气候变化领域集成服务门户(CCPortal): Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

CCPortal

DOI	10.1073/pnas.2103617118
	Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium
	Williams B.L.; Seager N.A.; Gardiner J.D.; Pappas C.M.; Cronin M.C.; di San Filippo C.A.; Anstadt R.A.; Liu J.; Toso M.A.; Nichols L.; Parnell T.J.; Eve J.R.; Bartel P.L.; Zouache M.A.; Richards B.T.; Hageman G.S.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:30
英文摘要	Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Age-related macular degeneration; Bruch’s membrane; Cis-regulatory element; HTRA1; Retinal pigment epithelium
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238851
作者单位	Steele Center for Translational Medicine, John A. Moran Eye Center, University of Utah, Salt Lake City, UT 84132, United States; Bioinformatics Analysis, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, United States
推荐引用方式 GB/T 7714	Williams B.L.,Seager N.A.,Gardiner J.D.,等. Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium[J],2021,118(30).
APA	Williams B.L..,Seager N.A..,Gardiner J.D..,Pappas C.M..,Cronin M.C..,...&Hageman G.S..(2021).Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium.Proceedings of the National Academy of Sciences of the United States of America,118(30).
MLA	Williams B.L.,et al."Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium".Proceedings of the National Academy of Sciences of the United States of America 118.30(2021).