUNDING: National Institutes of Health, National Heart Lung and Blood Institute, and US Environmental Protection Agency.

VL - 8 IS - 1 ER - TY - JOUR T1 - Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants. JF - Nat Commun Y1 - 2020 A1 - Zhao, Xutong A1 - Qiao, Dandi A1 - Yang, Chaojie A1 - Kasela, Silva A1 - Kim, Wonji A1 - Ma, Yanlin A1 - Shrine, Nick A1 - Batini, Chiara A1 - Sofer, Tamar A1 - Taliun, Sarah A Gagliano A1 - Sakornsakolpat, Phuwanat A1 - Balte, Pallavi P A1 - Prokopenko, Dmitry A1 - Yu, Bing A1 - Lange, Leslie A A1 - Dupuis, Josée A1 - Cade, Brian E A1 - Lee, Jiwon A1 - Gharib, Sina A A1 - Daya, Michelle A1 - Laurie, Cecelia A A1 - Ruczinski, Ingo A1 - Cupples, L Adrienne A1 - Loehr, Laura R A1 - Bartz, Traci M A1 - Morrison, Alanna C A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Taylor, Kent D A1 - Durda, Peter A1 - Johnson, W Craig A1 - Cornell, Elaine A1 - Guo, Xiuqing A1 - Liu, Yongmei A1 - Tracy, Russell P A1 - Ardlie, Kristin G A1 - Aguet, Francois A1 - VanDenBerg, David J A1 - Papanicolaou, George J A1 - Rotter, Jerome I A1 - Barnes, Kathleen C A1 - Jain, Deepti A1 - Nickerson, Deborah A A1 - Muzny, Donna M A1 - Metcalf, Ginger A A1 - Doddapaneni, Harshavardhan A1 - Dugan-Perez, Shannon A1 - Gupta, Namrata A1 - Gabriel, Stacey A1 - Rich, Stephen S A1 - O'Connor, George T A1 - Redline, Susan A1 - Reed, Robert M A1 - Laurie, Cathy C A1 - Daviglus, Martha L A1 - Preudhomme, Liana K A1 - Burkart, Kristin M A1 - Kaplan, Robert C A1 - Wain, Louise V A1 - Tobin, Martin D A1 - London, Stephanie J A1 - Lappalainen, Tuuli A1 - Oelsner, Elizabeth C A1 - Abecasis, Goncalo R A1 - Silverman, Edwin K A1 - Barr, R Graham A1 - Cho, Michael H A1 - Manichaikul, Ani KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Calcium-Binding Proteins KW - Feasibility Studies KW - Female KW - Follow-Up Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Lung KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Inhibitors of Activated STAT KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Physiological Phenomena KW - Small Ubiquitin-Related Modifier Proteins KW - Whole Genome Sequencing AB -

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

VL - 11 IS - 1 ER - TY - JOUR T1 - Association Between Preserved Ratio Impaired Spirometry and Clinical Outcomes in US Adults. JF - JAMA Y1 - 2021 A1 - Wan, Emily S A1 - Balte, Pallavi A1 - Schwartz, Joseph E A1 - Bhatt, Surya P A1 - Cassano, Patricia A A1 - Couper, David A1 - Daviglus, Martha L A1 - Dransfield, Mark T A1 - Gharib, Sina A A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - London, Stephanie J A1 - Navas-Acien, Ana A1 - O'Connor, George T A1 - Sanders, Jason L A1 - Smith, Benjamin M A1 - White, Wendy A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Female KW - Forced Expiratory Volume KW - Humans KW - Lung KW - Lung Diseases KW - Male KW - Middle Aged KW - Prevalence KW - Retrospective Studies KW - Spirometry KW - United States KW - Vital Capacity AB -

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.

VL - 326 IS - 22 ER - TY - JOUR T1 - Association of Midlife Cardiovascular Risk Factors With the Risk of Heart Failure Subtypes Later in Life. JF - J Card Fail Y1 - 2021 A1 - Cohen, Laura P A1 - Vittinghoff, Eric A1 - Pletcher, Mark J A1 - Allen, Norrina B A1 - Shah, Sanjiv J A1 - Wilkins, John T A1 - Chang, Patricia P A1 - Ndumele, Chiadi E A1 - Newman, Anne B A1 - Ives, Diane A1 - Maurer, Mathew S A1 - Oelsner, Elizabeth C A1 - Moran, Andrew E A1 - Zhang, Yiyi AB -

BACKGROUND: Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.

METHODS: We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.

RESULTS: A total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.

CONCLUSIONS: Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures.

VL - 27 IS - 4 ER - TY - JOUR T1 - Associations of Body Mass Index and Waist Circumference in Young Adulthood with Later Life Incident Diabetes. JF - J Clin Endocrinol Metab Y1 - 2021 A1 - Nair, Nandini A1 - Vittinghoff, Eric A1 - Pletcher, Mark J A1 - Oelsner, Elizabeth C A1 - Allen, Norrina B A1 - Ndumele, Chiadi E A1 - West, Nancy A A1 - Strotmeyer, Elsa S A1 - Mukamal, Kenneth J A1 - Siscovick, David S A1 - Biggs, Mary L A1 - Laferrère, Blandine A1 - Moran, Andrew E A1 - Zhang, Yiyi KW - Adolescent KW - Adult KW - Biomarkers KW - Body Mass Index KW - Diabetes Mellitus KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Obesity KW - Overweight KW - Prognosis KW - Prospective Studies KW - Risk Factors KW - United States KW - Waist Circumference KW - Young Adult AB -

CONTEXT: The independent contribution of young adult exposure to overweight and obesity to later-life incident diabetes is not well studied.

OBJECTIVE: To assess the associations of exposures to elevated body mass index (BMI) and waist circumference (WC) in young adulthood (ages 18-39 years) with incident diabetes later in life (≥40 years).

DESIGN: Pooled data from 6 US prospective cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Risk Development in Young Adults Study, Cardiovascular Health Study, (4) Framingham Heart Study Offspring Cohort, (5) Health, Aging and Body Composition Study, and (6) Multi-Ethnic Study of Atherosclerosis.

SETTING: Population-based cohort studies.

PARTICIPANTS: 30 780 participants (56.1% female, 69.8% non-Hispanic white) without a diagnosis of diabetes by age 40.

INTERVENTIONS: We imputed BMI and WC trajectories from age 18 for every participant and estimated time-weighted average exposures to BMI or WC during young adulthood and later life.

MAIN OUTCOME MEASURE(S): Incident diabetes defined as fasting glucose ≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or use of diabetes medications.

RESULTS: During a 9-year median follow-up, 4323 participants developed incident diabetes. Young adult BMI and WC were associated with later-life incident diabetes after controlling for later-life exposures [hazard ratios (HR) 1.99 for BMI ≥ 30 kg/m2 and 2.13 for WC > 88cm (women)/>102cm (men) compared to normal ranges]. Young adult homeostatic model of insulin resistance mediated 49% and 44% of the association between BMI and WC with later-life incident diabetes. High-density lipoproteins and triglycerides mediated a smaller proportion of these associations.

CONCLUSIONS: Elevated BMI and WC during young adulthood were independently associated with later-life incident diabetes. Insulin resistance may be a key mediator.

VL - 106 IS - 12 ER - TY - JOUR T1 - Estimating Systolic Blood Pressure Intervention Trial Participant Posttrial Survival Using Pooled Epidemiologic Cohort Data. JF - J Am Heart Assoc Y1 - 2021 A1 - Bellows, Brandon K A1 - Zhang, Yiyi A1 - Zhang, Zugui A1 - Lloyd-Jones, Donald M A1 - Bress, Adam P A1 - King, Jordan B A1 - Kolm, Paul A1 - Cushman, William C A1 - Johnson, Karen C A1 - Tamariz, Leonardo A1 - Oelsner, Elizabeth C A1 - Shea, Steven A1 - Newman, Anne B A1 - Ives, Diane G A1 - Couper, David A1 - Moran, Andrew E A1 - Weintraub, William S AB -

Background Intensive systolic blood pressure treatment (<120 mm Hg) in SPRINT (Systolic Blood Pressure Intervention Trial) improved survival compared with standard treatment (<140 mm Hg) over a median follow-up of 3.3 years. We projected life expectancy after observed follow-up in SPRINT using SPRINT-eligible participants in the NHLBI-PCS (National Heart, Lung, and Blood Institute Pooled Cohorts Study). Methods and Results We used propensity scores to weight SPRINT-eligible NHLBI-PCS participants to resemble SPRINT participants. In SPRINT participants, we estimated in-trial survival (<4 years) using a time-based flexible parametric survival model. In SPRINT-eligible NHLBI-PCS participants, we estimated posttrial survival (≥4 years) using an age-based flexible parametric survival model and applied the formula to SPRINT participants to predict posttrial survival. We projected overall life expectancy for each SPRINT participant and compared it to parametric regression (eg, Gompertz) projections based on SPRINT data alone. We included 8584 SPRINT and 10 593 SPRINT-eligible NHLBI-PCS participants. After propensity weighting, mean (SD) age was 67.9 (9.4) and 68.2 (8.8) years, and 35.5% and 37.6% were women in SPRINT and NHLBI-PCS, respectively. Using the NHLBI-PCS-based method, projected mean life expectancy from randomization was 21.0 (7.4) years with intensive and 19.1 (7.2) years with standard treatment. Using the Gompertz regression, life expectancy was 11.2 (2.3) years with intensive and 10.5 (2.2) years with standard treatment. Conclusions Combining SPRINT and NHLBI-PCS observed data likely offers a more realistic estimate of life expectancy than parametrically extrapolating SPRINT data alone. These results offer insight into the potential long-term effectiveness of intensive SBP goals.

VL - 10 IS - 10 ER - TY - JOUR T1 - A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. JF - Am J Epidemiol Y1 - 2021 A1 - Stilp, Adrienne M A1 - Emery, Leslie S A1 - Broome, Jai G A1 - Buth, Erin J A1 - Khan, Alyna T A1 - Laurie, Cecelia A A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Chen, Dongquan A1 - D'Augustine, Catherine M A1 - Heard-Costa, Nancy L A1 - Hohensee, Chancellor R A1 - Johnson, William Craig A1 - Juarez, Lucia D A1 - Liu, Jingmin A1 - Mutalik, Karen M A1 - Raffield, Laura M A1 - Wiggins, Kerri L A1 - de Vries, Paul S A1 - Kelly, Tanika N A1 - Kooperberg, Charles A1 - Natarajan, Pradeep A1 - Peloso, Gina M A1 - Peyser, Patricia A A1 - Reiner, Alex P A1 - Arnett, Donna K A1 - Aslibekyan, Stella A1 - Barnes, Kathleen C A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Cade, Brian E A1 - Chen, Ming-Huei A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - de Andrade, Mariza A1 - Ellinor, Patrick T A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Gan, Weiniu A1 - Ganesh, Santhi K A1 - Graffelman, Jan A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Hawley, Nicola L A1 - Hsu, Wan-Ling A1 - Jackson, Rebecca D A1 - Jaquish, Cashell E A1 - Johnson, Andrew D A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Lee, Jiwon A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - North, Kari E A1 - Nouraie, Seyed Mehdi A1 - Oelsner, Elizabeth C A1 - Pankratz, Nathan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Weeks, Daniel E A1 - Weiss, Scott T A1 - Wilson, Carla G A1 - Yanek, Lisa R A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Laurie, Cathy C AB -

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

ER - TY - JOUR T1 - Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study. JF - Eur Heart J Y1 - 2022 A1 - Eckhardt, Christina M A1 - Balte, Pallavi P A1 - Barr, Robert Graham A1 - Bertoni, Alain G A1 - Bhatt, Surya P A1 - Cuttica, Michael A1 - Cassano, Patricia A A1 - Chaves, Paolo A1 - Couper, David A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kronmal, Richard A1 - Lange, Leslie A1 - Loehr, Laura A1 - London, Stephanie J A1 - O'Connor, George T A1 - Rosamond, Wayne A1 - Sanders, Jason A1 - Schwartz, Joseph E A1 - Shah, Amil A1 - Shah, Sanjiv J A1 - Smith, Lewis A1 - White, Wendy A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Heart Failure KW - Hospitalization KW - Humans KW - Lung KW - National Heart, Lung, and Blood Institute (U.S.) KW - Prognosis KW - Risk Factors KW - Stroke Volume KW - United States AB -

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.

VL - 43 IS - 23 ER - TY - JOUR T1 - Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program. JF - Am J Hum Genet Y1 - 2022 A1 - Hu, Xiaowei A1 - Qiao, Dandi A1 - Kim, Wonji A1 - Moll, Matthew A1 - Balte, Pallavi P A1 - Lange, Leslie A A1 - Bartz, Traci M A1 - Kumar, Rajesh A1 - Li, Xingnan A1 - Yu, Bing A1 - Cade, Brian E A1 - Laurie, Cecelia A A1 - Sofer, Tamar A1 - Ruczinski, Ingo A1 - Nickerson, Deborah A A1 - Muzny, Donna M A1 - Metcalf, Ginger A A1 - Doddapaneni, Harshavardhan A1 - Gabriel, Stacy A1 - Gupta, Namrata A1 - Dugan-Perez, Shannon A1 - Cupples, L Adrienne A1 - Loehr, Laura R A1 - Jain, Deepti A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Morrison, Alanna C A1 - Vasan, Ramachandran S A1 - Washko, George A1 - Rich, Stephen S A1 - O'Connor, George T A1 - Bleecker, Eugene A1 - Kaplan, Robert C A1 - Kalhan, Ravi A1 - Redline, Susan A1 - Gharib, Sina A A1 - Meyers, Deborah A1 - Ortega, Victor A1 - Dupuis, Josée A1 - London, Stephanie J A1 - Lappalainen, Tuuli A1 - Oelsner, Elizabeth C A1 - Silverman, Edwin K A1 - Barr, R Graham A1 - Thornton, Timothy A A1 - Wheeler, Heather E A1 - Cho, Michael H A1 - Im, Hae Kyung A1 - Manichaikul, Ani AB -

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1 s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR] = 1.24 [95% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with ≥ 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p < 2.2 × 10 with portability gains ranging from 5% to 28%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

ER - TY - JOUR T1 - Pooled Cohort Probability Score for Subclinical Airflow Obstruction. JF - Ann Am Thorac Soc Y1 - 2022 A1 - Bhatt, Surya P A1 - Balte, Pallavi P A1 - Schwartz, Joseph E A1 - Jaeger, Byron C A1 - Cassano, Patricia A A1 - Chaves, Paulo H A1 - Couper, David A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - Kaplan, Robert A1 - Lloyd-Jones, Donald A1 - Newman, Anne B A1 - O'Connor, George A1 - Sanders, Jason L A1 - Smith, Benjamin M A1 - Sun, Yifei A1 - Umans, Jason G A1 - White, Wendy B A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Female KW - Forced Expiratory Volume KW - Humans KW - Lung KW - Male KW - Middle Aged KW - Nutrition Surveys KW - Pulmonary Disease, Chronic Obstructive KW - Risk Factors KW - Spirometry KW - Vital Capacity AB -

Early detection of chronic obstructive pulmonary disease (COPD) is a public health priority. Airflow obstruction is the single most important risk factor for adverse COPD outcomes, but spirometry is not routinely recommended for screening. To describe the burden of subclinical airflow obstruction (SAO) and to develop a probability score for SAO to inform potential detection and prevention programs. Lung function and clinical data were harmonized and pooled across nine U.S. general population cohorts. Adults with respiratory symptoms, inhaler use, or prior diagnosis of COPD or asthma were excluded. A probability score for prevalent SAO (forced expiratory volume in 1 second/forced vital capacity < 0.70) was developed via hierarchical group-lasso regularization from clinical variables in strata of sex and smoking status, and its discriminative accuracy for SAO was assessed in the pooled cohort as well as in an external validation cohort (NHANES [National Health and Nutrition Examination Survey] 2011-2012). Incident hospitalizations and deaths due to COPD (respiratory events) were defined by adjudication or administrative criteria in four of nine cohorts. Of 33,546 participants (mean age 52 yr, 54% female, 44% non-Hispanic White), 4,424 (13.2%) had prevalent SAO. The incidence of respiratory events ( = 14,024) was threefold higher in participants with SAO versus those without (152 vs. 39 events/10,000 person-years). The probability score, which was based on six commonly available variables (age, sex, race and/or ethnicity, body mass index, smoking status, and smoking pack-years) was well calibrated and showed excellent discrimination in both the testing sample (C-statistic, 0.81; 95% confidence interval [CI], 0.80-0.82) and in NHANES (C-statistic, 0.83; 95% CI, 0.80-0.86). Among participants with predicted probabilities ⩾ 15%, 3.2 would need to undergo spirometry to detect one case of SAO. Adults with SAO demonstrate excess respiratory hospitalization and mortality. A probability score for SAO using commonly available clinical risk factors may be suitable for targeting screening and primary prevention strategies.

VL - 19 IS - 8 ER - TY - JOUR T1 - Rare genetic variants explain missing heritability in smoking. JF - Nat Hum Behav Y1 - 2022 A1 - Jang, Seon-Kyeong A1 - Evans, Luke A1 - Fialkowski, Allison A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Blangero, John A1 - Bleecker, Eugene R A1 - Boorgula, Meher Preethi A1 - Bowden, Donald W A1 - Brody, Jennifer A A1 - Cade, Brian E A1 - Jenkins, Brenda W Campbell A1 - Carson, April P A1 - Chavan, Sameer A1 - Cupples, L Adrienne A1 - Custer, Brian A1 - Damrauer, Scott M A1 - David, Sean P A1 - de Andrade, Mariza A1 - Dinardo, Carla L A1 - Fingerlin, Tasha E A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Glahn, David C A1 - Haessler, Jeffrey A1 - Heckbert, Susan R A1 - Hokanson, John E A1 - Hou, Lifang A1 - Hwang, Shih-Jen A1 - Hyman, Matthew C A1 - Judy, Renae A1 - Justice, Anne E A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kelly, Shannon A1 - Kim, Wonji A1 - Kooperberg, Charles A1 - Levy, Daniel A1 - Lloyd-Jones, Donald M A1 - Loos, Ruth J F A1 - Manichaikul, Ani W A1 - Gladwin, Mark T A1 - Martin, Lisa Warsinger A1 - Nouraie, Mehdi A1 - Melander, Olle A1 - Meyers, Deborah A A1 - Montgomery, Courtney G A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Palmer, Nicholette D A1 - Payton, Marinelle A1 - Peljto, Anna L A1 - Peyser, Patricia A A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Qiao, Dandi A1 - Rader, Daniel J A1 - Rafaels, Nicholas A1 - Redline, Susan A1 - Reed, Robert M A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Silverman, Edwin K A1 - Smith, Nicholas L A1 - Smith, J Gustav A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Tang, Weihong A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Vasan, Ramachandran S A1 - Gordeuk, Victor R A1 - Wang, Zhe A1 - Wiggins, Kerri L A1 - Yanek, Lisa R A1 - Yang, Ivana V A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhang, Yingze A1 - Liu, Dajiang J A1 - Keller, Matthew C A1 - Vrieze, Scott AB -

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

ER - TY - JOUR T1 - Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease. JF - JAMA Cardiol Y1 - 2023 A1 - Dron, Jacqueline S A1 - Patel, Aniruddh P A1 - Zhang, Yiyi A1 - Jurgens, Sean J A1 - Maamari, Dimitri J A1 - Wang, Minxian A1 - Boerwinkle, Eric A1 - Morrison, Alanna C A1 - de Vries, Paul S A1 - Fornage, Myriam A1 - Hou, Lifang A1 - Lloyd-Jones, Donald M A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Bis, Joshua C A1 - Vasan, Ramachandran S A1 - Levy, Daniel A1 - Heard-Costa, Nancy A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Taylor, Kent D A1 - Gibbs, Richard A A1 - Rotter, Jerome I A1 - Willer, Cristen J A1 - Oelsner, Elizabeth C A1 - Moran, Andrew E A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Khera, Amit V AB -

IMPORTANCE: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.

OBJECTIVE: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.

EXPOSURES: PTVs in APOB and PCSK9.

MAIN OUTCOMES AND MEASURES: Estimated untreated LDL cholesterol levels and CHD.

RESULTS: Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).

CONCLUSIONS AND RELEVANCE: Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.

ER - TY - JOUR T1 - Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease. JF - Circulation Y1 - 2023 A1 - Zhang, Yiyi A1 - Dron, Jacqueline S A1 - Bellows, Brandon K A1 - Khera, Amit V A1 - Liu, Junxiu A1 - Balte, Pallavi P A1 - Oelsner, Elizabeth C A1 - Amr, Sami Samir A1 - Lebo, Matthew S A1 - Nagy, Anna A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Rotter, Jerome I A1 - Willer, Cristen A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Lutsey, Pamela L A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Floyd, James S A1 - Vasan, Ramachandran S A1 - Heard-Costa, Nancy L A1 - Carson, April P A1 - Hall, Michael E A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Kazi, Dhruv S A1 - de Ferranti, Sarah D A1 - Moran, Andrew E KW - Coronary Disease KW - Genotype KW - Humans KW - Hypercholesterolemia KW - Hyperlipoproteinemia Type II VL - 147 IS - 20 ER - TY - JOUR T1 - Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing. JF - Nat Genet Y1 - 2023 A1 - Chen, Fang A1 - Wang, Xingyan A1 - Jang, Seon-Kyeong A1 - Quach, Bryan C A1 - Weissenkampen, J Dylan A1 - Khunsriraksakul, Chachrit A1 - Yang, Lina A1 - Sauteraud, Renan A1 - Albert, Christine M A1 - Allred, Nicholette D D A1 - Arnett, Donna K A1 - Ashley-Koch, Allison E A1 - Barnes, Kathleen C A1 - Barr, R Graham A1 - Becker, Diane M A1 - Bielak, Lawrence F A1 - Bis, Joshua C A1 - Blangero, John A1 - Boorgula, Meher Preethi A1 - Chasman, Daniel I A1 - Chavan, Sameer A1 - Chen, Yii-der I A1 - Chuang, Lee-Ming A1 - Correa, Adolfo A1 - Curran, Joanne E A1 - David, Sean P A1 - Fuentes, Lisa de Las A1 - Deka, Ranjan A1 - Duggirala, Ravindranath A1 - Faul, Jessica D A1 - Garrett, Melanie E A1 - Gharib, Sina A A1 - Guo, Xiuqing A1 - Hall, Michael E A1 - Hawley, Nicola L A1 - He, Jiang A1 - Hobbs, Brian D A1 - Hokanson, John E A1 - Hsiung, Chao A A1 - Hwang, Shih-Jen A1 - Hyde, Thomas M A1 - Irvin, Marguerite R A1 - Jaffe, Andrew E A1 - Johnson, Eric O A1 - Kaplan, Robert A1 - Kardia, Sharon L R A1 - Kaufman, Joel D A1 - Kelly, Tanika N A1 - Kleinman, Joel E A1 - Kooperberg, Charles A1 - Lee, I-Te A1 - Levy, Daniel A1 - Lutz, Sharon M A1 - Manichaikul, Ani W A1 - Martin, Lisa W A1 - Marx, Olivia A1 - McGarvey, Stephen T A1 - Minster, Ryan L A1 - Moll, Matthew A1 - Moussa, Karine A A1 - Naseri, Take A1 - North, Kari E A1 - Oelsner, Elizabeth C A1 - Peralta, Juan M A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Rafaels, Nicholas A1 - Raffield, Laura M A1 - Reupena, Muagututi'a Sefuiva A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Schwartz, David A A1 - Shadyab, Aladdin H A1 - Sheu, Wayne H-H A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Sun, Xiao A1 - Taylor, Kent D A1 - Telen, Marilyn J A1 - Watson, Harold A1 - Weeks, Daniel E A1 - Weir, David R A1 - Yanek, Lisa R A1 - Young, Kendra A A1 - Young, Kristin L A1 - Zhao, Wei A1 - Hancock, Dana B A1 - Jiang, Bibo A1 - Vrieze, Scott A1 - Liu, Dajiang J KW - Biology KW - Drug Repositioning KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Tobacco Use KW - Transcriptome AB -

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

VL - 55 IS - 2 ER - TY - JOUR T1 - Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol. JF - JAMA Cardiol Y1 - 2024 A1 - Zhang, Yiyi A1 - Dron, Jacqueline S A1 - Bellows, Brandon K A1 - Khera, Amit V A1 - Liu, Junxiu A1 - Balte, Pallavi P A1 - Oelsner, Elizabeth C A1 - Amr, Sami Samir A1 - Lebo, Matthew S A1 - Nagy, Anna A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Rotter, Jerome I A1 - Willer, Cristen A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Lutsey, Pamela L A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Floyd, James S A1 - Vasan, Ramachandran S A1 - Heard-Costa, Nancy L A1 - Carson, April P A1 - Hall, Michael E A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Kazi, Dhruv S A1 - de Ferranti, Sarah D A1 - Moran, Andrew E AB -

IMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.

OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.

DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.

EXPOSURES: LDL-C, cumulative past LDL-C, FH variant status.

MAIN OUTCOMES AND MEASURES: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.

RESULTS: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.

CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

ER -