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

Autor: Betsy Campochiaro, Xiaoqi Liu, Peter A. Campochiaro, Dean Y. Li, Xiaolei Wang, Daniel Gibbs, Xufang Sun, Ruben Carmona, Haoyu Chen, Lisa Davey, Peiquan Zhao, Kevin Wang, Zongzhong Tong, Nicholas Katsanis, Matthew Bedell, Manjuxia Dixie, Zhenglin Yang, Yan Li, Yuhong Chen, Fang Lu, Yuanfeng Li, Nyall London, Chao Zhao, Daisuke Muramatsu, Daniel Kasuga, Donald J. Zack, Cai Li, Francesca Salasar, Jiexi Zeng, Kang Zhang, Yinbin Fu, Ruifu Yang, Ryan Constantine
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Male
Cancer Research
lcsh:QH426-470
Nonsense mutation
Biology
Genetics and Genomics/Complex Traits
Bioinformatics
Polymorphism
Single Nucleotide
Pathogenesis
Cohort Studies
Macular Degeneration
Downregulation and upregulation
Utah
Genetics
medicine
Humans
Genetic Predisposition to Disease
Allele
Luciferases
Molecular Biology
Gene
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
Genetics and Genomics/Genetics of Disease
Aged
Enzyme Assays
Genetics and Genomics/Medical Genetics
Chromosomes
Human
Pair 10
Genetics and Genomics/Functional Genomics
Haplotype
Serine Endopeptidases
Proteins
High-Temperature Requirement A Serine Peptidase 1
Macular degeneration
medicine.disease
eye diseases
Ophthalmology/Macular Disorders
Genetics and Genomics/Gene Function
lcsh:Genetics
Gene Expression Regulation
Haplotypes
Case-Control Studies
HTRA1
Genetics and Genomics/Gene Discovery
Female
Research Article
Zdroj: PLoS Genetics
PLoS Genetics, Vol 6, Iss 2, p e1000836 (2010)
ISSN: 1553-7404
1553-7390
Popis: 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.
Author Summary Age-related macular degeneration (AMD) is the leading blindness cause in western countries. Several genes encoding components of the complement pathway—including CFH, C2/BF, and C3—have been confirmed to be associated with AMD, as well as a region on 10q26 that encompasses two genes. Recent data have suggested that loss of LOC387715 on 10q26, mediated by an insertion/deletion (in/del) at its 3'UTR that destabilizes its message, is causally related with the disorder. We found that a common disease haplotype including the in/del and rs11200638 also has an effect on the transcriptional upregulation of the adjacent gene, HTRA1. We propose a binary model where downregulation of LOC387715 and concomitant upregulation of HTRA1 best explain the risk associated with the 10q26 AMD region.
Databáze: OpenAIRE
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