Wendy White

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2100 genes selected for cardiovascular diseases among 20 077 European-Americans and 6900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with per cent emphysema and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio and per cent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both single-nucleotide polymorphisms (SNPs) flank the gene for apolipoprotein M (APOM), a component of high-density lipoprotein (HDL) cholesterol. Both were replicated in an independent cohort. SNPs in a second gene related to apolipoprotein M and HDL, PCSK9, were associated with FEV1/FVC ratio among African-Americans. rs707974 was associated with per cent emphysema among European-Americans and African-Americans and APOM expression was related to FEV1/FVC ratio and per cent emphysema. Higher HDL levels were associated with lower FEV1/FVC ratio and greater per cent emphysema. These findings suggest a novel role for the apolipoprotein M/HDL pathway in the pathogenesis of COPD and emphysema. Findings from this study suggest a novel effect of the APOM/HDL pathway in the pathogenesis of COPD and emphysema http://ow.ly/t8Ao9

Genetic variability of smoking persistence in African Americans.

To date, most genetic association analyses of smoking behaviors have been conducted in populations of European ancestry and many of these studies focused on the phenotype that measures smoking quantity, that is, cigarettes per day. Additional association studies in diverse populations with different linkage disequilibrium patterns and an alternate phenotype, such as total tobacco exposure which accounts for intermittent periods of smoking cessation within a larger smoking period as measured in large cardiovascular risk studies, can aid the search for variants relevant to smoking behavior. For these reasons, we undertook an association analysis by using a genotyping array that includes 2,100 genes to analyze smoking persistence in unrelated African American participants from the Atherosclerosis Risk in Communities study. A locus located approximately 4 kb downstream from the 3′-UTR of the brain-derived neurotrophic factor (BDNF) significantly influenced smoking persistence. In addition, independent variants rs12915366 and rs12914385 in the cluster of genes encoding nicotinic acetylcholine receptor subunits (CHRNA5–CHRNA3–CHRNB4) on 15q25.1 were also associated with the phenotype in this sample of African American subjects. To our knowledge, this is the first study to more extensively evaluate the genome in the African American population, as a limited number of previous studies of smoking behavior in this population included evaluations of only single genomic regions. Cancer Prev Res; 4(5); 729–34. ©2011 AACR.

Asthma and Asthma Severity among African American Adults in the Jackson Heart Study

The aims of this study were to investigate the baseline prevalence of and risk factors associated with asthma, classify asthma severity, and describe medication use in a population-based sample of African American men and women 21 to 84 years of age from the Jackson Heart Study (JHS). Participants provided responses to respiratory and medical history questions and a medication inventory and underwent spirometry and other clinical examinations. These data were used to examine the extent to which novel and traditional risk factors were associated with asthma. Of the 4,098 participants included in this analysis, 9.4% reported lifetime asthma (5.7% current, 3.7% former), and current asthma was higher in women (6.8%) than in men (3.8%). An additional 9.8% reported an attack of wheeze with shortness of breath or non-doctor confirmed asthma (i.e., “probable” asthma). The mean forced expiratory volume in 1 second (FEV1)% predicted was lower in those reporting current asthma (women: 83.7 ± 18.0; men: 75.2 ± 16.8) compared to those not reporting asthma (women: 95.6 ± 16.7; men: 91.7 ± 16.0). Current and probable asthma was associated with lower serum cortisol levels and hypertension medication use, along with traditional risk factors (i.e., lower socio-economic status, higher global stress scores, obesity, and fair to poor perceived general health). Severe asthma was low among participants reporting current (9.8%), former (3.3%), and probable (4.9%) asthma. Asthma medication use was reported by nearly 60% of the participants reporting current asthma. Asthma in African American adults is associated with decreased serum cortisol, hypertension medication use, and considerable lung function impairment compared to those who did not report asthma. The prevalence of asthma in the JHS is lower than state and national estimates, although the estimates are not directly comparable. Furthermore, asthma is drastically underdiagnosed in this population.

Replication and fine mapping of asthma-associated loci in individuals of African ancestry

Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.

The association between cigarette smoking and inflammation: The Genetic Epidemiology Network of Arteriopathy (GENOA) study

To inform the study and regulation of emerging tobacco products, we sought to identify sensitive biomarkers of tobacco-induced subclinical cardiovascular damage by testing the cross-sectional associations of smoking with 17 biomarkers of inflammation in 2,702 GENOA study participants belonging to sibships ascertained on the basis of hypertension. Cigarette smoking was assessed by status, intensity (number of cigarettes per day), burden (pack-years of smoking), and time since quitting. We modeled biomarkers as geometric mean (GM) ratios using generalized estimating equations (GEE). The mean age of participants was 61 ±10 years; 64.5% were women and 54.4% African American. The prevalence of smoking was 12.2%. After adjusting for potential confounders, 6 of 17 biomarkers were significantly higher among current smokers at a Bonferroni adjusted p-value threshold (p<0.003). High sensitivity C-reactive protein was the most elevated biomarker among current smokers when compared to never smokers [GM ratio = 1.39 (95% CI: 1.23, 1.57); p <0.001]. Among former smokers, each pack-year of cigarettes smoked was associated with a 0.4% higher serum level of hsCRP [GM ratio = 1.004 (95% CI: 1.001, 1.006); p = 0.002] and each 5-year lapsed since quitting was associated with a 4% lower serum level of hsCRP [GM ratio = 0.96 (95% CI: 0.93, 0.99); p = 0.006]. However, we found no significant association of smoking intensity or burden with biomarkers of inflammation among current smokers. HsCRP appears to be the most sensitive biomarker of inflammation associated with cigarette smoking of those investigated, and could be a useful biomarker of smoking-related injury for the study and regulation of emerging tobacco products.

Joint effects of smoking and sedentary lifestyle on lung function in African Americans: the Jackson Heart Study cohort.

This study examined: (a) differences in lung function between current and non current smokers who had sedentary lifestyles and non sedentary lifestyles and (b) the mediating effect of sedentary lifestyle on the association between smoking and lung function in African Americans. Sedentary lifestyle was defined as the lowest quartile of the total physical activity score. The results of linear and logistic regression analyses revealed that non smokers with non sedentary lifestyles had the highest level of lung function, and smokers with sedentary lifestyles had the lowest level. The female non-smokers with sedentary lifestyles had a significantly higher FEV1% predicted and FVC% predicted than smokers with non sedentary lifestyles (93.3% vs. 88.6%; p = 0.0102 and 92.1% vs. 86.9%; p = 0.0055 respectively). FEV1/FVC ratio for men was higher in non smokers with sedentary lifestyles than in smokers with non sedentary lifestyles (80.9 vs. 78.1; p = 0.0048). Though smoking is inversely associated with lung function, it seems to have a more deleterious effect than sedentary lifestyle on lung function. Physically active smokers had higher lung function than their non physically active counterparts.

Cigarette Smoking and Incident Heart Failure: Insights From the Jackson Heart Study

Background: Cigarette smoking has been linked with several factors associated with cardiac dysfunction. We hypothesized that cigarette smoking is associated with left ventricular (LV) structure and function, and incident heart failure (HF) hospitalization. Methods: We investigated 4129 (never smoker n=2884, current smoker n=503, and former smoker n=742) black participants (mean age, 54 years; 63% women) without a history of HF or coronary heart disease at baseline in the Jackson Heart Study. We examined the relationships between cigarette smoking and LV structure and function by using cardiac magnetic resonance imaging among 1092 participants, cigarette smoking and brain natriuretic peptide levels among 3325 participants, and incident HF hospitalization among 3633 participants with complete data. Results: After adjustment for confounding factors, current smoking was associated with higher mean LV mass index and lower mean LV circumferential strain (P<0.05, for both) in comparison with never smoking. Smoking status, intensity, and burden were associated with higher mean brain natriuretic peptide levels (all P<0.05). Over 8.0 years (7.7–8.0) median follow-up, there were 147 incident HF hospitalizations. After adjustment for traditional risk factors and incident coronary heart disease, current smoking (hazard ratio, 2.82; 95% confidence interval, 1.71–4.64), smoking intensity among current smokers (≥20 cigarettes/d: hazard ratio, 3.48; 95% confidence interval, 1.65–7.32), and smoking burden among ever smokers (≥15 pack-years: hazard ratio, 2.06; 95% confidence interval, 1.29–3.3) were significantly associated with incident HF hospitalization in comparison with never smoking. Conclusions: In blacks, cigarette smoking is an important risk factor for LV hypertrophy, systolic dysfunction, and incident HF hospitalization even after adjusting for effects on coronary heart disease.

High-intensity cigarette smoking is associated with incident diabetes mellitus in black adults: The Jackson Heart Study

Background Previous reports on whether smoking is associated with insulin resistance and diabetes mellitus have yielded inconsistent findings. We aimed to evaluate the relationship between cigarette smoking and incident diabetes mellitus in the Jackson Heart Study. Methods and Results Jackson Heart Study participants enrolled at baseline without prevalent diabetes mellitus (n=2991) were classified by self‐report as current smokers, past smokers (smoked ≥400 cigarettes/life and no longer smoking), or never smokers. We quantified smoking intensity by number of cigarettes smoked daily; we considered ≥20 cigarettes per day (1 pack) “high‐intensity.” We defined diabetes mellitus as fasting glucose ≥126 mg/dL, hemoglobin A1c ≥6.5% or International Federation of Clinical Chemistry units HbA1c 48 mmol/mol, or use of diabetes mellitus medication. We estimated the adjusted associations of smoking status, intensity, and dose (pack‐years) with incident diabetes mellitus using Poisson regression models. At baseline there were 361 baseline current (1–10 cigarettes per day [n=242]; ≥20 [n=119]), 502 past, and 2128 never smokers. From Visit 1 to Visit 3 (mean 8.0±0.9 years), 479 participants developed incident diabetes mellitus. After adjustment for covariates, baseline current smokers who smoked less than a pack/d and past smokers had similar rates of incident diabetes mellitus compared with never smokers (incidence rate ratios 1.04, 95% confidence interval, 0.69–1.58 and 1.08, 95% confidence interval, 0.82–1.42, respectively). Baseline current high‐intensity smokers had a 79% (95% confidence interval, 1.14–2.81) higher incidence of diabetes mellitus compared with never smokers. Smoking dose (per 10 pack‐years) was also associated with a higher incidence of diabetes mellitus (incidence rate ratios 1.10, 95% confidence interval, 1.03–1.19) in adjusted models. Conclusions High‐intensity cigarette smoking and smoking pack‐years are associated with an increased risk of developing diabetes mellitus in blacks.

Albuminuria, Lung Function Decline, and Risk of Incident COPD: 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.

Harmonization of Respiratory Data From 9 US Population-Based Cohorts

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.