GENETIC MUTATIONS AS ETIOLOGIC FACTORS IN OSTEOARTHRITIS

基因突变作为骨关节炎的病因

• 批准号: 6632671
• 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/6632671
• 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：（逐字化） - 目前骨关节炎（OA）的病因 未知。遗传，环境，代谢和生物力学因素已经 建议扮演可能的角色。对遗传作用的兴趣 OA的病因已根据阳性的临床鉴定扩展 某些疾病子集的遗传模式，例如Heberden的节点， 不同种族和人群之间OA患病率的差异，以及 II型胶原蛋白基因（COL2A1）突变的演示是 原发性OA。有证据表明除COL2A1以外的其他基因座突变 在家族的OA中也可能很重要。我们的研究表明了多个 与家族性OA相关的Col2A1突变（arg519-cys，arg75-cys）的基因座 并且，根据创始人研究，确定了易感性位点（“热点”） 突变。此外，我们的血清标记研究表明 在突变阳性，OA阳性的矩阵降解和合成之间 个人。我们在进一步的研究中提出的研究将： 目标1）定位和识别胶原蛋白和/或非胶原基质相关基因 与主要OA相关的已经使用了35多个家庭 可用的;研究方法包括候选基因筛查； 使用高度多态性的人类基因组的高通量链接分析 标记；并使用源自基因组的数据对复杂性状进行分析 与计算机建模和仿真方法结合筛选；和 目标2）扩展我们对血清标记的研究，以进一步定义病理生理 OA中的机制和临床实用性现在利用新的多个大型品种 可用的。基于注定为基因突变的个体的研究 在定义的年龄（第2至3世纪）开发OA，允许独特，否则 无法获得相关标记评估的机会。总体 提案将进一步了解与遗传相关的OA，以及 病理生理机制。