Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Cardiac Magnetic Resonance Imaging Findings and the Risk of Cardiovascular Events in Patients With Recent Myocardial Infarction or Suspected or Known Coronary Artery Disease

The goal of this study was to review the prognostic value of cardiac magnetic resonance (CMR) imaging findings for future cardiovascular events in patients with a recent myocardial infarction (MI) and patients with suspected or known coronary artery disease (CAD). Although the diagnostic value of CMR findings is established, the independent prognostic association with future cardiovascular events remains largely unclear. Studies published by February 2013, identified by systematic MEDLINE and EMBASE searches, were reviewed for associations between CMR findings (left ventricular ejection fraction [LVEF], wall motion abnormalities [WMA], abnormal myocardial perfusion, microvascular obstruction, late gadolinium enhancement, edema, and intramyocardial hemorrhage) and hard events (all-cause mortality, cardiac death, cardiac transplantation, and MI) or major adverse cardiovascular events (MACE) (hard events and other cardiovascular events defined by the authors of the evaluated papers). Fifty-six studies (n = 25,497) were evaluated. For patients with recent MI, too few patients were evaluated to establish associations between CMR findings and hard events. LVEF (range of adjusted hazard ratios [HRs]: 1.03 to 1.05 per % decrease) was independently associated with MACE. In patients with suspected or known CAD, WMA (adjusted HRs: 1.87 to 2.99), inducible perfusion defects (adjusted HRs: 3.02 to 7.77), LVEF (adjusted HRs: 0.72 to 0.82 per 10% increase), and infarction (adjusted HRs: 2.82 to 9.43) were independently associated with hard events, and the presence of inducible perfusion defects was associated with MACE (adjusted HRs: 1.76 to 3.21). The independent predictor of future cardiovascular events for patients with a recent MI was LVEF, and the predictors for patients with suspected or known CAD were WMA, inducible perfusion defects, LVEF, and presence of infarction

Rationale and design of the measuring athlete’s risk of cardiovascular events (MARC) study : The role of coronary ct in the cardiovascular evaluation of middle-aged sportsmen

BACKGROUND: More than 90 % of exercise-related cardiac arrests occur in men, predominantly those aged 45 years and older with coronary artery disease (CAD) as the main cause. The current sports medical evaluation (SME) of middle-aged recreational athletes consists of a medical history, physical examination, and resting and exercise electrocardiography. Coronary CT (CCT) provides a minimally invasive low radiation dose opportunity to image the coronary arteries. We present the study protocol of the Measuring Athlete's Risk of Cardiovascular events (MARC) study. MARC aims to assess the additional value of CCT to a routine SME in asymptomatic sportsmen ≥45 years without known CAD. DESIGN: MARC is a prospective study of 300 asymptomatic sportsmen ≥45 years who will undergo CCT if the SME does not reveal any cardiac abnormalities. The prevalence and determinants of CAD (coronary artery calcium score ≥100 Agatston Units (AU) or ≥50 % luminal stenosis) will be reported. The number needed to screen to prevent the occurrence of one cardiovascular event in the next 5 years, conditional to adequate treatment, will be estimated. DISCUSSION: We aim to determine the prevalence and severity of CAD and the additional value of CCT in asymptomatic middle-aged (≥45 years) sportsmen whose routine SME revealed no cardiac abnormalities