GENETIC MUTATIONS AS ETIOLOGIC FACTORS IN OSTEOARTHRITIS

基因突变作为骨关节炎的病因

• 批准号: 6193935
• 负责人: ROLAND W MOSKOWITZ
• 金额: $ 22.95万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6193935
• 关键词: biomarker; blood chemistry; clinical research; collagen; disease /disorder etiology; disease /disorder onset; extracellular matrix proteins; family genetics; gene environment interaction; gene mutation; genetic mapping; genetic polymorphism; genetic screening; genetic susceptibility; high throughput technology; human genetic material tag; human subject; mathematical model; osteoarthritis

DESCRIPTION: (Verbatim) - The etiology of osteoarthritis (OA) is at present unknown. Genetic, environmental, metabolic, and biomechanical factors have been suggested as playing possible roles. Interest in a genetic role for the etiology of OA has expanded based on clinical identification of positive inheritance patterns in certain disease subsets such as Heberden's nodes, differences in the prevalence of OA among different races and populations, and the demonstration of type II collagen gene (COL2A1) mutations as a cause of primary generalized OA. Evidence suggests mutations in loci other than COL2A1 may be important in familial OA as well. Our studies have demonstrated multiple loci of COL2A1 mutations (Arg519-Cys, Arg75-Cys) associated with familial OA and, based on founder studies, identified susceptibility sites ("hot-spots") of mutation. In addition, our serum marker studies have demonstrated an imbalance between matrix degradation and synthesis in mutation-positive, OA-positive individuals. The studies proposed in our further series of investigations will: Aim 1) locate and identify collagen and/or non-collagen matrix-associated genes which are associated with primary OA utilizing the over 35 families already available; investigational approaches include candidate gene screening; high-throughput linkage analysis of the human genome using highly polymorphic markers; and analysis of complex traits using data derived from genome screening in combination with computerized modeling and simulation methods; and Aim 2) expand our study of serum markers to further define pathophysiologic mechanisms and clinical utility in OA utilizing new multiple large kindreds now available. Studies based on individuals with genetic mutations destined to develop OA at a defined age (2nd to 3rd decades) allow a unique, otherwise unavailable opportunity for correlative marker assessments. The overall proposal will further insights into genetically related OA, and pathophysiologic mechanisms.

描述：（逐字记录）- 骨关节炎 (OA) 的病因目前是 未知。遗传、环境、代谢和生物力学因素 建议扮演可能的角色。对遗传作用的兴趣 基于阳性的临床鉴定，OA 的病因已得到扩展 某些疾病子集的遗传模式，例如赫伯登结节， 不同种族和人群之间 OA 患病率的差异，以及 证明 II 型胶原蛋白基因 (COL2A1) 突变是导致 原发性全身性 OA。有证据表明 COL2A1 以外的基因座发生突变 对于家族性 OA 也可能很重要。我们的研究证明了多种 与家族性 OA 相关的 COL2A1 突变位点（Arg519-Cys、Arg75-Cys） 并且，根据创始人研究，确定了易感位点（“热点”） 突变。此外，我们的血清标志物研究表明存在不平衡 突变阳性、OA 阳性的基质降解和合成之间的关系 个人。我们进一步的系列调查中提出的研究将： 目标 1) 定位并鉴定胶原蛋白和/或非胶原蛋白基质相关基因 与使用超过 35 个家庭的主要 OA 相关 可用的;研究方法包括候选基因筛选； 使用高度多态性对人类基因组进行高通量连锁分析 标记；使用基因组数据分析复杂性状 结合计算机建模和模拟方法进行筛选；和 目标 2) 扩大我们对血清标志物的研究，以进一步定义病理生理学 现在利用新的多个大家族在 OA 中的机制和临床实用性 可用的。基于具有基因突变的个体的研究注定 在规定的年龄（二至三十岁）发展 OA 允许独特的，否则 没有机会进行相关标记评估。整体 该提案将进一步深入了解与遗传相关的 OA，以及 病理生理机制。