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1.  Effects of Mineralocorticoid Receptor Antagonists on the Risk of Sudden Cardiac Death in Patients With Left Ventricular Systolic Dysfunction 
Circulation. Heart failure  2013;6(2):166-173.
Sudden cardiac death (SCD) is an important cause of death in patients with left ventricular systolic dysfunction. Mineralocorticoid receptor antagonists (MRAs) may attenuate this risk. The objective of this meta-analysis was to assess the impact of MRAs on SCD in patients with left ventricular systolic dysfunction.
Methods and Results
We systematically searched PubMed, EMBASE, Cochrane, and other databases through March 30, 2012, without language restrictions. We included trials that enrolled patients with left ventricular ejection fraction of ≤45%, randomized subjects to MRAs versus control and reported outcomes on SCD, total and cardiovascular mortality. Eight published trials that enrolled 11875 patients met inclusion criteria. Of these, 6 reported data on SCD and cardiovascular mortality, and 7 reported data on total mortality. No heterogeneity was observed among the trials. Patients treated with MRAs had 23% lower odds of experiencing SCD compared with controls (odds ratio, 0.77; 95% confidence interval, 0.66–0.89; P=0.001). Similar reductions were observed in cardiovascular (0.75; 95% confidence interval, 0.68– 0.84; P<0.001) and total mortality (odds ratio, 0.74; 95% confidence interval, 0.63–0.86; P<0.001). Although publication bias was observed, the results did not change after a trim and fill test, suggesting that the impact of this bias was likely insignificant.
MRAs reduce the risk of SCD in patients with left ventricular systolic dysfunction. Comparative effectiveness studies of MRAs on SCD in usual care as well as studies evaluating the efficacy of other therapies to prevent SCD in patients receiving optimal MRA therapy are needed to guide clinical decision-making.
PMCID: PMC3893922  PMID: 23403436
left ventricular systolic dysfunction; meta-analysis; mineralocorticoid receptor antagonists; sudden cardiac death
2.  The effect of excess weight gain with intensive diabetes treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes: Results from the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) study 
Circulation  2012;127(2):10.1161/CIRCULATIONAHA.111.077487.
Intensive diabetes therapy of type 1 diabetes (T1DM) reduces diabetes complications but can be associated with excess weight gain, central obesity, and dyslipidemia.
The purpose of this study was to determine if excessive weight gain with diabetes therapy of T1DM is prospectively associated with atherosclerotic disease.
Methods and Results
Subjects with T1DM (97% Caucasian, 45% female, mean age 35 years) randomly assigned to intensive (INT) or conventional (CONV) diabetes treatment during the Diabetes Control and Complications Trial (DCCT) underwent intima-media thickness (IMT) (n=1015) and coronary artery calcium (CAC) score (n=925) measurements during follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. INT subjects were classified by quartile of BMI change during the DCCT. Excess gainers (4th quartile, including CONV subjects meeting this threshold) maintained greater BMI and waist circumference (WC), needed more insulin, had greater IMT (+5%, P<0.001 EDIC year 1, P=0.003 EDIC year 6), and trended towards greater CAC scores (OR 1.55, CI 0.97 – 2.49, P=0.07) than minimal gainers. DCCT subjects meeting metabolic syndrome criteria for WC and blood pressure had greater IMT in both EDIC years (P =0.02 to <0.001); those meeting HDL criteria had greater CAC scores (OR 1.6 and CI 1.1 – 2.4, P=0.01) during follow-up. Increasing frequency of a family history of diabetes, hypertension, and hyperlipidemia was associated with greater IMT thickness with INT but not CONV.
Excess weight gain in DCCT is associated with sustained increases in central obesity, insulin resistance, dyslipidemia and blood pressure, as well as more extensive atherosclerosis during EDIC.
PMCID: PMC3819101  PMID: 23212717
diabetes mellitus; carotid intima media thickness; coronary artery calcium; imaging; obesity
3.  Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility 
Human genetics  2013;132(4):431-441.
Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r2 = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.
PMCID: PMC3600068  PMID: 23299987
4.  Gender Differences of Airway Dimensions in Anatomically Matched Sites on CT in Smokers 
COPD  2011;8(4):285-292.
Rationale and Objectives
There are limited data on, and controversies regarding gender differences in the airway dimensions of smokers. Multi-detector CT (MDCT) images were analyzed to examine whether gender could explain differences in airway dimensions of anatomically matched airways in smokers.
Materials and Methods
We used VIDA imaging software to analyze MDCT scans from 2047 smokers (M:F, 1021:1026) from the COPDGene® cohort. The airway dimensions were analyzed from segmental to subsubsegmental bronchi. We compared the differences of luminal area, inner diameter, wall thickness, wall area percentage (WA%) for each airway between men and women, and multiple linear regression including covariates (age, gender, body sizes, and other relevant confounding factors) was used to determine the predictors of each airway dimensions.
Lumen area, internal diameter and wall thickness were smaller for women than men in all measured airway (18.4 vs 22.5 mm2 for segmental bronchial lumen area, 10.4 vs 12.5 mm2 for subsegmental bronchi, 6.5 vs 7.7 mm2 for subsubsegmental bronchi, respectively p < 0.001). However, women had greater WA% in subsegmental and subsubsegmental bronchi. In multivariate regression, gender remained one of the most significant predictors of WA%, lumen area, inner diameter and wall thickness.
Women smokers have higher WA%, but lower luminal area, internal diameter and airway thickness in anatomically matched airways as measured by CT scan than do male smokers. This difference may explain, in part, gender differences in the prevalence of COPD and airflow limitation.
PMCID: PMC3703311  PMID: 21756032
Airway dimensions; CT scan; Gender differences; Smoker
5.  Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD 
Respiratory Research  2013;14(1):42.
Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease.
Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema.
In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables.
Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.
PMCID: PMC3627637  PMID: 23566024
Emphysema; Chest CT scan; Small airways; Lung function tests; Smoking
6.  The Association of Genome-Wide Significant Spirometric Loci with Chronic Obstructive Pulmonary Disease Susceptibility 
Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV1 and FEV1/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.
PMCID: PMC3262664  PMID: 21659657
7.  Genome-wide association study of smoking behaviors in COPD patients 
Thorax  2011;66(10):894-902.
Cigarette smoking is a major risk factor for COPD and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a Dopamine Beta-Hydroxylase (DBH) locus associated with smoking cessation in multiple populations.
To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in COPD subjects.
GWAS were conducted in 4 independent cohorts encompassing 3,441 ever-smoking COPD subjects (GOLD stage II or higher). Untyped SNPs were imputed using HapMap (phase II) panel. Results from all cohorts were meta-analyzed.
Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within alpha-nicotinic acetylcholine receptors 3/5 (CHRNA3/CHRNA5; e.g. p=0.00011 for SNP rs1051730) and Cytochrome P450 2A6 (CYP2A6; e.g. p=2.78×10−5 for a nonsynonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in the DBH was significantly (p=0.015) associated with smoking cessation.
We identified two candidate regions associated with age at smoking initiation in COPD subjects. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviors of COPD patients.
PMCID: PMC3302576  PMID: 21685187
Chronic Obstructive Pulmonary Disease (COPD); Genome Wide Association study (GWAS); smoking behaviors; Single Nucleotide Polymorphism (SNP)
8.  Early-Onset Chronic Obstructive Pulmonary Disease Is Associated with Female Sex, Maternal Factors, and African American Race in the COPDGene Study 
Rationale: The characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights.
Methods: We analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n = 70, age < 55 yr, FEV1 < 50% predicted) were compared with older subjects with COPD (n = 306, age > 64 yr, FEV1 < 50% predicted).
Measurements and Main Results: Subjects with severe, early-onset COPD were predominantly females (66%), P = 0.0004. Proportionally, early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P < 0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P = 0.008). Maternal smoking (70 vs. 44%, P = 0.0001) and maternal COPD (23 vs. 12%, P = 0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3–24; P = 0.0007); maternal COPD, OR, 4.7 (95% CI, 1.3–17; P = 0.02); female sex, OR, 3.1 (95% CI, 1.1–8.7; P = 0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96–1.0; P = 0.03).
Conclusions: These observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.
PMCID: PMC3175544  PMID: 21562134
chronic obstructive pulmonary disease; female; African Americans
9.  Clinical and Radiographic Predictors of GOLD–Unclassified Smokers in the COPDGene Study 
Rationale: A significant proportion of smokers have lung function impairment characterized by a reduced FEV1 with a preserved FEV1/FVC ratio. These smokers are a poorly characterized group due to their systematic exclusion from chronic obstructive pulmonary disease (COPD) studies.
Objectives: To characterize the clinical, functional, and radiographic features of Global Initiative for Chronic Obstructive Lung Disease (GOLD)-Unclassified (FEV1/FVC ≥ 0.7 and FEV1 < 80% predicted) and lower limits of normal (LLN)-unclassified (FEV1/FVC ≥ LLN and FEV1 < LLN) subjects compared to smokers with normal lung function and subjects with COPD.
Methods: Data from the first 2,500 subjects enrolled in the COPDGene study were analyzed. All subjects had 10 or more pack-years of smoking and were between the ages of 45 and 80 years. Multivariate regression models were constructed to determine the clinical and radiological variables associated with GOLD-Unclassified (GOLD-U) and LLN-Unclassified status. Separate multivariate regressions were performed in the subgroups of subjects with complete radiologic measurement variables available.
Measurements and Main Results: GOLD-U smokers account for 9% of smokers in COPDGene and have increased body mass index (BMI), a disproportionately reduced total lung capacity, and a higher proportion of nonwhite subjects and subjects with diabetes. GOLD-U subjects exhibit increased airway wall thickness compared to smoking control subjects and decreased gas trapping and bronchodilator responsiveness compared to subjects with COPD. When LLN criteria were used to define the “unclassified” group, African American subjects were no longer overrepresented. Both GOLD-U and LLN-Unclassified subjects demonstrated a wide range of lung function impairment, BMI, and percentage of total lung emphysema.
Conclusions: Subjects with reduced FEV1 and a preserved FEV1/FVC ratio are a heterogeneous group with significant symptoms and functional limitation who likely have a variety of underlying etiologies beyond increased BMI.
Clinical trial registered with (NCT000608764).
PMCID: PMC3172890  PMID: 21493737
lung diseases, classification; lung diseases, diagnosis; lung diseases, epidemiology
10.  The independent relationship between triglycerides and coronary heart disease 
The aim was to review epidemiologic studies to reassess whether serum levels of triglycerides should be considered independently of high-density lipoprotein-cholesterol (HDL-C) as a predictor of coronary heart disease (CHD).
Methods and results:
We systematically reviewed population-based cohort studies in which baseline serum levels of triglycerides and HDL-C were included as explanatory variables in multivariate analyses with the development of CHD (coronary events or coronary death) as dependent variable. A total of 32 unique reports describing 38 cohorts were included. The independent association between elevated triglycerides and risk of CHD was statistically significant in 16 of 30 populations without pre-existing CHD. Among populations with diabetes mellitus or pre-existing CHD, or the elderly, triglycerides were not significantly independently associated with CHD in any of 8 cohorts. Triglycerides and HDL-C were mutually exclusive predictors of coronary events in 12 of 20 analyses of patients without pre-existing CHD.
Epidemiologic studies provide evidence of an association between triglycerides and the development of primary CHD independently of HDL-C. Evidence of an inverse relationship between triglycerides and HDL-C suggests that both should be considered in CHD risk estimation and as targets for intervention.
PMCID: PMC2672447  PMID: 19436658
coronary heart disease; triglycerides; high-density lipoprotein-cholesterol; low-density lipoprotein-cholesterol; hypercholesterolemia
11.  Gender Differences in the Prognostic Value of Exercise Treadmill Test Characteristics 
American heart journal  2011;161(5):908-914.
Although exercise treadmill testing (ETT) is known to be less sensitive and specific for diagnosis of coronary disease in women, little is known about gender differences in the prognostic importance of ETT variables.
We studied9569 consecutive patients (46.8% women) referred for ETT between July 2001- June 2004 in a community-based system. We assessed the association between ETT variables (exercise capacity, symptoms, ST-segment deviations, heart rate recovery, and chronotropic response) and time to all-cause death and myocardial infarction adjusting for patient and stress test characteristics. Models were stratified by gender to determine the relationship between ETT variables and outcomes.
In the entire population, exercise capacity and heart rate recovery were significantly associated with all-cause death, whereas, exercise capacity, chest pain and ST-segment deviations were significantly associated with subsequent MI. The relationship between ETT variables and outcomes were similar between men and women except for abnormal exercise capacity, which was had a significantly stronger association with death in men (men: HR = 2.89, 95% CI 1.89–4.44; women: HR = 0.99, 95% CI 0.52–1.93; interaction
While many traditional ETT variables had similar prognostic value in both men and women, exercise capacity was more prognostically important in men and chronotropic incompetence was more important in women. Future studies should confirm these findings in additional populations.
PMCID: PMC3096065  PMID: 21570521
gender differences; stress testing; prognosis
Coronary artery calcification (CAC) and thoracic aortic calcificatio (TAC) are frequently detected on ungated multi-detector computed tomography (MDCT) performed for lung evaluations. We sought to evaluate concordance of CAC and TAC scores on ungated (thoracic) and ECG-gated (cardiac) MDCT scans.
Fifty patients, enrolled in the Genetic Epidemiology of COPD study (COPDGene), were recruited to undergo gated CAC scans using 64-detector row CT, in addition to the ungated thoracic studies already being obtained as part of their study evaluation. Coronary and thoracic calcium was measured similarly (Agatston score, requiring 3 contiguous voxels of >130 Hounsfield units) using low-dose ungated studies and ECG-gated MDCT performed at the same scanning session. Intertechnique scoring variability and concordance were calculated.
Correlations between gated and ungated CAC and TAC were excellent (r = 0.96). The relative differences (median variability) measured by ECG-gated vs. ungated MDCT were relatively high for CAC (44%) but not for TAC (8%). Prevalence of depicted CAC (n=33, 66%) and TAC (n=21, 42%) were coincident between ECG-gated and ungated MDCT, respectively (inter-technique concordance 100%). Bland-Altman plots for CAC demonstrated mean differences of 354 (CI 169–538) and 16.1(CI −89–121).
Low-dose ungated MDCT is reliable for prediction of the presence of CAC and assessment of Agatston score. Concordance between methods and between TAC and CAC is high. This technique should allow for atherosclerotic disease risk stratification among patients undergoing ungated lung CT evaluation without requiring additional scanning. Measurement of TAC is almost as accurate from gated CT, and CAC scores are highly concordant.
PMCID: PMC3075464  PMID: 21167806
Diabetes Care  2011;34(2):454-458.
The objective of this study is to examine the relationship among serum levels of 25-hydroxyvitamin D (25[OH]D), polymorphisms in vitamin D-associated genes, and the presence and progression of coronary artery calcification (CAC) in adults with type 1 diabetes.
This prospective study included 374 non-Hispanic white individuals with type 1 diabetes (mean age 40 ± 9 years; 46% were male). CAC was measured at the baseline and 3- and 6-year follow-up visits were determined by electron beam computed tomography. Serum 25[OH]D levels were measured by liquid chromatography tandem mass spectrometry at the 3-year visit.
Normal (>30 ng/mL), insufficient (20–30 ng/mL), and deficient (<20 ng/mL) 25-[OH]D levels were present in 65%, 25%, and 10% of the individuals with type 1 diabetes, respectively. 25[OH]D deficiency was associated with the presence of CAC at the 3-year visit, odds ratio (OR) = 3.3 (95% CI 1.6–7.0), adjusting for age, sex, and hours of daylight. In subjects free of CAC at the 3-year visit, 25[OH]D deficiency predicted the development of CAC over the next 3 years in those with the vitamin D receptor M1T CC genotype (OR = 6.5 [1.1–40.2], P = 0.04) than in those with the CT or TT genotype (OR = 1.6 [0.3–8.6], P = 0.57).
Vitamin D deficiency independently predicts prevalence and development of CAC, a marker of coronary artery plaque burden, in individuals with type 1 diabetes.
PMCID: PMC3024366  PMID: 20978098
Diabetes  2010;59(7):1771-1779.
Individuals with type 1 diabetes have a less atherogenic fasting lipid profile than those without diabetes but paradoxically have increased rates of cardiovascular disease (CVD). We investigated differences in lipoprotein subfraction cholesterol distribution and insulin resistance between subjects with and without type 1 diabetes to better understand the etiology of increased CVD risk.
Fast protein liquid chromatography was used to fractionate lipoprotein cholesterol distribution in a substudy of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (n = 82, age 46 ± 8 years, 52% female, 49% with type 1 diabetes for 23 ± 8 years). Insulin resistance was assessed by a hyperinsulinemic-euglycemic clamp.
Among men, those with type 1 diabetes had less VLDL and more HDL cholesterol than control subjects (P < 0.05), but among women, those with diabetes had a shift in cholesterol to denser LDL, despite more statin use. Among control subjects, men had more cholesterol distributed as VLDL and LDL but less as HDL than women; however, among those with type 1 diabetes, there was no sex difference. Within sex and diabetes strata, a more atherogenic cholesterol distribution by insulin resistance was seen in men with and without diabetes, but only in women with type 1 diabetes.
The expected sex-based less atherogenic lipoprotein cholesterol distribution was not seen in women with type 1 diabetes. Moreover, insulin resistance was associated with a more atherogenic lipoprotein cholesterol distribution in all men and in women with type 1 diabetes. This lipoprotein cholesterol distribution may contribute to sex-based differences in CVD in type 1 diabetes.
PMCID: PMC2889778  PMID: 20393149
To assess the relationship between mortality and impairment and decline in a specific executive cognitive function, the capacity for behavioral self-regulation.
Study Design & Setting
This study examined the association between mortality and baseline and 22-month decline in the capacity for behavioral self-regulation, as measured by the Behavioral Dyscontrol Scale, among 1,293 participants of the San Luis Valley Health and Aging Study (SLVHAS), a population-based longitudinal study. The Behavioral Dyscontrol Scale and a measure of overall mental status, the Mini-Mental State Examination, were administered at baseline and follow-up interviews. Cox regression was used to examine baseline and decline in capacity for behavioral self-regulation as possible predictors of morality.
Baseline Behavioral Dyscontrol Scale score was predictive of mortality, independent of demographics and comorbidity count (HR=1.07; 95% CI:1.04–1.09). It remained a significant predictor with further adjustment for Mini-Mental State Examination score. Decline in this specific executive cognitive function was associated with mortality after adjustment for covariates and baseline cognitive scores (HR=1.09; 95% CI:1.04–1.13).
Thus, both baseline capacity for behavioral self-regulation and its decline over time predicted mortality in the SLVHAS cohort. These associations may partly be due to maintaining the ability for self-care. Understanding how specific forms of impairment contribute to mortality may help identify patients who could benefit from early intervention.
PMCID: PMC2822133  PMID: 19716261
executive cognitive function; cognitive impairment; cognitive decline; mortality; Hispanic; San Luis Valley Health and Aging Study
COPD  2010;7(1):32-43.
COPDGeneis a multicenter observational study designed to identify genetic factors associated with COPD. It will also characterize chest CT phenotypes in COPD subjects, including assessment of emphysema, gas trapping, and airway wall thickening. Finally, subtypes of COPD based on these phenotypes will be used in a comprehensive genome-wide study to identify COPD susceptibility genes.
COPDGene will enroll 10,000 smokers with and without COPD across the GOLD stages. Both Non-Hispanic white and African-American subjects are included in the cohort. Inspiratory and expiratory chest CT scans will be obtained on all participants. In addition to the cross-sectional enrollment process, these subjects will be followed regularly for longitudinal studies. A genome-wide association study (GWAS) will be done on an initial group of 4000 subjects to identify genetic variants associated with case-control status and several quantitative phenotypes related to COPD. The initial findings will be verified in an additional 2000 COPD cases and 2000 smoking control subjects, and further validation association studies will be carried out.
COPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans. Understanding genetic factors and CT phenotypes that define COPD will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
PMCID: PMC2924193  PMID: 20214461
Respiratory Research  2011;12(1):9.
Cigarette smoking is the principal environmental risk factor for developing COPD, and nicotine dependence strongly influences smoking behavior. This study was performed to elucidate the relationship between nicotine dependence, genetic susceptibility to nicotine dependence, and volumetric CT findings in smokers.
Current smokers with COPD (GOLD stage ≥ 2) or normal spirometry were analyzed from the COPDGene Study, a prospective observational study. Nicotine dependence was determined by the Fagerstrom test for nicotine dependence (FTND). Volumetric CT acquisitions measuring the percent of emphysema on inspiratory CT (% of lung <-950 HU) and gas trapping on expiratory CT (% of lung <-856 HU) were obtained. Genotypes for two SNPs in the CHRNA3/5 region (rs8034191, rs1051730) previously associated with nicotine dependence and COPD were analyzed for association to COPD and nicotine dependence phenotypes.
Among 842 currently smoking subjects (335 COPD cases and 507 controls), 329 subjects (39.1%) showed high nicotine dependence. Subjects with high nicotine dependence had greater cumulative and current amounts of smoking. However, emphysema severity was negatively correlated with the FTND score in controls (ρ = -0.19, p < .0001) as well as in COPD cases (ρ = -0.18, p = 0.0008). Lower FTND score, male gender, lower body mass index, and lower FEV1 were independent risk factors for emphysema severity in COPD cases. Both CHRNA3/5 SNPs were associated with FTND in current smokers. An association of genetic variants in CHRNA3/5 with severity of emphysema was only found in former smokers, but not in current smokers.
Nicotine dependence was a negative predictor for emphysema on CT in COPD and control smokers. Increased inflammation in more highly addicted current smokers could influence the CT lung density distribution, which may influence genetic association studies of emphysema phenotypes.
Trial registration
ClinicalTrials (NCT): NCT00608764
PMCID: PMC3033825  PMID: 21232152
Cystatin C has been proposed to better estimate renal function and predict cardiovascular disease (CVD) than serum creatinine. To expand on our previous report, we investigated whether the relationship of cystatin C to progression of coronary artery atherosclerosis (CA) differed between individuals with type 1 diabetes (T1D) and persons without diabetes.
Coronary artery calcium was measured twice over 2.4 ± 0.4 years (n = 1,123, age = 39 ± 9 years, 47% male, 45% T1D). Significant CA progression was defined as a ≥2.5 increase in square root calcium volume score or development of clinical coronary artery disease. Stepwise multiple logistic regression was performed to investigate whether the association of cystatin C to CA progression differed by T1D status.
The main finding and novelty of this article is that while the univariate association of cystatin C to CA progression was similar in T1D patients and persons without diabetes mellitus and in the expected direction (increased cystatin C as a biomarker of worsening renal function associated with CA progression), the association of cystatin C to progression of CA differed by T1D status (P = 0.01) after adjustment for other CVD risk factors. Unexpectedly, in persons without diabetes mellitus having relatively normal renal function, increased cystatin C was associated with decreased CA progression (odd ratio [OR] = 0.65, 95% confidence interval 0.44–0.96, P = 0.029) after adjustment, primarily due to adjustment for body mass index (BMI). Removal of BMI from this model resulted in a 49% change in the OR.
Our hypothesis-generating data suggest a complex relationship among cystatin C, BMI, and CA progression that requires further study.
PMCID: PMC2883530  PMID: 20082582
Biochimica et biophysica acta  2009;1791(11):1057-1065.
Our aim was to identify an insulin response element (IRE) in the lipoprotein lipase (LPL) gene. We identified a 19 bp sequence as a putative IRE in LPL non-coding exon 10 using bioinformatics. Upon sequencing the IRE region, a novel 5 bp deletion was identified in Hispanics (N=406) with a carrier frequency of 4.2% but not in non-Hispanic whites (N=604) or Africans. Electrophoretic mobility shift assay revealed binding sites for regulatory factor(s) in muscle cell nuclear extracts with putative IRE sequence. Antibody supershift assay using human aorta smooth muscle cell nuclear extract revealed that Elk-1 specifically binds to putative IRE. TaqMan real-time RT-PCR of the 5 bp deletion, the mutant and wild type cDNA expressed in COS-1 and human muscle cells revealed that the 5 bp deletion was associated with modest reduction in LPL expression. There was also a slight reduction in LPL translation in the deletion mutant. Our data suggest the presence of an IRE in the 3′UTR of the LPL gene.
PMCID: PMC2753688  PMID: 19563912
Lipoprotein lipase; Exon 10 mutation; Electrophoretic mobility shift assay
Nature genetics  2010;42(3):200-202.
Substantial evidence suggests that there is genetic susceptibility to chronic obstructive pulmonary disease (COPD). To identify common genetic risk variants, we performed a genome-wide association study in 2940 cases and 1380 smoking controls with normal lung function. We demonstrate a novel susceptibility locus at 4q22.1 in FAM13A (rs7671167, OR=0.76, P=8.6×10−8) and provide evidence of replication in one case-control and two family-based cohorts (for all studies, combined P=1.2×10−11).
PMCID: PMC2828499  PMID: 20173748
Diabetes  1995;44(10):1218-1226.
Levels of lipoprotein (a) [Lp(a)], apolipoprotein (apo) B, and lipoprotein cholesterol distribution using density-gradient ultracentrifugation were measured as part of a cross-sectional study at the final follow-up examination (mean 6.2 years) in the Diabetes Control and Complications Trial. Compared with the subjects in the conventionally treated group (n = 680), those subjects receiving intensive diabetes therapy (n = 667) had a lower level of Lp(a) (Caucasian subjects only, median 10.7 vs. 12.5 mg/dl, respectively; P = 0.03), lower apo B (mean 83 vs. 86 mg/dl, respectively; P = 0.01), and a more favorable distribution of cholesterol in the lipoprotein fractions as measured by density-gradient ultracentrifugation with less cholesterol in the very-low-density lipoprotein and the dense low-density lipoprotein fractions and greater cholesterol content of the more buoyant low-density lipoprotein. Compared with a nondiabetic Caucasian control group (n = 2,158), Lp(a) levels were not different in the intensive treatment group (median 9.6 vs. 10.7 mg/dl, respectively; NS) and higher in the conventional treatment group (9.6 vs. 12.5 mg/dl, respectively; P less than 0.01). No effect of renal dysfunction as measured by increasing albuminuria or reduced creatinine clearance on Lp(a) levels could be demonstrated in the diabetic subjects. Prospective follow-up of these subjects will determine whether these favorable lipoprotein differences in the intensive treatment group persist and whether they influence the onset of atherosclerosis in insulin-dependent diabetes.
PMCID: PMC2866034  PMID: 7556961
Adolescent; Adult; African Continental Ancestry Group; Apolipoproteins B; Blood Glucose; Cholesterol; Cholesterol; LDL; Diabetes Mellitus; Type 1; Diabetes Mellitus; Type 1; European Continental Ancestry Group; Female; Follow-Up Studies; Hemoglobin A; Glycosylated; Humans; Hypoglycemic Agents; Longitudinal Studies; Male; Probability; Reference Values; Sex Characteristics; Triglycerides
Rationale: Extracellular superoxide dismutase (EC-SOD) is a potent antioxidant that plays an important role in controlling oxidant-mediated stress and inflammation. High levels of EC-SOD are found in the lung. Acute lung injury (ALI) frequently occurs in patients with infection, and levels of EC-SOD have been shown to modulate severity of lung injury in transgenic animal models of endotoxemia-induced ALI. An R213G single nucleotide polymorphism (SNP) has been shown to alter levels of EC-SOD and patient outcomes in chronic obstructive pulmonary disease (COPD) and ischemic heart disease.
Objectives: To determine genetic variation in the promoter and EC-SOD gene and to examine whether EC-SOD haplotype blocks are associated with clinical outcomes.
Methods: We sequenced the EC-SOD promoter and gene to determine genetic variation and linkage disequilibrium (LD) patterns in a European American population. Two separate patient populations with infection-associated ALI were also evaluated to determine whether EC-SOD haplotypes were associated with clinical outcomes.
Measurements and Main Results: Sequencing resulted in the identification of 28 SNPs with relatively strong LD and 1 block consisting of 4691-5321-5360-5955-5982. This specific block was shown to be protective in two separate patient populations with infection associated ALI. In particular, patients with a GCCT haplotype had a reduced risk of time on the ventilator and mortality.
Conclusions: These results indicate that a GCCT haplotype may reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with infection-induced ALI.
PMCID: PMC2633057  PMID: 18948423
EC-SOD; haplotypes; acute lung injury; single nucleotide polymorphism
In this study we sought to validate urinary biomarkers for diabetes and two common complications, coronary artery disease (CAD) and diabetic nephropathy (DN).
A CAD score calculated by summing the product of a classification coefficient and signal amplitude of 15 urinary polypeptides was previously developed. Five sequences of biomarkers in the panel were identified as fragments of collagen Α-1(I) and Α-1(III). Prospectively collected urine samples available for analysis from 19 out of 20 individuals with CAD (15 with type 1 diabetes [T1D] and four without diabetes) and age-, sex-, and diabetes-matched controls enrolled in the Coronary Artery Calcification in Type 1 Diabetes study were analyzed for the CAD score using capillary electrophoresis and electrospray ionization mass spectrometry. Two panels of biomarkers that were previously defined to distinguish diabetes status were analyzed to determine their relationship to T1D. Three biomarker panels developed to distinguish DN (DNS) and two biomarker panels developed to distinguish renal disease (RDS) were examined to determine their relationship with renal function.
The CAD score was associated with CAD (odds ratio with 95% confidence interval, 2.2 [1.3–5.2]; P = 0.0016) and remained significant when adjusted individually for age, albumin excretion rate (AER), blood pressure, waist circumference, intraabdominal fat, glycosylated hemoglobin, and lipids. DNS and RDS were significantly correlated with AER, cystatin C, and serum creatinine. The biomarker panels for diabetes were both significantly associated with T1D status (P < 0.05 for both).
We validated a urinary proteome pattern associated with CAD and urinary proteome patterns associated with T1D and DN.
PMCID: PMC2939844  PMID: 19132849
Diabetes care  1999;22(7):1165-1170.
This population study examines the relationship between LDL density and persistent albuminuria in subjects with type 1 diabetes at the end of the Diabetes Control and Complications Trial (DCCT).
Subjects were classified as persistently normoalbuminuric (albumin excretion rate [AER] <30 mg/d, n = 1,056), microalbuminuric (AER ≥30–299 mg/day, n = 80), and macroalbuminuric (AER = 300 mg/day, n = 24) based on the last two AER measures.
Triglyceride (P <0.01) and LDL cholesterol (P <0.01) levels were higher in macroalbuminuric subjects compared with normoalbuminuric subjects. Cholesterol distribution by density-gradient ultracentrifugation showed an increase in intermediate-density lipoprotein (IDL) and a shift in peak LDL from buoyant toward more dense particles with progressive albuminuria. In the entire group, there was a significant negative correlation between the peak buoyancy of LDL particles and albuminuria (r = −0.238, P <0.001, n = 1,160). This correlation persisted in the normoalbuminuric DCCT group (r = −0.138, P<0.001, n = 1,056).
As albuminuria increases in subjects with type 1 diabetes, dyslipidemia occurs with an increase in IDL and dense LDL that may lead to increased cardiovascular disease.
PMCID: PMC2635089  PMID: 10388983

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