title: Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis.
abstract: 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 x 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 x 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.
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. i.meulenbelt@lumc.nl
authors.forename: Ingrid
authors.initials: I
authors.lastname: Meulenbelt
authors.forename: Josine L
authors.initials: JL
authors.lastname: Min
authors.forename: Steffan
authors.initials: S
authors.lastname: Bos
authors.forename: Naghmeh
authors.initials: N
authors.lastname: Riyazi
authors.forename: Jeanine J
authors.initials: JJ
authors.lastname: Houwing-Duistermaat
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: van der Wijk
authors.forename: Herman M
authors.initials: HM
authors.lastname: Kroon
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: Wendy M
authors.initials: WM
authors.lastname: van der Deure
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
authors.forename: Albert B
authors.initials: AB
authors.lastname: Seymour
authors.forename: Nico
authors.initials: N
authors.lastname: Lakenberg
authors.forename: Ruud
authors.initials: R
authors.lastname: van der Breggen
authors.forename: Dennis
authors.initials: D
authors.lastname: Kremer
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Margreet
authors.initials: M
authors.lastname: Kloppenburg
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
mesh_terms: D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010003:Osteoarthritis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014284:Triiodothyronine / Q000378:metabolism; D006113:United Kingdom; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II