Relationship Between High-Sensitivity Cardiac Troponin I and Blood Pressure Among Young and Healthy Adults

BACKGROUND The aim of this study was to evaluate the relationship of cardiac troponin (cTn) levels with conventional and ambulatory blood pressure (BP) in young and healthy adults. METHODS We performed a population based cross-sectional analysis among 2,072 young and healthy adults aged 25-41 years free of cardiovascular disease and diabetes mellitus. cTnI was measured using a highly sensitive (hs) assay. The relationships of high sensitivity cardiac tropononin I (hs-cTnI) with office and 24-hour BP were assessed using multivariable regression analyses. RESULTS Median age was 37 years and 975 (47%) participants were male. hs-cTnI levels were detectable in 2,061 (99.5%) individuals. Median (interquartile range) hs-cTnI levels were 0.98 (0.71; 1.64) ng/L among men and 0.48 (0.33; 0.71) ng/L among women. Systolic BP, but not diastolic BP, gradually increased across hs-cTnI quartiles (118, 120, 121, and 122 mm Hg for conventional BP; P = 0.0002; 122, 123, 124, and 124 mm Hg for 24-hour BP, P = 0.0001). In multivariable linear regression analyses, the β estimates for systolic BP per 1-unit increase in log transformed hs-cTnI were 2.52 for conventional BP (P = 0.0001); 2.75 for 24-hour BP (P < 0.0001); 2.71 and 2.41 (P < 0.0001 and P = 0.0002) for day and nighttime BP, respectively. There was a significant relationship between hs-cTnI and the Sokolow-Lyon Index (odds ratio (95% confidence interval): 2.09 (1.37; 3.18), P < 0.001). CONCLUSION Using a hs assay, hs-cTnI was detectable in virtually all participants of a young and healthy population. hs-cTnI was independently associated with systolic BP and left ventricular hypertroph

An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the <i>HLA-DRB1</i> locus

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n=63), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (&gt;700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis

Massive migration from the steppe is a source for Indo-European languages in Europe

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost four hundred thousand polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of western and far eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ~8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary, and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ~24,000 year old Siberian6 . By ~6,000-5,000 years ago, a resurgence of hunter-gatherer ancestry had occurred throughout much of Europe, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ~4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ~3/4 of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ~3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for the theory of a steppe origin of at least some of the Indo-European languages of Europe

MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium.

Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.This work was supported by the National Institutes of Health [R01CA136725 to T.L.V. and D.C.W, T32CA009168 to T.L.V, and K05CA124911 to T.L.V.]. Additional funding sources for individual studies included in the BEACON GWAS, and for BEACON investigators, have been acknowledged previously (16).This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.012861

Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies

Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×$10^{−9}$). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci