Epidemiology,genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene

Background

Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV₁ in the setting of a preserved FEV₁/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.

Methods

Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45–80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.

Results

The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter’s syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative “COPD-subtype”, “Restrictive-subtype”, and a highly symptomatic “Metabolic-subtype”.

Conclusions

PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.

Trial registration

Clinicaltrials.gov Identifier: NCT000608764.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0089-y) contains supplementary material, which is available to authorized users.     

Relationships among the concentrations of 25 inflammation-associated proteins during the first postnatal weeks in the blood of infants born before the 28th week of gestation

Background

Inflammation appears to be involved in processes leading to organ damage in preterm newborns, yet little is known about the relationships among elevated concentrations of inflammation-associated proteins in the blood of preterm newborns.

Methods

In this exploratory study, we used an electrochemiluminescence method to measure 25 proteins in blood obtained on postnatal day 1 (range 1-3), day 7 (range 5-8), and day 14 (range 12-15) from 939 children born before the 28th week of gestation and evaluated to what extent those whose concentration of each protein was elevated (defined as in the highest quartile for gestational age and day the specimen was obtained) also had an elevated concentration of every other protein the same day or on a day 1 or 2 weeks later (p < .0001).

Results

On each of the 3 days assessed, elevated concentrations of 17 proteins were associated with elevated concentrations of 15 or more of the other 24 proteins. VEGF, VEGF-R1, VEGF-R2 were among these proteins, while IGFBP-1 was associated with 13 other proteins on day 7. An elevated concentration of eight proteins on day 1 predicted an elevated concentration of 10 or more proteins on day 7, while an elevated concentration of only two proteins on day 7 were associated with elevated concentrations of 10 or more proteins on day-14. Few associations were seen between days 1 and 14.

Conclusions/inferences

Inflammation is a diffuse process in ELGANs, with elevated concentrations of cytokines, chemokines, adhesion molecules, matrix metalloproteinases, a growth factor and its receptors, as well as a growth factor binding protein associated with each other the same day, as well as on subsequent days.     

Genetics of sputum gene expression in chronic obstructive pulmonary disease

Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.     

Are There Gender Differences in Coronary Artery Disease? The Malaysian National Cardiovascular Disease Database – Percutaneous Coronary Intervention (NCVD-PCI) Registry

Objectives

To assess whether gender differences exist in the clinical presentation, angiographic severity, management and outcomes in patients with coronary artery disease (CAD).

Methods

The study comprised of 1,961 women and 8,593 men who underwent percutaneous coronary intervention (PCI) and were included in the Malaysian NCVD-PCI Registry from 2007–2009. Significant stenosis was defined as ≥70% stenosis in at least one of the epicardial vessels.

Results

Women were significantly older and had significantly higher rates of diabetes mellitus, hypertension, chronic renal failure, new onset angina and prior history of heart failure whereas smokers and past history of myocardial infarction were higher in men. In the ST-elevation myocardial infarction (STEMI) cohort, more women were in Killip class III-IV, had longer door-to-balloon time (169.5 min. vs 127.3 min, p<0.052) and significantly longer transfer time (300.4 min vs 166.3 min, p<0.039). Overall, women had significantly more left main stem (LMS) disease (1.3% vs 0.6%, p<0.003) and smaller diameter vessels (<3.0 mm: 45.5% vs 34.8%, p<0.001). In-hospital mortality rates for all PCI, STEMI, Non-STEMI (NSTEMI) and unstable angina for women and men were 1.99% vs 0.98%, Odds ratio (OR): 2.06 (95% confidence interval (CI): 1.40 to 3.01), 6.19% vs 2.88%, OR: 2.23 (95% CI: 1.31 to 3.79), 2.90% vs 0.79%, OR: 3.75 (95% CI: 1.58 to 8.90) and 1.79% vs 0.29%, OR: 6.18 (95% CI: 0.56 to 68.83), respectively. Six-month adjusted OR for mortality for all PCI, STEMI and NSTEMI in women were 2.18 (95% CI: 0.97 to 4.90), 2.68 (95% CI: 0.37 to 19.61) and 2.66 (95% CI: 0.73 to 9.69), respectively.

Conclusions

Women who underwent PCI were older with more co-morbidities. In-hospital and six-month mortality for all PCI, STEMI and NSTEMI were higher due largely to significantly more LMS disease, smaller diameter vessels, longer door-to-balloon and transfer time in women.     

Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study

Background

To investigate the ameliorating effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood glucose control in patients with type 2 diabetes mellitus who were previously untreated with or who have a poor responsive to existing antidiabetic drugs.

Methods

Sitagliptin (50 mg/day) was added on to the pre-existing therapy for type 2 diabetes and changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline and performed exploratory analysis.

Results

HbA1c levels were significantly decreased after 1 month of treatment compared to baseline, with a mean change in HbA1c level from baseline of ?0.73% (range, ?0.80 to ?0.67) in the entire study population at 3 months. Patients who received a medium dose of glimepiride showed the least improvement in HbA1c levels. The percentage of patients who achieved an HbA1c level of <7.0% significantly increased after 1 month of treatment, reaching 53.1% at 3 months. The percentage of patients who achieved a fasting blood glucose level of <130 mg/dL significantly increased after 1 month of treatment, reaching 50.9% at 3 months.

Conclusions

Sitagliptin improved the HbA1c level and rate of achieving the target control levels in patients with type 2 diabetes mellitus who were previously untreated with, or poorly responsive to, existing antidiabetic drugs. Thus, sitagliptin is expected to be useful in this patient group. However, the additional administration of sitagliptin in patients treated with medium-dose glimepiride only slightly improved blood glucose control when corrected for baseline HbA1c level.

     

Association between Serum Ferritin and Osteocalcin as a Potential Mechanism Explaining the Iron-Induced Insulin Resistance

Background

Increased iron stores are associated with increased risk of type 2 diabetes, however, the mechanisms underlying these associations are poorly understood. Because a reduction of circulating osteocalcin levels after iron overload have been demonstrated in cell cultures, and osteocalcin is related to glucose and insulin metabolism, the iron-induced osteocalcin reductions could contribute to explain the role of iron metabolism in the development of type 2 diabetes mellitus.

Objective

To analyzed the associations between serum total and uncarboxylated osteocalcin and adiponectin concentrations with serum ferritin and soluble transferrin receptor (sTfR) in elderly subjects.

Design

We evaluated a total of 423 subjects from the PREDIMED cohort in a population-based cross-sectional analysis. Extensive clinical, nutritional and laboratory measurements, including total and uncarboxylated osteocalcin, adiponectin, ferritin and sTfR were recorded.

Results

Serum ferritin was positively correlated with increased glucose and insulin circulating levels but also with HOMA-IR, and was inversely associated with total osteocalcin and adiponectin. A regression analysis revealed that serum ferritin and transferrin receptor levels were significantly associated with a decrease in total and uncarboxylated osteocalcin. Serum sTfR levels were associated with lower uncarboxylated osteocalcin levels in the whole-study subjects and remained significant only in the IFG (impaired fasting glucose) individuals.

Conclusions

We described, for the first time, an inverse association between serum ferritin and sTfR with osteocalcin and extend previous results on adiponectin, thus supporting that factors related to iron metabolism could contribute to the insulin resistance and the development of type 2 diabetes mellitus.

Trial Registration

Controlled-Trials.com ISRCTN35739639 <ISRCTN35739639>.     

In a subgroup of high-risk Asians, telmisartan was non-inferior to ramipril and better tolerated in the prevention of cardiovascular events

Background and Objectives

Results of the recently published ONTARGET study (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) showed that telmisartan (80 mg/day) was non-inferior to ramipril (10 mg/day) in reducing cardiovascular events. Clinicians in Asia doubt tolerability of these doses for their patients. We therefore analyzed data from this study and a parallel study TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease). Our objectives were to compare Asians and non-Asians with respect to the following:

1. 1) Effectiveness of telmisartan vs. ramipril in reducing cardiovascular events;
2. 2) Proportions who reached the full dose of telmisartan, ramipril or placebo; and
3. 3) Proportions of overall discontinuations, and discontinuations due to adverse effects.

Method

The ONTARGET study randomized 25,620 patients at risk of cardiovascular events to ramipril, telmisartan, or their combination. The primary composite endpoint was death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. TRANSCEND randomized 5926 high-risk patients with a history of intolerance to ACE-inhibitors to telmisartan or placebo. The primary outcome was the same. In this substudy, we compared Asians and non-Asians as to how well they tolerated telmisartan (given in both studies) and ramipril (given in ONTARGET).

Results

1) Telmisartan was non-inferior to ramipril in lowering the primary endpoint among Asians (RR = 0.92; 95% CI: 0.74, 1.13); 2) more Asians achieved the full dose of either drug; 3) less withdrew (overall); and 4) less withdrew for adverse effects. Furthermore, telmisartan was better tolerated than ramipril. This advantage was greater among Asians.

Conclusion and Significance

Although Asians had lower BMI than non-Asians, Asians tolerated both drugs better. Regulatory agencies require reporting of safety and effectiveness data by ethnicity, but few comply with this requirement. This study shows that safety data in ethnic subgroups can help assess applicability of results to specific populations.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00153101","term_id":"NCT00153101"}}NCT00153101     

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Coalescent-based estimation of population parameters when the number of demes changes over time

We expand a coalescent-based method that uses serially sampled genetic data from a subdivided population to incorporate changes to the number of demes and patterns of colonization. Often, when estimating population parameters or other parameters of interest from genetic data, the demographic structure and parameters are not constant over evolutionary time. In this paper, we develop a Bayesian Markov chain Monte Carlo method that allows for step changes in mutation, migration, and population sizes, as well as changing numbers of demes, where the times of these changes are also estimated. We show that in parameter ranges of interest, reliable estimates can often be obtained, including the historical times of parameter changes. However, posterior densities of migration rates can be quite diffuse and estimators somewhat biased, as reported by other authors.