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

Generation of two iPSC lines derived from two unrelated patients with Gaucher disease

Gaucher disease is the most common autosomal recessive lysosomal storage disorder, caused by mutations in the β-glucocerebrosidase gene GBA. Here we describe generation of iPSC from skin-derived fibroblasts from two unrelated individuals with neuronopathic forms of Gaucher disease. The donor for line iPSC-GBA-1, a 21 month old girl, carried the recurring GBA mutation c.1448 T > C, p.Leu483Pro at homozygous state; fibroblasts for line iPS-GBA-2 were obtained from a 4 year old girl compound heterozygous for the GBA mutations c.667 T > C, p.Trp223Arg and c.1226A > G, p.Asn409Ser. iPSCs were developed using integration free episomal vectors (OCT4, KLF4; L-MYC, SOX2 (OSKM) and LIN28).Resource tableUnlabelled TableUnique stem cell lines identifierHIHRSi001-AHIHRSi002-AAlternative names of stem cell linesiPSC-GBA-1 (HIHRSi001-A)iPSC-GBA-2 (HIHRSi002-A)InstitutionHertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases (DZNE), Tübingen, GermanyContact information of distributorRebecca Schü[email protected] of cell linesInduced pluripotent stem cell (iPSC)OriginHumanCell sourceFibroblastsClonalityClonalMethod of reprogrammingNon-integrating episomal plasmidsMultiline rationaleTwo cell lines carrying individual GBA mutationsGene modificationYesType of modificationinherited mutationAssociated diseaseGaucher Disease, neuronopathic (OMIM # 230900, 23100)Gene/locusGBAiPSC-GBA-1: NM_000157.3(GBA): c.[1448 T > C]; [1448 T > C] | p.[Leu483Pro]; [Leu483Pro] (originally published as Leu444Pro (Tsuji et al., 1987))iPSC-GBA-2: NM_000157.3(GBA): c.[667 T > C];[1226A > G] | p.[Trp223Arg];[Asn409Ser] (Trp223Arg originally published as Trp184Arg (Choy et al., 2000))Method of modificationN/AName of transgene or resistanceN/AInducible/constitutive systemN/ADate archived/stock dateJune 2017Cell line repository/bankN/AEthical approvalInstitutional Review Board (“Ethikkommission”) University of Tübingen Medical School, Germany, approval number 819/2016A (2016/12/21

Optimization of Enzyme Essays to Enhance Reliability of Activity Measurements in Leukocyte Lysates for the Diagnosis of Metachromatic Leukodystrophy and Gangliosidoses

(1) Lysosomal storage diseases are rare inherited disorders with no standardized or commercially available tests for biochemical diagnosis. We present factors influencing the quality of enzyme assays for metachromatic leukodystrophy (MLD) and gangliosidoses (GM1; GM2 variants B and 0) and validate the reliability and stability of testing in a retrospective analysis of 725 samples. (2) Patient leukocytes were isolated from ethylene-diamine-tetra-acetic acid (EDTA) blood and separated for subpopulation experiments using density gradient centrifugation or magnetic cell separation. Enzyme activities in whole leukocyte lysate and leukocyte subpopulations were determined. (3) The enzyme activities in leukocyte subpopulations differed significantly. Compared to lymphocytes, the respective enzyme activities were 2.31–4.57-fold higher in monocytes and 1.64–2.81-fold higher in granulocytes. During sample preparation, a considerable amount of the lysosomal enzymes was released from granulocytes. Nevertheless, with the sample preparation method used here, total leukocyte count proved to be more accurate than total protein amount as a reference unit for enzyme activities. Subsequent analysis of 725 individuals showed clear discrimination of enzyme activities in patient samples (48 MLD; 21 gangliosidoses), with a sensitivity of 100% and specificity of 98–99%