Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis
Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis
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DOI：
10.1093/hmg/ddn082
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发表时间：
2008-06-15
影响因子：
3.5
通讯作者：
Slagboom, P. Eline
中科院分区：
文献类型：
--
作者：
Meulenbelt, Ingrid;Min, Josine L.;Slagboom, P. Eline
骨关节炎[MIM 165720]是一种常见的迟发性关节疾病，目前尚无药物干预可减轻软骨退变。为了确定一个新的骨关节炎易感位点，对179名受影响的兄弟姐妹和4名患有全身性骨关节炎的三人组进行了全基因组连锁扫描和联合连锁关联分析（GARP研究）。我们在英国人群中对1478名需要关节置换的受试者和734名对照者进行了测试，以通过相关性进行确认。在来自鹿特丹研究的1582名基于人群的女性中进行了额外的重复测试，该研究包括94例明确的髋关节骨关节炎病例，267例有症状的髋关节骨关节炎日本女性和465例对照。在GARP研究中，在染色体14q32.11上观察到了连锁的证据（优势对数= 3.03，P = 1.9x10（-4））。对三个重要候选基因的单核苷酸多态性进行基因分型，发现2型碘甲腺原氨酸脱碘酶（D2）基因（DIO 2 [MIM 601413]）中存在一个共同的编码变体（rs 225014; Thr 92 Ala），这显著解释了连锁信号（P = 0.006）。在另外的骨关节炎研究中通过关联的确认和复制表明了共同的DIO 2单倍型，仅包含次要等位基因rs 225014和共同等位基因rs 12885300，组合隐性优势比为1.79，晚期/症状性髋关节骨关节炎女性病例的95%置信区间（CI）为1.37-2.34，P = 2.02x10（-5）。该DIO 2的基因产物将细胞内激素原-3，3 '，5，5'-四碘甲腺原氨酸（T4）转化为活性甲状腺激素3，3 '，5-三碘甲腺原氨酸（T3），从而调节靶组织如生长板中活性T3的细胞内水平。我们的研究结果表明，一个新的易感基因（DIO 2）赋予骨关节炎的风险。
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 = 1.9x10(-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 = 2.02x10(-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.