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Deletion Variant Against Age-Related Macular Degeneration In Laboratory Investigation (2017) 97, 43–52 © 2017 USCAP, Inc All rights reserved 0023-6837/17 Protective effects of an HTRA1 insertion–deletion variant against age-related macular degeneration in the Chinese populations Tsz Kin Ng1, Xiao Ying Liang1, Fang Lu2,3, David TL Liu1, Gary HF Yam1,LiMa1, Pancy OS Tam1, Haoyu Chen4, Ling Ping Cen4, Li Jia Chen1, Zhenglin Yang2,3 and Chi Pui Pang1 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. Laboratory Investigation (2017) 97, 43–52; doi:10.1038/labinvest.2016.117; published online 14 November 2016 Age-related macular degeneration (AMD) is a leading cause of HTRA1 is in strong linkage disequilibrium with an adjacent visual impairment and irreversible blindness in most devel- hypothetical gene LOC387715 (ARMS2), which has also been oped countries, affecting about 50 million elderly people proposed to be an AMD candidate gene.5 A non-synonymous worldwide.1 Excessive drusen, the clinical hallmark of AMD, variant (p.(Ala69Ser); rs10490924:G4T) was suggested to can lead to retinal pigment epithelium (RPE) damage, which affect the presumptive function of the LOC387715 protein in instigates geographic atrophy (non-exudative type), vascular mitochondria or cytoskeleton.6,7 In the LOC387715 gene, an endothelial growth factor (VEGF) expression and choroidal insertion–deletion (indel) variant (c.372_815del443ins54), in neovascularization (CNV; exudative type) with chronic the same haplotype with the rs11200638 risk allele, down- aberrant inflammation.2 AMD is a complex disease influenced regulates LOC387715 mRNA although it might not correlate by multiple genes and environmental factors. We previously with LOC387715 level in the retina or blood.8,9 Concurrently, identified a variant (rs11200638) in the promoter region of this indel allele might also upregulate HTRA1 expression.10 the high temperature requirement factor A1 (HTRA1) gene However, a nonsense variant (p.(Arg38Ter); rs2736911: on chromosome 10q26 associated with exudative AMD.3,4 C4T), located in a non-risk haplotype, also led to reduction 1Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Kowloon, Hong Kong; 2The Sichuan Key Laboratory for Human Disease Gene Study, Chengdu, China; 3The Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China and 4The Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, China Correspondence: Professor Z Yang, PhD, Center for Human Molecular Biology and Genetics, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, 32 The First Round Road 2 West, Chengdu, Sichuan, China or Professor CP Pang, DPhil, Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, 4/F, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, Hong Kong. E-mail: [email protected] or [email protected] Received 18 August 2016; revised 13 October 2016; accepted 14 October 2016 www.laboratoryinvestigation.org | Laboratory Investigation | Volume 97 January 2017 43 HTRA1 variant protects against AMD TK Ng et al in LOC387715 mRNA.8,10 These findings suggested that drusen, no abnormal RPE change and no foveal reflex. The LOC387715 insufficiency alone may not lead to the develop- study protocol was approved by the Ethics Committee for ment of AMD on 10q26.8 Human Research at the Chinese University of Hong Kong Human HTRA1 belongs to the evolutionarily conserved and the Sichuan Provincial People’s Hospital. It was in HtrA family of chymotrypsin-like serine protease with accordance with the tenets of the Declaration of Helsinki. temperature-dependent proteolytic and molecular chaperone Informed consent was obtained from the study subjects after activities.11 It was first identified in SV40-transformed explanation of the nature and possible consequences of fibroblasts and osteoarthritic cartilage12,13 and predicted to the study. possess a N-terminal secretory signal peptide, a mac25-like domain and a C-terminal HtrA (proteolytic and PDZ) HTRA1 Genotyping domain. Mutations in the HTRA1 gene are associated with Genomic DNA from peripheral venous blood samples cerebral autosomal-recessive arteriopathy with subcortical of the study subjects was extracted (QIAamp DNA Kit; infarcts and leukoencephalopathy.14 Downregulation of Qiagen, Germany) according to the supplier’s instructions. HTRA1 has been detected in cancers, whereas HTRA1 The genotype of c.34delCinsTCCT in HTRA1 overexpression enhanced cell apoptosis and reduced cell (ENSG00000166033; Ensembl Genome Browser: http:// proliferation in cancer cell lines.15 Upregulation of HTRA1 www.ensembl.org/) was determined by PCR (forward primer: was reported in placentation,16 preeclampsia,17 arthritis,13 5′-GTCCCCAAGGCGGCTCGT-3′, reverse primer: 5′-CGC Alzheimer’s disease,18 Duchenne muscular dystrophy19 and GAAGCTCGGTTCCGAGG-3′)23 and direct sequencing idiopathic dilated cardiomyopathy.20 Analogously, HTRA1 (BigDye Terminator Cycle Sequencing Reaction Kit v3.1; mRNA and protein expression are elevated in the lympho- Applied Biosystems, Foster City, CA, USA) on a DNA cytes and RPE of AMD patients carrying the risk-associated sequencer (ABI 3130XL; Applied Biosystems). variant,4 while different reported studies had been inconsistent.8 HTRA1 protein expression is elevated in Meta-Analysis drusen, abnormal RPE and CNV lesion of AMD eyes.4,21 In The meta-analysis of the Hong Kong and Chengdu cohorts addition, we found an association of HTRA1 with VEGF in was performed by the Review Manager software (RevMan, human vitreous humors and fetal RPE cells upon cell stress version 5.2, The Cochrane Collaboration, Copenhagen, and inflammation.22 Collectively, these evidences indicate Denmark) to generate the Z-scores. The exact P-values with that HTRA1 could be involved in AMD pathogenesis. the Z-scores were then calculated using R (v3.0.0, http://cran. 2 Our previous sequencing study, which involved 163 r-project.org/). The I statistic was used to assess the exudative AMD patients and 183 control subjects, identified heterogeneity among studies, which corresponds to no an indel variant (c.34delCinsTCCT) in the coding region of (o25%), low (25%–50%), moderate (50%–75%) and high HTRA1 gene.23 In the present study, genotyping was extended heterogeneity (≥75%). The random effects model was to increased number of AMD and control subjects in the adopted in the meta-analysis. Summary Po0.05 was Hong Kong Chinese cohort. An additional independent considered statistically significant. Chinese cohort (Chengdu) was also included to validate the association. The properties of the recombinant HTRA1 Haplotype Analysis variant protein were investigated. We aimed to further verify The genotypes of rs2736911 and rs10490924 in LOC387715 the protective role of this HTRA1 indel variant in AMD. and rs11200638 in HTRA1 were collected from previous studies for haplotype construction and estimation of four MATERIALS AND METHODS LOC387715/HTRA1 polymorphisms (http://www.broad.mit. Study Subjects edu/mpg/haploview/, Haploview version 4.2, Massachusetts Unrelated Chinese exudative AMD patients and age- and Institute of Technology, Cambridge, MA, USA).23,25 Haplo- gender-matched control subjects (Supplementary Table S1) type conditional analysis was performed using PLINK (v1.07; were recruited at the Prince of Wales Hospital and the Hong http://pngu.mgh.harvard.edu/purcell/plink/) to test whether Kong Eye Hospital in Hong Kong (195 patients and 390 the 34delCinsTCCT haplotype had an independent haplotype controls) and at the Sichuan Provincial People’s Hospital in effect. Moreover, the haplotypes containing rs11200638 and Chengdu (168 patients and 210 controls). All study subjects c.34delCinsTCCT of HTRA1 were also determined using were given
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