Genetic and Functional Dissection of HTRA1 and LOC387715 in Age-Related Macular Degeneration

• DOI: 10.1371/journal.pgen.1000836
• Publication Date: 2010-02-04T22:45:13Z
• Authors: Zhenglin Yang; Zongzhong Tong; Yuhong Chen; Jiexi Zeng; Fang Lu; Xufang Sun; Chao Zhao; Kevin Wang; Lisa Davey; Haoyu Chen; Nyall London; Daisuke Muramatsu; Francesca Salasar; Ruben Carmona; Daniel Kasuga; Xiaolei Wang; Matthew Bedell; Manjuxia Dixie; Peiquan Zhao; Ruifu Yang; Daniel Gibbs; Xiaoqi Liu; Yan Li; Cai Li; Yuanfeng Li; Betsy Campochiaro; Ryan Constantine; Donald J. Zack; Peter Campochiaro; Yinbin Fu; Dean Y. Li; Nicholas Katsanis; Kang Zhang
• Keywords: Male; QH426-470; Polymorphism, Single Nucleotide; Cohort Studies; Macular Degeneration; 03 medical and health sciences; 0302 clinical medicine; Utah; Genetics; Humans; Genetic Predisposition to Disease; Luciferases; Aged; Enzyme Assays; Chromosomes, Human, Pair 10; Serine Endopeptidases; Proteins; High-Temperature Requirement A Serine Peptidase 1; 3. Good health; Gene Expression Regulation; Haplotypes; Case-Control Studies; Female; Research Article

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.