Journal Article

Identification of <i>DIO2</i> as a new susceptibility locus for symptomatic osteoarthritis

Ingrid Meulenbelt, Josine L. Min, Steffan Bos, Naghmeh Riyazi, Jeanine J. Houwing-Duistermaat, Henk-Jan van der Wijk, Herman M. Kroon, Masahiro Nakajima, Shiro Ikegawa, André G. Uitterlinden, Joyce B.J. van Meurs, Wendy M. van der Deure, Theo J. Visser, Albert B. Seymour, Nico Lakenberg, Ruud van der Breggen, Dennis Kremer, Cornelia M. van Duijn, Margreet Kloppenburg, John Loughlin and P. Eline Slagboom

in Human Molecular Genetics

Volume 17, issue 12, pages 1867-1875
Published in print June 2008 | ISSN: 0964-6906
Published online March 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn082
Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis

Show Summary Details

Preview

Osteoarthritis [MIM 165720] is a common late-onset articular joint disease for which no pharmaceutical intervention is available to attenuate the cartilage degeneration. To identify a new osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis were applied to 179 affected siblings and four trios with generalized osteoarthritis (The GARP study). We tested, for confirmation by association, 1478 subjects who required joint replacement and 734 controls in a UK population. 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 (log of odds = 3.03, P = 1.9×10−4). Genotyping tagging single-nucleotide polymorphisms covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 [MIM 601413]) 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 = 2.02×10−5 in female 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.

Journal Article.  7011 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.