- 學位論文
痛風/高尿酸血症之環境與遺傳因素研究
The Study on Environmental and Genetic Factors of Gout/Hyperuricemia
摘要
台灣原住民族群中，有相當高痛風及高尿酸血症的盛行率，尤其普遍存在於布農族、泰雅族及排灣族。學界普遍認為痛風受到環境、遺傳因素或其間交互作用的共同影響，故本研究想探討痛風 / 高尿酸血症之環境與遺傳因素的特性。 第一部份主要探討痛風重要的危險因子：高尿酸血症的環境因素。回顧文獻時經常可以發現高三酸甘油脂血症與高尿酸血症同是痛風的危險因子，彼此之間有很強的相關性，但時序關係未明。本研究欲探討高三酸甘油脂血症是否會誘發高尿酸血症，以釐清這兩者間的時序關係，並了解其他危險因子對於高尿酸血症的相對危險性。 第二部分則是探討台灣原住民痛風的候選基因座位置。雖然先前的研究缺乏導致痛風之主要基因的證據，但是此疾病依然被認為有遺傳上的趨向。在本篇研究中，吾人希望找尋台灣原住民家族性痛風的遺傳因子。我們利用複雜連鎖分析來解析此疾病遺傳方面的因素。 所得結果如下： (一) 痛風 / 高尿酸血症的環境因素研究：本研究利用美兆診所的健康檢查資料庫，以回溯追蹤法，又稱世代研究法，將第一次檢診時血清尿酸值為正常的受檢者，共6718人，分為高三酸甘油脂暴露組與正常組，並分別追蹤1-6年，觀察是否有高尿酸血症的發生。高尿酸血症每1000人年的發生率在高暴露組為150.3，在正常組則為83.4；第六年全體的累積發生機率在高暴露組為0.63，在正常組為0.42。Cox氏等比危害模式，在控制干擾因素後，顯示性別、體重指數、體脂肪率、三酸甘油脂達顯著差異，其危害對比值分別為：1.67、1.48、1.36、1.38 (p＝0.000)；而腰臀比、肌酸酐、及收縮壓亦有顯著相關，其危害對比值分別為：1.18、1.24、1.27 (p＜0.05)。 (二) 台灣原住民家族性痛風的遺傳因素研究：所有原住民痛風指標病例 (probands)，皆經由風濕科專科醫師診斷確認。一共包含了 36 個核心家庭，127 人，112 對同胞手足。我們採用手足配對連鎖分析 (sib-pair linkage analysis) 以及合併傳遞連鎖不平衡檢定 (combined transmission / disequilibrium test) 來偵測其遺傳上的組成。在手足配對連鎖分析的結果顯示，有一群位置相近的遺傳標記，與致病基因座有顯著性的連鎖。即，位於第一號染色體長臂 1q21-1q22 的位置，包括：D1S498 (迴歸係數=-0.52)，D1S2635 (-0.47) 和 D1S196 (-0.51) (P＜0.005)。而在傳遞連鎖不平衡檢定的結果中亦顯示：位於相同區域的遺傳標記 D1S484 之對偶基因 1，有比較高的頻率被遺傳至有病的下一代，此標記達到顯著性的相關 (連鎖) (P＜0.005)。 本研究發現高三酸甘油脂血症的確會獨立影響高尿酸血症的發生，另外在家族性痛風遺傳上的證據，則證明台灣原住民家族性痛風的族群，確實受到基因調控的影響；吾人認為第一號染色體長臂 1q21-1q22 的位置，可能隱藏了家族性痛風的易感性基因座。
並列摘要
Taiwanese aborigines have a remarkably high prevalence of gout and hyperuricemia, especially among Bunun, Atayal and Paiwan tribes. We think that the environment, genetics and the interaction between them influence the formation of gout. So this study wants to explore the environmental and genetic factors of gout and hyperuricemia. On the first part of the study, we want to identify the environmental factors of the most important risk factor of gout, hyperuricemia. Reviewing the literatures, it was often seen that the hyperuricemia and hypertriglycerides were both the risk factors of gout. They are associated with each other, but the time sequence remains unclear. We sought to examine the relationship and identify the potential risk factors of hyperuricemia. On the second part of this study, we try to explore the candidate locus of familial gout in Taiwanese aborigines. Although previous studies have failed to find evidence of a major gene responsible for gout, the disease is thought to involve genetic predisposition. In this report, we sought to identify the genetic factors of familial gout among Taiwanese aborigines. The results were followings: (1) We used the database of MJ Health Screening Center with the retrospective prospective study, also called the cohort study and excluded the subjects whose serun uric acid were abnormal at the first screening. There were totally 6718 persons including in this report. Then we divided them into two groups: the hypertriglycerides and normaltriglycerides, and follow up for one to six years for observing the incidence of hyperuricemia. The incidence of hyperuricemia between the hypertriglycerides and normaltriglycerides were 150.3 and 83.4 per 1000 person-year. The 6th year cumulative proportion of incidence in the high exposure and normal group were 0.63 and 0.42, respectively. After adjusting the covariates in the Cox hazard regression model, it showed that the sex, BMI, bodyfat and triglycerides were significant, the hazard ratio were 1.67, 1.48, 1.36 and 1.38, respectively (p=0.000). Other significant factors were waist-hip ratio, creatinine and systoic blood pressure, their hazard ratio were 1.18, 1.24 and 1.27, respectively (p<0.05). (2) We performed complex linkage analysis to reveal the genetic agents. Rheumatologists diagnosed and confirmed gout in all aboriginal gout probands. The study samples comprised 36 nuclear families, 127 persons, and 112 full-sib pairs. Sib-pair linkage and combined transmission /disequilibrium test analyses were performed to test the genetic components. In sib-pair analysis, there was a clustering of many flanking markers showing significant linkage, including D1S498 (regression coefficient = -0.52), D1S2635 (-0.47) and D1S196 (-0.51) around chromosome 1q21 region (P<0.005). Results of the combined TDT showed that the marker D1S484 was significantly associated (and linkage) with allele 1 and was transmitted more frequently to the affected offspring (P<0.005). This study provided evidences taht hypertriglycerides did induce the development of hyperuricemia, and we’ve found the genetic effects controlling for familial gout in the aboriginal Taiwanese population, and suggests that a susceptibility locus may be harbored around the region of chromosome 1q21.