Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis.
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.
Meulenbelt
Ingrid
I
Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. i.meulenbelt@lumc.nl
Min
Josine L
JL
Bos
Steffan
S
Riyazi
Naghmeh
N
Houwing-Duistermaat
Jeanine J
JJ
van der Wijk
Henk-Jan
HJ
Kroon
Herman M
HM
Nakajima
Masahiro
M
Ikegawa
Shiro
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Uitterlinden
André G
AG
van Meurs
Joyce B J
JB
van der Deure
Wendy M
WM
Visser
Theo J
TJ
Seymour
Albert B
AB
Lakenberg
Nico
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van der Breggen
Ruud
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Kremer
Dennis
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van Duijn
Cornelia M
CM
Kloppenburg
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Loughlin
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Slagboom
P Eline
PE
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
D007453:Iodide Peroxidase; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II