蝕骨細胞抑制因子 (osteoprotegerin) 基因多形性與台灣人僵直性脊椎炎之相關

Association between osteoprotegerin genetic polymorphism and Taiwanese ankylosing spondylitis

黃駿煌(Jun-Huang Huang)

指導教授 ： 李鴻森 ； 翁瑞宏

中山醫學大學/醫學院/醫學研究所/碩士(2009年)

https://doi.org/10.6834/CSMU.2009.00064

摘要

僵直性脊椎炎 (ankylosing spondylitis；AS) 被報告具有骨質流失的現象，而造骨細胞 (osteoblast) 與蝕骨細胞 (osteoclast) 的作用一旦失衡時，可造成骨質的異常。造骨細胞所產生的細胞核因子kB配位體接受器活化因子 (receptor activator for nuclear factor kappa B ligand；RANKL) 結合於蝕骨細胞前驅細胞膜上的細胞核因子kB接受器活化因子 (receptor activator of nuclear factor kappa B；RANK)，可導致蝕骨細胞的分化與成熟；而蝕骨細胞抑制因子 (osteoprotegerin；OPG) 為調節骨吸收的醣蛋白，可與細胞核因子kB配位體接受器活化因子 (RANKL) 結合，進而抑制骨吸收作用。然而，骨質重塑模式之RANK/RANKL/OPG基因於僵直性脊椎炎中之分子角色是不清楚的。因此，我們設計一個以醫院為基礎的病例對照研究來評估RANK、RANKL及OPG基因多形性是否相關於僵直性脊椎炎的發生及其臨床表徵。研究中納入330名僵直性脊椎炎病患與330名以性別及年齡配對的健康對照，利用聚合酶鏈鎖反應-限制酵素片段長度多形性 (polymerase chain reaction-restriction fragment length polymorphism) 來判定RANK C575T、RANKL C-290T與OPG G1181C基因多形性；僵直性脊椎炎患者之疾病活性與功能狀態則藉由巴斯僵直性脊椎炎疾病活性指數 (Bath Akylosing Spondylitis Disease Activity Index；BASDAI)、巴斯僵直性脊椎炎功能性指數 (Bath Akylosing Spondylitis Functional Index；BASFI)、以及巴斯僵直性脊椎炎健康綜合評分 (Bath Akylosing Spondylitis Global；BAS-G) 來評估。結果顯示攜帶OPG GG基因型者相較於GC與CC基因型者具有較高的僵直性脊椎炎發生危險 (matched odds ratio；ORm = 1.74，95% confidence interval；C.I. = 1.26-2.40)，攜帶G對偶基因者相較於攜帶C對偶基因者也具有較高的僵直性脊椎炎發生危險 (ORm = 1.59, 95% C.I. = 1.21-2.09)。此外，初始症狀發病年齡之分佈與周邊關節炎之比例在不同OPG G1181C基因型上具有顯著差異。攜帶OPG C對偶基因之HLA-B27陽性者具有最早的初始症狀發病年齡 (26.6 ± 9.6歲，標準差)，依次的初始症狀發病年齡在於攜帶OPG G對偶基因之HLA-B27陽性病患 (32.6 ± 12.2歲)、攜帶OPG G對偶基因之HLA-B27陰性者 (38.1 ± 13.6歲)、與攜帶OPG C對偶基因之HLA-B27陰性者 (38.6 ± 9.8歲)。因此，OPG基因所誘發的骨質流失機制可能相關於僵直性脊椎炎之發展，並且與疾病的臨床表徵具有相關。

關鍵字

僵直性脊椎炎 ； 蝕骨細胞抑制因子 ； 基因多形性 ； 初始症狀發病年齡

並列摘要

Bone loss was one of the symptoms reported in ankylosing spondylitis (AS). And once the balance between osteoblasts and osteoclasts has been disrupted, abnormalities in bone mineral occur. Receptor activator of nuclear factor kappa B ligand (RANKL) produced by osteoblasts binds to receptor activator of nuclear factor kappa B (RANK) on the surface of osteoclast precursors, leading to the differentiation and maturation of osteoclasts. Osteoprotegerin (OPG), a glycoprotein that modulates bone absorptions, would bind to RANKL and inhibit bone absorptions. However, the molecular mechanisms of RANK/RANKL/OPG genes on bone remodeling in AS development remain unclear. Therefore, we designed a hospital-based case-control study to evaluate the association between occurance and clinical features of AS and RANK, RANKL and OPG genetic polymorphisms. A total of 330 AS patients and 330 age and gender-matched controls were recruited in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to identify the RANK C575T, RANKL C-290T and OPG G1181C genotypes. The disease activity and functional status of AS patients were evaluated by Bath Akylosing Spondylitis Disease Activity Index (BASDAI), Bath Akylosing Spondylitis Functional Index (BASFI), and Bath Akylosing Spondylitis Global (BAS-G). Our results showed that OPG GG genotype carriers had an elevated risk of AS as compared to those with the GC/CC genotypes (matched odds ratio, ORm = 1.74; 95% confidence interval, C.I. = 1.26-2.40). Individuals carrying OPG G allele also had a higher risk of AS than subjects carrying the C allele (ORm = 1.59, 95% C.I. = 1.21-2.09). In addition, the age on AS initial symptom and the percentage of patients experienced peripheral arthritis significantly differs among different OPG G1181C genotypes. HLA-B27 positive subjects with the OPG C allele had the earliest age of onset (26.6 ± 9.6 years, standard deviation; SD), followed by HLA-B27 positive subjects with the OPG G allele (32.6 ± 12.2 years), HLA-B27 negative subjects with the OPG G allele (38.1 ± 13.6 years), and HLA-B27 negative subjects with the OPG C allele (38.6 ± 9.8 years). In conclusion, OPG-mediated bone loss may be associated with the development of AS, as well as its clinical manifestations.

並列關鍵字

Ankylosing spondylitis ； Osteoprotegerin ； Polymorphism ； Age of onset

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