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

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Characterization of interventricular desynchronization in heart failure patients

Currently, QRS width and bundle branch block morphology are used as electrocardiographic guideline criterias to selectheart failure (HF) patients with interventricular desynchronization in sinus rhythm (SR) for cardiac resynchronisationtherapy (CRT). Nevertheless, up to 30% of these patients do not benefit from implantation of CRT systems. Esophagealleft ventricular electrogram (LVE) enables semi-invasive measurement of interventricular conduction delays (IVCD)even in patients with atrial fibrillation (AF). To routinely apply this method, a programmer based semi-invasiveautomatic quantification of IVCD should to be developed. Our aims were todefine interventricular conduction delaysby analyzing fractionated left ventricular (LV) deflections in the esophageal left ventricular electrogram of HF patientsin SR or AF. In 66 HF patients (49 male,17 female, age 65 ± 10 years) a 5F TOslim electrode (Osypka AG, Germany) was perorallyapplied. Using BARD EP Lab, cardiac desynchronization was quantified as interval IVCD between onset of QRS insurface ECG and the investigator-determined onset of the left ventricular deflection in LVE. IVCD was compared withthe intervals between QRS onset and the first maximum (IVCDm1) and between QRS onset and the second maximum(IVCDm2) of the LV complex. QRS of 173 ± 26 ms was linked with empirical IVCD of 75 ± 25 ms, at mean. First and second LV maximum could beascertained beyond doubt in all patients. Significant correlations of the p<0,01 level were found between IVCD and theIVCDm1 of 96 ± 28 ms as well as between IVCD and the IVCDm2 of 147 ± 31 ms, at mean. To standardize automatic measurement of interventricular conduction delays with respect to patients with fractionatedLV complexes, the first maximum of the LV deflection should be utilized to qualify the IVCD of HF patients with sinusrhythm and atrial fibrillation

Kann die Effektivität einer Resynchronisationstherapie der Herzschwäche gesteigert werden?

Die kardiale Resynchronisationstherapie ist ein großer Segen für viele Patienten mit einer Herzschwäche, die auf einen krankhaften Verlust der synchronen Kontraktion beider Herzkammern zurückzuführen ist. Warum einige von ihnen jedoch nicht darauf ansprechen, wird gegenwärtig erforscht. Als eine neue Methode mit dem Ziel der Effektivitätssteigerung dieser Therapie mit elektronischen Implantaten demonstrieren wir die Nutzbarkeit von durch eine Schluckelektrode aus der Speiseröhre abgeleiteten Elektrokardiogrammen