Background:
We investigated whether the aortic augmentation index (AIx), a measure of arterial wave reflection and stiffness, is associated with cardiorespiratory fitness in men without known ...coronary heart disease (CHD).
Methods:
Asymptomatic men (n = 201, mean age 51 ± 9.2 years) referred for a screening exercise electrocardiogram (ECG) underwent applanation tonometry to obtain radial artery pulse waveforms, and an ascending aortic pressure waveform was derived by a transfer function. The AIx is the difference between the first and second systolic peak of the ascending aortic pressure waveform, expressed as a percentage of the pulse pressure. Cardiorespiratory fitness was assessed by maximal oxygen consumption (VO2max mL/min/kg) during a symptom-limited graded exercise test. Multivariable regression analyses were used to identify significant independent determinants of AIx and of VO2 max.
Results:
Diabetes was present in 2.5% of subjects, 34.8% had history of smoking, and 29% were hypertensive. Mean (± SD) AIx was 19.9% ± 9.0% and mean VO2 max was 33.9 ± 6.4 mL/min/kg. In a multivariable linear regression model, AIx was positively associated with age, hypertension, and history of smoking and inversely with heart rate, height, and body mass index (BMI). The VO2 max was significantly inversely related to AIx after adjustment for age, heart rate, height, and BMI (r = −0.22, P = .002), after further adjustment for CHD risk factors (total cholesterol, HDL-cholesterol, history of smoking, diabetes, hypertension) (P = .006), and after additional adjustment for behavioral factors (physical activity score, alcohol intake, and percent body fat) (P = .022).
Conclusions:
These findings indicate that AIx, a measure of arterial wave reflection and stiffness, is inversely associated with cardiorespiratory fitness in men without CHD.
Polygenic risk scores (PRS) have led to enthusiasm for precision medicine. However, it is well documented that PRS do not generalize across groups differing in ancestry or sample characteristics ...e.g., age. Quantifying performance of PRS across different groups of study participants, using genome-wide association study (GWAS) summary statistics from multiple ancestry groups and sample sizes, and using different linkage disequilibrium (LD) reference panels may clarify which factors are limiting PRS transferability. To evaluate these factors in the PRS generation process, we generated body mass index (BMI) PRS (PRSBMI) in the Electronic Medical Records and Genomics (eMERGE) network (N=75,661). Analyses were conducted in two ancestry groups (European and African) and three age ranges (adult, teenagers, and children). For PRSBMI calculations, we evaluated five LD reference panels and three sets of GWAS summary statistics of varying sample size and ancestry. PRSBMI performance increased for both African and European ancestry individuals using cross-ancestry GWAS summary statistics compared to European-only summary statistics (6.3% and 3.7% relative R2 increase, respectively, pAfrican=0.038, pEuropean=6.26x10-4). The effects of LD reference panels were more pronounced in African ancestry study datasets. PRSBMI performance degraded in children; R2 was less than half of teenagers or adults. The effect of GWAS summary statistics sample size was small when modeled with the other factors. Additionally, the potential of using a PRS generated for one trait to predict risk for comorbid diseases is not well understood especially in the context of cross-ancestry analyses - we explored clinical comorbidities from the electronic health record associated with PRSBMI and identified significant associations with type 2 diabetes and coronary atherosclerosis. In summary, this study quantifies the effects that ancestry, GWAS summary statistic sample size, and LD reference panel have on PRS performance, especially in cross-ancestry and age-specific analyses.
We explored premature stop-gain variants to test the hypothesis that variants, which are likely to have a consequence on protein structure and function, will reveal important insights with respect to ...the phenotypes associated with them. We performed a phenome-wide association study (PheWAS) exploring the association between a selected list of functional stop-gain genetic variants (variation resulting in truncated proteins or in nonsense-mediated decay) and an extensive group of diagnoses to identify novel associations and uncover potential pleiotropy.
In this study, we selected 25 stop-gain variants: 5 stop-gain variants with previously reported phenotypic associations, and a set of 20 putative stop-gain variants identified using dbSNP. For the PheWAS, we used data from the electronic MEdical Records and GEnomics (eMERGE) Network across 9 sites with a total of 41,057 unrelated patients. We divided all these samples into two datasets by equal proportion of eMERGE site, sex, race, and genotyping platform. We calculated single effect associations between these 25 stop-gain variants and ICD-9 defined case-control diagnoses. We also performed stratified analyses for samples of European and African ancestry. Associations were adjusted for sex, site, genotyping platform and the first three principal components to account for global ancestry. We identified previously known associations, such as variants in LPL associated with hyperglyceridemia indicating that our approach was robust. We also found a total of three significant associations with p < 0.01 in both datasets, with the most significant replicating result being LPL SNP rs328 and ICD-9 code 272.1 "Disorder of Lipoid metabolism" (pdiscovery = 2.59x10-6, preplicating = 2.7x10-4). The other two significant replicated associations identified by this study are: variant rs1137617 in KCNH2 gene associated with ICD-9 code category 244 "Acquired Hypothyroidism" (pdiscovery = 5.31x103, preplicating = 1.15x10-3) and variant rs12060879 in DPT gene associated with ICD-9 code category 996 "Complications peculiar to certain specified procedures" (pdiscovery = 8.65x103, preplicating = 4.16x10-3).
In conclusion, this PheWAS revealed novel associations of stop-gained variants with interesting phenotypes (ICD-9 codes) along with pleiotropic effects.
The emerging scientific field of proteomics encompasses the identification, characterization, and quantification of the protein content or proteome of whole cells, tissues, or body fluids. The ...potential for proteomic technologies to identify and quantify novel proteins in the plasma that can function as biomarkers of the presence or severity of clinical disease states holds great promise for clinical use. However, there are many challenges in translating plasma proteomics from bench to bedside, and relatively few plasma biomarkers have successfully transitioned from proteomic discovery to routine clinical use. Key barriers to this translation include the need for "orthogonal" biomarkers (i.e., uncorrelated with existing markers), the complexity of the proteome in biological samples, the presence of high abundance proteins such as albumin in biological samples that hinder detection of low abundance proteins, false positive associations that occur with analysis of high dimensional datasets, and the limited understanding of the effects of growth, development, and age on the normal plasma proteome. Strategies to overcome these challenges are discussed.
Background: Inflammation is proposed to play a role in the development of Alzheimer's disease, and may also be involved in the pathogenesis of mild cognitive impairment (MCI). This study examined the ...association of inflammatory markers in serum or plasma with prevalent MCI and MCI subtypes in a population-based sample. Methods: Olmsted County, MN, residents aged 70-89 years on October 1, 2004, were evaluated using the Clinical Dementia Rating Scale, a neurological evaluation, and neuropsychological testing. Information ascertained for each participant was reviewed by an expert panel of neuropsychologists, physicians, and nurses, and a diagnosis of normal cognition, MCI, or dementia was made by consensus. C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis alpha (TNFα), and adiponectin were measured at baseline. Results: Among 313 subjects with MCI and 1570 cognitively normal subjects, a CRP level in the upper quartile (>3.3 mg/L) was significantly associated with MCI (odds ratio OR, 1.42; 95% confidence interval CI, 1.00-2.01) and with nonamnestic MCI (OR, 2.05; 95% CI, 1.12-3.78) after adjusting for age, sex, and years of education. However, there was no association with amnestic MCI (OR, 1.21; 95% CI, 0.81-1.82). No association was observed with the other inflammatory markers. Conclusions: Plasma CRP is associated with prevalent MCI and with nonamnestic MCI in elderly, nondemented persons in a population-based setting. These findings suggest the involvement of inflammation in the pathogenesis of MCI.
The level of CYP2D6 metabolic activity can be predicted by pharmacogenomic testing, and concomitant use of clinical decision support has the potential to prevent adverse effects from those drugs ...metabolized by this enzyme. Our initial findings after implementation of clinical decision support alerts integrated in the electronic health records suggest high feasibility, but also identify important challenges.
PDF
