SIBLING STUDY OF AGE-RELATED MACULAR DEGENERATION

描述(由申请者提供)：我们建议招募一对兄弟姐妹进行分子遗传学研究，寻找在新生血管性老年性黄斑变性(AMD)发生中起作用的基因。将招募两种类型的兄弟姐妹对，极端不和谐的兄弟姐妹对和极其和谐的兄弟姐妹对。极度不协调的同胞对将由一个成员组成，即患有新生血管性AMD的指数同胞，以及第二个成员，在指数同胞发展为新生血管性AMD的年龄，几乎没有或没有黄斑衰老迹象。非常和谐的兄弟姐妹将由两个患有新生血管性AMD的兄弟姐妹组成。从这些兄弟姐妹身上采集的血液样本中将提纯白细胞DNA。这些同胞对将构成全基因组连锁研究的基础，以寻找染色体区域，在这些区域中，平均而言，极度不一致的同胞对拥有的等位基因比随机预期的要少，而极度一致的同胞对的平均等位基因比预期的要多。具有这些特性的染色体区域可能含有AMD基因。此外，可能在AMD易感性中起作用的候选基因，如ABCA4和apoE，将通过评估这些基因中的DNA序列变异并寻找任何等位基因与新生血管性AMD之间的相关性来进行分析。据我们所知，基于极端不一致和极度一致的同胞对寻找新生血管性AMD基因的分子遗传学方法之前还没有任何其他研究小组进行过。如果成功，我们的工作将在确定新生血管性AMD的遗传原因方面取得实质性进展，AMD是老年人法律失明的主要原因之一。

DESCRIPTION (provided by applicant): We propose to recruit pairs of siblings for a molecular genetic search for genes having a role in the development of neovascular age-related macular degeneration (AMD). Two types of sibling pairs will be recruited, extremely discordant sibpairs and extremely concordant sibpairs. Extremely discordant sibpairs will be composed of one member, the index sib, with neovascular AMD, and the second member with few or no aging signs of the macula at the age at which the index sibling developed neovascular AMD. Extremely concordant sibpairs will be composed of two siblings with neovascular AMD. Leukocyte DNA will be purified from blood samples collected from these siblings. The sibpairs will form the basis for a genome-wide linkage study to search for chromosomal regions where the extremely discordant pairs, on average, share fewer alleles than expected by chance alone, and where the extremely concordant sibpairs, on average, share more alleles than expected. Chromosomal regions having these properties are likely to harbor AMD genes. In addition, candidate genes that may have a role in susceptibility to AMD, such as ABCA4 and apoE, will be analyzed by evaluating DNA sequence variations in those genes and looking for a correlation between any alleles and neovascular AMD. To our knowledge, a molecular genetics approach to finding genes for neovascular AMD based on extremely discordant and extremely concordant sibpairs has not been previously carried out by any other group of investigators. If successful, our work should provide substantial progress toward identifying the genetic causes of neovascular AMD, one of the leading causes of legal blindness among the elderly.