GENETIC MUTATIONS AS ETIOLOGIC FACTORS IN OSTEOARTHRITIS

描述：（逐字）-骨关节炎（OA）的病因目前 未知遗传、环境、代谢和生物力学因素一直是 被认为扮演着可能的角色。对遗传作用的兴趣， OA的病因学已经扩展，基于临床鉴定的阳性 某些疾病亚群的遗传模式，如Heberden淋巴结， 不同种族和人群中OA患病率的差异，以及 II型胶原基因（COL 2A 1）突变是导致 原发性泛发性OA有证据表明COL 2A 1以外的基因座突变 在家族性OA中可能也很重要。我们的研究表明， 与家族性OA相关的COL 2A 1突变位点（Arg 519-Cys，Arg 75-Cys） 并根据创始人的研究，确定了易感位点（“热点”）， 突变此外，我们的血清标记物研究表明， 在突变阳性、OA阳性 个体我们在进一步的一系列调查中提出的研究将： 目的1）定位和鉴定胶原和/或非胶原基质相关基因 这些与已经使用超过35个家庭的原发性骨关节炎相关 可用;研究方法包括候选基因筛选; 使用高度多态性的人类基因组的高通量连锁分析 标记;以及使用来自基因组的数据分析复杂性状 结合计算机建模和模拟方法进行筛选;以及 目的2）扩大我们对血清标志物的研究，以进一步确定病理生理 目前，在OA中使用新的多种大激酶的机制和临床效用 available.基于具有基因突变的个体的研究， 在确定的年龄（第2至第3个十年）发生OA允许独特的，否则 相关标志物评估的机会不可用。整体 该提案将进一步深入了解遗传相关的OA， 病理生理机制

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.