title: Protective effects of an HTRA1 insertion-deletion variant against age-related macular degeneration in the Chinese populations.
abstract: Age-related macular degeneration (AMD) is a leading cause of visual impairment and irreversible blindness in most developed countries, affecting about 50 million elderly people worldwide. Retinal pigment epithelial (RPE) cell degeneration is the pathophysiological cause of AMD, leading to geographic atrophy and choroidal neovascularization. We and others have previously identified several polymorphisms on chromosome 10q26 (HTRA1 rs11200638 as well as LOC387715 rs10490924 and c.372_815del443ins54) associated with AMD. In this study, we confirmed the association of our previously identified HTRA1 insertion-deletion (indel) variant (c.34delCinsTCCT) in 195 exudative AMD patients and 390 controls from the Hong Kong Chinese cohort with additional 168 patients and 210 controls from the Chengdu Chinese cohort and followed by studying its biological functions in RPE cells. Genetic analysis verified the higher prevalence of c.34delCinsTCCT allele in control subjects (8.0%) than in AMD patients (1.9%; P=7.87 × 10-5, odds ratio=0.229). This protective effect was validated as the haplotype of the c.34delCinsTCCT allele existed independent of the risk haplotype (P=1.17 × 10-5). In vitro studies showed that recombinant HTRA1 c.34delCinsTCCT variant protein was more localized in the endoplasmic reticulum of RPE cells compared with the wild-type protein, and its secretion was delayed. Moreover, ARPE-19 cells expressing HTRA1 c.34delCinsTCCT variant had higher cell viability, lower cell apoptosis and were less responsive to anoikis, supporting its protective role. We revealed a protective AMD-associated HTRA1 variant in Chinese populations and the biological role of HTRA1 in RPE cell degeneration, indicating its involvement in AMD pathogenesis.
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Tsz Kin
authors.identifier: 0000-0001-7863-7229
authors.initials: TK
authors.lastname: Ng
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Xiao Ying
authors.initials: XY
authors.lastname: Liang
authors.affiliation: The Sichuan Key Laboratory for Human Disease Gene Study, Chengdu, China.|The Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: David Tl
authors.initials: DT
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Gary Hf
authors.initials: GH
authors.lastname: Yam
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Pancy Os
authors.initials: PO
authors.lastname: Tam
authors.affiliation: The Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, China.
authors.forename: Haoyu
authors.identifier: 0000-0003-0676-4610
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, China.
authors.forename: Ling Ping
authors.initials: LP
authors.lastname: Cen
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Li Jia
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: The Sichuan Key Laboratory for Human Disease Gene Study, Chengdu, China.|The Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Chi Pui
authors.initials: CP
authors.lastname: Pang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D002681:China; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006723:Hong Kong; D006801:Humans; D054643:INDEL Mutation; D015151:Immunoblotting; D008268:Macular Degeneration / Q000208:ethnology / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases