Human Molecular Genetics Advance Access published online on March 11, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn082
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Identification of DIO2 as new susceptibility locus for symptomatic Osteoarthritis
,*1 Departments of Molecular Epidemiology, Leiden University Medical Center, 2300RC. Leiden, The Netherlands 2 Departments of Rheumatology, Leiden University Medical Center, 2300RC. Leiden, The Netherlands 3 Departments of Medical Statistics and Bio-informatic Leiden University Medical Center, 2300RC. Leiden, The Netherlands 4 Departments of Radiology of the Leiden University Medical Center, 2300RC. Leiden, The Netherlands 5 Departments of Internal Medicine Erasmus University Medical School, 3015 GE, Rotterdam, The Netherlands 6 Departments of Epidemiology & Biostatistics of the Erasmus University Medical School, 3015 GE, Rotterdam, The Netherlands 7 Departments of Pfizer Research technology Center, Cambridge, MA 02139, USA 8 Departments of Clinical Epidemiology and Haematology, 2300 RC, Leiden University Medical Center The Netherlands 9 University of Oxford, Nuffield Department of Orthopaedic Surgery, Institute of Musculoskeletal Sciences, Botnar Research Centre, OX3 7LD Oxford, UK 10 Laboratory for Bone and Joint Diseases, SRC, RIKEN, University of Tokyo, Minato-ku, Tokyo, Japan
* To whom correspondence should be addressed at: Section Molecular Epidemiology, Leiden University Medical Centre, Postzone S-05-P, PO Box 9600, 2300 RC Leiden, The Netherlands Tel. +31 71 526 9734; Fax +31 71 526 8280 E-mail: i.meulenbelt{at}lumc.nl
Received February 7, 2008; Revised March 9, 2008; Accepted March 9, 2008
Osteoarthritis [MIM 165720 [OMIM] ] is a common late-onset articular joint disease for which no pharmaceutical intervention is available that attenuates the cartilage degeneration. To identify a new osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis was applied to 179 affected siblings and 4 trios with generalized osteoarthritis (The GARP study). We tested for confirmation by association in a UK population consisting of 1478 subjects who required joint replacement and 734 controls. Additional replication was tested in 1582 population based females from the Rotterdam study that contained 94 cases with defined hip osteoarthritis and in 267 Japanese females with symptomatic hip osteoarthritis and 465 controls. Suggested evidence for linkage in the GARP study was observed on chromosome 14q32.11 (LOD=3.03, P=1.9x10–4). Genotyping tagging SNPs covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 [MIM 601413 [OMIM] ]) which significantly explained the linkage signal (P=0.006). Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval [CI] 1.37-2.34 with P=2.02x10–5 in females cases with advanced / symptomatic hip osteoarthritis. The gene product of this DIO2 converts intracellular pro-hormone-3,3’,5,5’-tetraiodothyronine (T4) into the active thyroid hormone 3,3’,5-triiodothyronine (T3) thereby regulating intracellular levels of active T3 in target tissues such as the growth plate. Our results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis.
Both authors contributed equally to the paper.
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