Wellcome Trust Sanger Institute, Morgan Building, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.
Lancet. 2012 Sep 1;380(9844):815-23. doi: 10.1016/S0140-6736(12)60681-3. Epub 2012 Jul 3.
Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity.
We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent.
We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects.
Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.
arcOGEN was funded by a special purpose grant from Arthritis Research UK.
骨关节炎是全球最常见的关节炎形式，也是老年人疼痛和残疾的主要原因。随着肥胖症患病率和预期寿命的增加，骨关节炎的健康经济负担也在不断增加。骨关节炎具有很强的遗传成分，但由于样本量不足和表型异质性，先前的遗传研究取得的成功有限。
我们在 arcOGEN 研究中对 7410 名无血缘关系的、经回顾性和前瞻性选择的严重骨关节炎患者进行了一项大型全基因组关联研究（GWAS），其中 80%的患者接受了全关节置换，以及从英国的 11009 名无血缘关系的对照中进行了研究。我们在来自冰岛、爱沙尼亚、荷兰和英国的多达 7473 例病例和 42938 例对照的独立研究中复制了最有希望的信号。所有患者和对照均为欧洲血统。
我们确定了与骨关节炎相关的五个全基因组显著位点（二项检验 p≤5.0×10(-8)）和三个接近此阈值的位点。最强的关联位于 3 号染色体上，与 rs6976 相关（优势比 1.12[95%CI 1.08-1.16]；p=7.24×10(-11)），该 SNP 与 rs11177 完全连锁不平衡。该 SNP 编码核干细胞编码基因 GNL3 内的错义多态性。在功能研究中，来自骨关节炎患者的软骨细胞中核干细胞水平升高。其他显著的位点位于 9 号染色体接近 ASTN2 的位置，6 号染色体位于 FILIP1 和 SENP6 之间，12 号染色体接近 KLHDC5 和 PTHLH 的位置，以及 12 号染色体上另一个接近 CHST11 的区域。接近全基因组显著水平的一个信号位于 FTO 基因内，该基因参与体重调节-这是骨关节炎的一个强烈危险因素。所有风险变异均为常见频率，并产生较小的影响。
我们的研究结果提供了关节炎遗传学的深入了解，并确定了可能适用于未来治疗干预的新途径。
arcOGEN 由关节炎研究英国的一项特殊用途拨款资助。
