摘要:退化性骨關節炎(Osteoarthritis, OA)是一個結合肌肉、骨骼、軟骨及神經系統之一種疾病,縱然它影響的層面是如此廣泛且深遠,但對其致病之機轉卻甚少了解,或將之歸因於過度使用或創傷等機械因素,以致於關於檢測、預防及治療退化性骨關節炎的研究貧乏。手指骨關節炎(Hand osteoarthritis, HOA)的發生除了與手部使用率及工作性質呈正相關之外,臨床上卻同時發現有些平日甚少勞務工作,甚至連家事也幾乎絕緣的病例發生手指骨關節炎,甚至嚴重到需要開刀治療。這些病例的年齡傾向於較年輕(40歲上下),且常見於母女、或姐妹同時發生,使人聯想遺傳因素涉入,本研究團隊依據此一致病可能關聯性,提出此一計劃”手指關節炎之基因研究”。2014年五月Nature Genetics發表了一篇文章,學者Unnur Styrkarsdottir用Genome-wide association study (GWAS) 研究方法,以冰島民眾為樣本群,發現具有基因乙醛脫氫酶2型(ALDH1A2) 變異型者同時具有嚴重手關節炎,這對我們之研究具有重大意義。其一:此為高加索民族,亞洲民族之情形未知。其二:此研究是以血液為樣本分析,不是原位組織。本研究團隊早已於2011年申請台大醫院IRB計畫,IRB之協同主持人李明達博士已對膝退化性關節炎組織之基因變化發表3篇論文,我們研究團隊接續之前的研究經驗及成果,著手收集手指骨樣本,採原位組織與血液雙重分析,對退化性手關節炎組織及血液進行基因差異性分析。本計畫預計收樣30個個案,且均為嚴重手指骨關節炎,並且嚴重至須接受手術,施行手指關節固定術 (Arthrodesis of Distal Interphalangeal Joint, DIP Joint),將因治療需要在手術中取下患部組織,主要為關節面軟骨(Articular Cartilage)及部分軟骨下骨組織(Subchondral bone),作基因差別性分析,以供找尋手指骨關節炎的相關遺傳因子標記及可能影響之因子,以便提出HOA致病機制,以供後續治療HOA所需。並期許這些研究所發現之基因標記,將有助於HOA的早期篩檢、提升臨床診斷的準確性、並發展基因治療方案之可能性。本計畫預計以三年時間完成下列之研究工作:第一年:研究重點將利用遺傳生物標記及遺傳變異分析方法(SNP)來探討敏感性基因乙醛脫氫酶2型(ALDH1A2)於微環境下的變異性,再透過各種分子生物技術、細胞生物技術、組織切片法分析包括:RT-QPCR, ICC, IHC…等方法來探討患部組織型態差異性、表現差異性、功能差異性, 第一年工作是驗證HOA標記分子在漢民族的有效性、組織歧異性以及功能差異性。第二年:研究重點將蒐集更多漢民族之HOA樣本數,以Genome-wide association study (GWAS)研究方法篩選出亞洲民族HOA生物標記的高顯著性、高勝算率及精確性。第三年:驗證第二年所獲之敏感性標記分子,進而建立HOA之可能機制理論,進而提出相關偵測、診斷、治療之可行策略。此一計畫具醫療前瞻性、共通性與本土性,預期研發成果將涵蓋基因體學科技與生技、健康醫療科技等,將產出豐碩成果與相關專利。
Abstract: Osteoarthritis (OA) is one kind of diseases to combine the muscle, bone, cartilage and nervous system. It shows great impact on quality of life because of pain and loss of joint function. The etiology of OA is still under study and people believed that OA is highly associated with some mechanical factors such as overuse or trauma. There are many mysteries in the aspect of joint biology because the lack of understanding biological pathogenesis of OA. So, we cannot get much improvement about detection, diagnosis and treatment in OA. Hand OA is a very popular condition if the people got older. The occupation and daily loading played the important roles in the development of hand OA. But in the daily clinic practice, we can find some people took very few labor work but they suffered from Hand OA severely in the early adult age. Furthermore, these cases will have genetic associations because they are mother/daughter or sisters. These observations imply the genetic factor to relevance of early occurrence of HOA to need more research to answer this question. Based on this rationale, we proposed the project “Genome-wide Study for Disease Susceptibility Gene(s) in Patients with Hand Osteoarthritis (HOA)”.Styrkarsdottir U. et al. carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. They found significantly associated loci in the Icelandic discovery set at 15q22 in the ALDH1A2 gene. This research is meaningful for our study. First, the population is Caucasian whereas the Han Chinese is still unknown. Second, the research sample is blood but not the primary joint tissue. In this study, we will do the local tissue and blood analysis both in Han Chinese. We have applied for the IRB proposal in 2011. Our co-researcher, Dr. Lee, was the pioneer about knee OA genetic study and has published two papers about genes expression of the knee OA. Based on these foundations, we kept out pace to study the Hand OA genetic study. The spotlight is that the Hand OA tissues are very difficult to gather. A minimum of 30 severe osteoarthritis patients meeting the recruiting criteria will be included.We intend to achieve the following specific aims in this proposed research: (i) the validation of HOA marker gene ALDH1A2 variants and expression level in the severe HOA subject of Han Chinese population (CHS) via molecule approach (SNP, RT-QPCR). The differential expression and function will be tested. In addition, specific spatial pattern for the biomarker of HOA will be tested, either analysis including ICC or IHC. (ii) New marker of biological network including in severe HOA of Han Chinese population of novel probing, transcriptome, exon scan and epigenetic analysis will be proceeded and analyzed. (iii) The validation of new biomarker proceeded from HOA group genes. The outcome of this study will support future studies in precision medicine and development of more novel mechanism of HOA. We foresee the practical use of these novel biomarkers in the prognosis of severe HOA, intervention recipe, and the development of accuracy biological assays and differential assay for HOA therapeutic approaches.