Center for Human Molecular Biology and Genetics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
PLoS Genet. 2010 Feb 5;6(2):e1000836. doi: 10.1371/journal.pgen.1000836.
A common haplotype on 10q26 influences the risk of age-related macular degeneration (AMD) and encompasses two genes, LOC387715 and HTRA1. Recent data have suggested that loss of LOC387715, mediated by an insertion/deletion (in/del) that destabilizes its message, is causally related with the disorder. Here we show that loss of LOC387715 is insufficient to explain AMD susceptibility, since a nonsense mutation (R38X) in this gene that leads to loss of its message resides in a protective haplotype. At the same time, the common disease haplotype tagged by the in/del and rs11200638 has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.
一种常见的 10q26 单倍型影响年龄相关性黄斑变性 (AMD) 的风险，包含两个基因 LOC387715 和 HTRA1。最近的数据表明，由插入/缺失 (in/del) 介导的 LOC387715 缺失导致其信使不稳定，与该疾病有因果关系。在这里，我们表明 LOC387715 的缺失不足以解释 AMD 的易感性，因为该基因中的无义突变 (R38X) 导致其信使丢失，位于保护性单倍型中。同时，由 in/del 和 rs11200638 标记的常见疾病单倍型对相邻基因 HTRA1 的转录上调有影响。这些数据表明 HTRA1 表达增加与 AMD 的发病机制有关，并强调了探索与复杂特征易感性相关的单倍型中等位基因的多种功能后果的重要性。
