Dataset Information

HTRA1 (high temperature requirement A serine peptidase 1) gene is transcriptionally regulated by insertion/deletion nucleotides located at the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene in patients with age-related macular degeneration.

ABSTRACT: Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, whereas Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 (age-related maculopathy susceptibility 2) and HTRA1 (high temperature requirement A serine peptidase 1) genes. Transcription regulator activity was localized in mouse retinas using heterozygous HtrA1 knock-out mice in which HtrA1 exon 1 was replaced with ?-galactosidase cDNA, thereby resulting in dominant expression of the photoreceptors. The insertion/deletion sequence significantly induced HTRA1 transcription regulator activity in photoreceptor cell lines but not in retinal pigmented epithelium or other cell types. A deletion construct of the HTRA1 regulatory region indicated that potential transcriptional suppressors and activators surround the insertion/deletion sequence. Ten double-stranded DNA probes for this region were designed, three of which interacted with nuclear extracts from 661W cells in EMSA. Liquid chromatography-mass spectrometry (LC-MS/MS) of these EMSA bands subsequently identified a protein that bound the insertion/deletion sequence, LYRIC (lysine-rich CEACAM1 co-isolated) protein. In addition, induced pluripotent stem cells from wet AMD patients carrying the insertion/deletion sequence showed significant up-regulation of the HTRA1 transcript compared with controls. These data suggest that the insertion/deletion sequence alters the suppressor and activator cis-elements of HTRA1 and triggers sustained up-regulation of HTRA1. These results are consistent with a transgenic mouse model that ubiquitously overexpresses HtrA1 and exhibits characteristics similar to those of wet AMD patients.

SUBMITTER: Iejima D

PROVIDER: S-EPMC4317043 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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HTRA1 (high temperature requirement A serine peptidase 1) gene is transcriptionally regulated by insertion/deletion nucleotides located at the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene in patients with age-related macular degeneration.

Iejima Daisuke D Itabashi Takeshi T Kawamura Yuich Y Noda Toru T Yuasa Shinsuke S Fukuda Keiichi K Oka Chio C Iwata Takeshi T

The Journal of biological chemistry 20141217 5

Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, whereas Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 (age-related maculopathy susceptibility 2) and HTRA1 (high temperature requirement A serine peptidase 1) genes. Transcription regulator activity was localized ...[more]

PMID: 25519903

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Project description:PurposeTo investigate the association between the serum high sensitivity C-reactive protein (hs-CRP) levels and variants in age-related maculopathy susceptibility 2 (ARMS2)/HtrA serine peptidase 1 (HTRA1) genes in normal subjects with no evidence of age-related macular degeneration (AMD).MethodsAfter clinical evaluation, information related to medical and social history was collected from 476 Japanese individuals (age range 17-89 years) along with blood samples. These subjects were medical checkup participants recruited at Nagoya University Hospital with no macular disease, as confirmed by fundus photographs. Serum hs-CRP levels were measured using a highly sensitive latex aggregation immunoassay. The genotypes of three polymorphisms in the ARMS2/HTRA1 locus, i.e., *372_815del443ins54 (del/ins), rs10490924, and rs11200638 were determined using direct sequencing and/or PCR-based assays. After the haplotype was constructed and analyzed, the associations between hs-CRP levels and representative del/ins genotypes were studied with and without adjustment for potential confounding factors.ResultsAll three polymorphisms in the ARMS2/HTRA1 region were in almost complete linkage disequilibrium. Haplotype analyses showed the existence of only two common haplotypes, together comprising 98.9%. Regression analyses showed that the level of hs-CRP was positively correlated with increasing age. This age-dependent increase of hs-CRP levels was greatest in those with homozygous del/ins alleles and lowest in those with homozygous wild-type alleles, which was significant assuming an additive model for gene-dosage association (univariate analyses: p=0.016, multivariate analyses including smoking status, past medical history, and BMI: p=0.043). Consequently, the level of hs-CRP was greatest in those with homozygous del/ins alleles and lowest in those with homozygous wild-type alleles when subjects older than 60 were analyzed. This was significant assuming an additive model for gene-dosage association (univariate analyses: p=0.032).ConclusionsAn age-dependent elevation of serum hs-CRP levels may be accelerated in normal subjects with one or two risk alleles in the ARMS2/HTRA1 locus compared to those with homozygous wild-type alleles. The results of the current study show that the as-yet undetermined function of variants in the ARMS2/HTRA1 locus might be linked to inflammation, possibly contributing to the development of neovascular AMD.

Project description:BackgroundSingle-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26 (Chr10 locus).ResultsBy refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes.ConclusionsOur study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.

Dataset Information

HTRA1 (high temperature requirement A serine peptidase 1) gene is transcriptionally regulated by insertion/deletion nucleotides located at the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene in patients with age-related macular degeneration.

Publications

HTRA1 (high temperature requirement A serine peptidase 1) gene is transcriptionally regulated by insertion/deletion nucleotides located at the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene in patients with age-related macular degeneration.

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