Human Molecular Genetics Advance Access originally published online on May 7, 2009
Human Molecular Genetics 2009 18(15):2825-2838; doi:10.1093/hmg/ddp218
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Positional identification of variants of Adamts16 linked to inherited hypertension
1 Physiological Genomics Laboratory, Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Avenue, Toledo, OH 43614-2598, USA 2 Department of Pharmacology and Physiology, The George Washington University, Washington, D.C., USA 3 Department of Biomedical Engineering and Orthopedic Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA 4 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA 5 Department of Preventive Medicine, Laval University, Quebec, Canada 6 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 7 Division of Cardiology, Geneva University Hospital, Geneva, Switzerland 8 National Human Genome Research Institute, Bethesda, MD, USA 9 Department of Preventive Medicine and Epidemiology, Stritch School of Medicine, Loyola University, Chicago, IL, USA 10 Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA 11 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
* To whom correspondence should be addressed. Tel: +1 4193834415; Fax: +1 4193832871; Email: bina.joe{at}utoledo.edu
Received March 4, 2009; Revised April 24, 2009; Accepted May 5, 2009
A previously reported blood pressure (BP) quantitative trait locus on rat Chromosome 1 was isolated in a short congenic segment spanning 804.6 kb. The 804.6 kb region contained only two genes, LOC306664 and LOC306665. LOC306664 is predicted to translate into A Disintegrin-like and Metalloproteinase with Thrombospondin Motifs-16 (Adamts16). LOC306665 is a novel gene. All predicted exons of both LOC306664 and LOC306665 were sequenced. Non-synonymous variants were identified in only one of these genes, LOC306664. These variants were naturally existing polymorphisms among inbred, outbred and wild rats. The full-length rat transcript of Adamts16 was detected in multiple tissues. Similar to ADAMTS16 in humans, expression of Adamts16 was prominent in the kidney. Renal transcriptome analysis suggested that a network of genes related to BP was differential between congenic and S rats. These genes were also differentially expressed between kidney cell lines with or without knock-down of Adamts16. Adamts16 is conserved between rats and humans. It is a candidate gene within the homologous region on human Chromosome 5, which is linked to systolic and diastolic BP in the Quebec Family Study. Multiple variants, including an Ala to Pro variant in codon 90 (rs2086310) of human ADAMTS16, were associated with human resting systolic BP (SBP). Replication study in GenNet confirmed the association of two variants of ADAMTS16 with SBP, including rs2086310. Overall, our report represents a high resolution positional cloning and translational study for Adamts16 as a candidate gene controlling BP.