Aref-Eshghi Erfan, Zhang Yuhua, Hart Deborah, Valdes Ana M, Furey Andrew, Martin Glynn, Sun Guang, Rahman Proton, Arden Nigel, Spector Tim D, Zhai Guangju
Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.
PLoS One. 2014 May 22;9(5):e97786. doi: 10.1371/journal.pone.0097786. eCollection 2014.
A newly-described syndrome called Aneurysm-Osteoarthritis Syndrome (AOS) was recently reported. AOS presents with early onset osteoarthritis (OA) in multiple joints, together with aneurysms in major arteries, and is caused by rare mutations in SMAD3. Because of the similarity of AOS to idiopathic generalized OA (GOA), we hypothesized that SMAD3 is also associated with GOA and tested the hypothesis in a population-based cohort.
Study participants were derived from the Chingford study. Kellgren-Lawrence (KL) grades and the individual features of osteophytes and joint space narrowing (JSN) were scored from radiographs of hands, knees, hips, and lumbar spines. The total KL score, osteophyte score, and JSN score were calculated and used as indicators of the total burden of radiographic OA. Forty-one common SNPs within SMAD3 were genotyped using the Illumina HumanHap610Q array. Linear regression modelling was used to test the association between the total KL score, osteophyte score, and JSN score and each of the 41 SNPs, with adjustment for patient age and BMI. Permutation testing was used to control the false positive rate.
A total of 609 individuals were included in the analysis. All were Caucasian females with a mean age of 60.9±5.8. We found that rs3825977, with a minor allele (T) frequency of 20%, in the last intron of SMAD3, was significantly associated with total KL score (β = 0.14, Ppermutation = 0.002). This association was stronger for the total JSN score (β = 0.19, Ppermutation = 0.002) than for total osteophyte score (β = 0.11, Ppermutation = 0.02). The T allele is associated with a 1.47-fold increased odds for people with 5 or more joints to be affected by radiographic OA (Ppermutation = 0.046).
We found that SMAD3 is significantly associated with the total burden of radiographic OA. Further studies are required to reveal the mechanism of the association.
最近报道了一种新描述的综合征，称为动脉瘤 - 骨关节炎综合征（AOS）。AOS表现为多关节的早发性骨关节炎（OA），同时伴有主要动脉的动脉瘤，由SMAD3中的罕见突变引起。由于AOS与特发性全身性骨关节炎（GOA）相似，我们假设SMAD3也与GOA相关，并在基于人群的队列中对该假设进行了检验。
研究参与者来自Chingford研究。根据手、膝、髋和腰椎的X线片对Kellgren-Lawrence（KL）分级以及骨赘和关节间隙狭窄（JSN）的个体特征进行评分。计算总KL评分、骨赘评分和JSN评分，并将其用作放射学OA总负担的指标。使用Illumina HumanHap610Q芯片对SMAD3内的41个常见单核苷酸多态性（SNP）进行基因分型。采用线性回归模型检验总KL评分、骨赘评分和JSN评分与41个SNP中的每一个之间的关联，并对患者年龄和体重指数进行调整。采用置换检验控制假阳性率。
共有609人纳入分析。所有参与者均为白种女性，平均年龄为60.9±5.8岁。我们发现，位于SMAD3最后一个内含子中的rs3825977，其次要等位基因（T）频率为20%，与总KL评分显著相关（β = 0.14，置换P值 = 0.002）。该关联在总JSN评分（β = 0.19，置换P值 = 0.002）中比在总骨赘评分（β = 0.11，置换P值 = 0.02）中更强。T等位基因与5个或更多关节受放射学OA影响的人群的患病几率增加1.47倍相关（置换P值 = 0.046）。
我们发现SMAD3与放射学OA的总负担显著相关。需要进一步研究以揭示这种关联的机制。
