Search Vanderbilt Publications

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
Copyright © 2018 American Society of Human Genetics. All rights reserved.

There is a paucity of data on risk factors for lung cancer among never smokers. Here, we have carried out the first large study of circulating inflammation markers and lung cancer risk among female never smokers in Shanghai. A study of 248 lung cancer cases in female never smokers and 263 controls was nested within the Shanghai Women's Health Study (n = 75221), matched by dates of birth and blood collection (mean follow-up time = 7.5 years). Prediagnostic plasma levels of 65 inflammation markers were measured using a Luminex bead-based assay. Odds ratios (ORs) were estimated with multivariable logistic regression. Nine of 61 evaluable markers were statistically significantly associated with lung cancer risk among never smoking Chinese women (P-trend across categories <0.05). Soluble interleukin-6 receptor [sIL-6R; highest versus lowest category OR = 2.37; 95% confidence interval (CI) 1.40-4.02) and chemokine (C-C motif) ligand 2/monocyte chemotactic protein 1; (OR = 1.62; 95% CI 0.94-2.80) were associated with an increased risk of lung cancer, whereas interleukin (IL)-21 (OR = 0.53; 95%CI 0.31-0.93), chemokine (C-X3-C motif) ligand 1/fractalkine (OR = 0.54; 95% CI 0.30-0.96), soluble vascular endothelial growth factor receptor 2 (sVEGFR2, OR = 0.45; 95% CI 0.26-0.76), sVEGFR3 (OR = 0.53; 95% CI 0.32-0.90), soluble tumor necrosis factor receptor I (OR = 0.49; 95% CI 0.29-0.83), IL-10 (OR = 0.60; 95% CI 0.34-1.05) and C-reactive protein (OR = 0.63; 95% CI 0.37-1.06) were associated with a decreased risk. sIL-6R remained significantly associated with lung cancer risk >7.5 years prior to diagnosis. Markers involved in various aspects of the immune response were associated with subsequent lung cancer risk, implicating inflammation in the etiology of lung cancer among female never smokers.
Published by Oxford University Press 2017.

Background - Circulating concentrations of B vitamins and factors related to one-carbon metabolism have been found to be strongly inversely associated with lung cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The extent to which these associations are present in other study populations is unknown.
Methods - Within 20 prospective cohorts from the National Cancer Institute Cohort Consortium, a nested case-control study was designed including 5364 incident lung cancer case patients and 5364 control subjects who were individually matched to case patients by age, sex, cohort, and smoking status. Centralized biochemical analyses were performed to measure circulating concentrations of vitamin B6, folate, and methionine, as well as cotinine as an indicator of recent tobacco exposure. The association between these biomarkers and lung cancer risk was evaluated using conditional logistic regression models.
Results - Participants with higher circulating concentrations of vitamin B6 and folate had a modestly decreased risk of lung cancer risk overall, the odds ratios when comparing the top and bottom fourths (OR 4vs1 ) being 0.88 (95% confidence interval [CI] = 0.78 to 1.00) and 0.86 (95% CI = 0.74 to 0.99), respectively. We found stronger associations among men (vitamin B6: OR 4vs1 = 0.74, 95% CI = 0.62 to 0.89; folate: OR 4vs1 = 0.75, 95% CI = 0.61 to 0.93) and ever smokers (vitamin B6: OR 4vs1 = 0.78, 95% CI = 0.67 to 0.91; folate: OR 4vs1 = 0.87, 95% CI = 0.73 to 1.03). We further noted that the association of folate was restricted to Europe/Australia and Asia, whereas no clear association was observed for the United States. Circulating concentrations of methionine were not associated with lung cancer risk overall or in important subgroups.
Conclusions - Although confounding by tobacco exposure or reverse causation cannot be ruled out, these study results are compatible with a small decrease in lung cancer risk in ever smokers who avoid low concentrations of circulating folate and vitamin B6.
© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

BACKGROUND - Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk.
METHODS - We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a value of <1.0×10 (Bonferroni correction for 50 tests).
RESULTS - We identified novel gene-smoking interaction for a variant upstream of the gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (=1.3×10) in comparison with 5% in ever-smokers (=2.5×10), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction value=8.7×10). The protective T allele at rs7178051 was also associated with reduced expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular expression may contribute to the loss of CHD protection in smokers.
© 2017 American Heart Association, Inc.

BACKGROUND - The lifetime risk of heart failure (HF) is higher in the black population than in other racial groups in the United States.
METHODS AND RESULTS - We measured the Life's Simple 7 ideal cardiovascular health metrics in 4195 blacks in the JHS (Jackson Heart Study; 2000-2004). We evaluated the association of Simple 7 metrics with incident HF and left ventricular structure and function by cardiac magnetic resonance (n=1188). Mean age at baseline was 54.4 years (65% women). Relative to 0 to 2 Simple 7 factors, blacks with 3 factors had 47% lower incident HF risk (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.39-0.73; <0.0001); and those with ≥4 factors had 61% lower HF risk (HR, 0.39; 95% CI, 0.24-0.64; =0.0002). Higher blood pressure (HR, 2.32; 95% CI, 1.28-4.20; =0.005), physical inactivity (HR, 1.65; 95% CI, 1.07-2.55; =0.02), smoking (HR, 2.04; 95% CI, 1.43-2.91; <0.0001), and impaired glucose control (HR, 1.76; 95% CI, 1.34-2.29; <0.0001) were associated with incident HF. The age-/sex-adjusted population attributable risk for these Simple 7 metrics combined was 37.1%. Achievement of ideal blood pressure, ideal body mass index, ideal glucose control, and nonsmoking was associated with less likelihood of adverse cardiac remodeling by cardiac magnetic resonance.
CONCLUSIONS - Cardiovascular risk factors in midlife (specifically elevated blood pressure, physical inactivity, smoking, and poor glucose control) are associated with incident HF in blacks and represent targets for intensified HF prevention.
© 2017 American Heart Association, Inc.

OBJECTIVE - Depressive symptom clusters are differentially associated with prognosis among patients with cardiovascular disease (CVD). Few studies have prospectively evaluated the association between depressive symptom clusters and risk of CVD. Previously, we observed that smoking and global depressive symptoms were synergistically associated with coronary artery calcification (CAC). The purpose of this study was to determine whether the smoking by depressive symptoms interaction, measured cumulatively over 25 years, differed by depressive symptom cluster (negative affect, anhedonia, and somatic symptoms) in association with CAC.
METHODS - Participants (N = 3,189: 54.5% female; 51.5% Black; average age = 50.1 years) were followed from 1985-1986 through 2010-2011 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Smoking exposure was measured by cumulative cigarette pack-years (cigarette packs smoked per day × number of years smoking; year 0 through year 25). Depressive symptoms were measured using a 14-item, 3-factor (negative affect, anhedonia, somatic symptoms) model of the Center for Epidemiologic Studies Depression (CES-D) Scale (years 5, 10, 15, 20, and 25). CAC was assessed at year 25. Logistic regression models were used to evaluate the association between the smoking by depressive symptom clusters interactions with CAC ( = 0 vs. > 0), adjusted for CVD-related sociodemographic, behavioral, and clinical covariates.
RESULTS - 907 participants (28% of the sample) had CAC > 0 at year 25. The depressive symptom clusters did not differ significantly between the two groups. Only the cumulative somatic symptom cluster by cumulative smoking exposure interaction was significantly associated with CAC > 0 at year 25 (p = .028). Specifically, adults with elevated somatic symptoms (score 9 out of 18) who had 10, 20, or 30 pack-years of smoking exposure had respective odds ratios (95% confidence intervals) of 2.06 [1.08, 3.93], 3.71 [1.81, 7.57], and 6.68 [2.87, 15.53], ps < .05. Negative affect and anhedonia did not significantly interact with smoking exposure associated with CAC >0, ps > .05.
CONCLUSIONS - Somatic symptoms appear to be a particularly relevant cluster of depressive symptomatology in the relationship between smoking and CVD risk.

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.
Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.

The molecular determinants of lung cancer risk remain largely unknown. Airway epithelial cells are prone to assault by risk factors and are considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into the molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushing specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified 2,869 proteins, of which 312 proteins demonstrated a trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for 7 months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-C] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results provide a rationale for the development of potentially new chemopreventive strategies and selection of patients for surveillance programs.

OBJECTIVE - Evaluate whether smoking exposure and depressive symptoms accumulated over 25 years are synergistically associated with subclinical heart disease, measured by coronary artery calcification (CAC).
METHOD - Participants (baseline: 54.5% women; 51.5% Black; age range = 18-30 years) were followed prospectively from 1985 to 2010 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Smoking status was queried yearly from Year 0 to Year 25 to compute packyears of smoking exposure. Depressive symptoms were measured on the Center for Epidemiologic Studies Depression (CES-D) scale every 5 years to compute cumulative scores from Year 5 to Year 25. A three-level multinomial logistic regression was used to evaluate the association between cumulative smoking, cumulative depressive symptoms, and their interaction with moderate-risk CAC (score 1-99) and higher-risk CAC (score ≥100) compared with no CAC (score = 0) at Year 25. Models were adjusted for sociodemographic, clinical, and behavioral covariates.
RESULTS - Among 3,189 adults, the cumulative Smoking × Depressive Symptoms interaction was not significant for moderate-risk CAC (p = .057), but was significant for higher-risk CAC (p = .001). For adults with a 30-packyear smoking history, average CES-D scores 2, 10, and 16 were, respectively, associated with odds ratios (95% confidence intervals) 3.40 (2.36-4.90), 4.82 (3.03-7.66), and 6.25 (3.31-11.83) for higher-risk CAC (all ps < .05).
CONCLUSION - Cumulative smoking exposure and cumulative depressive symptoms have a synergistic association with subclinical heart disease, where higher lifetime smoking exposure and depressive symptoms are associated with greater odds of CAC. (PsycINFO Database Record
(c) 2017 APA, all rights reserved).

Populations in sub-Saharan Africa are shifting from rural to increasingly urban. Although the burden of cardiovascular disease is expected to increase with this changing landscape, few large studies have assessed a wide range of risk factors in urban and rural populations, particularly in West Africa. We conducted a cross-sectional, population-based survey of 3317 participants from Ghana (≥18 years old), of whom 2265 (57% female) were from a mid-sized city (Sunyani, population ~250,000) and 1052 (55% female) were from surrounding villages (populations <5000). We measured canonical cardiovascular disease risk factors (BMI, blood pressure, fasting glucose, lipids) and fibrinolytic markers (PAI-1 and t-PA), and assessed how their distributions and related clinical outcomes (including obesity, hypertension and diabetes) varied with urban residence and sex. Urban residence was strongly associated with obesity (OR: 7.8, 95% CI: 5.3-11.3), diabetes (OR 3.6, 95% CI: 2.3-5.7), and hypertension (OR 3.2, 95% CI: 2.6-4.0). Among the quantitative measures, most affected were total cholesterol (+0.81 standard deviations, 95% CI 0.73-0.88), LDL cholesterol (+0.89, 95% CI: 0.79-0.99), and t-PA (+0.56, 95% CI: 0.48-0.63). Triglycerides and HDL cholesterol profiles were similarly poor in both urban and rural environments, but significantly worse among rural participants after BMI-adjustment. For most of the risk factors, the strength of the association with urban residence did not vary with sex. Obesity was a major exception, with urban women at particularly high risk (26% age-standardized prevalence) compared to urban men (7%). Overall, urban residents had substantially worse cardiovascular risk profiles, with some risk factors at levels typically seen in the developed world.