Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Abstract

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.

Variability in Retinal Neuron Populations and Associated Variations in Mass Transport Systems of the Retina in Health and Aging

“…A large part of our understanding in this regard comes from samples selected based on the absence of phenotypes traditionally associated with vitreoretinal disorders. But many (Zouache et al, 2020;Williams et al, 2021) have shown that defining retinal diseases using phenotype alone is not sufficient. The consequences of genetic mutations driving AMD is for instance often detected late in life; however, their effect on retinal and choroidal structures is likely to begin much earlier.…”

Targeting Lipid Metabolism for the Treatment of Age-Related Macular Degeneration: Insights from Preclinical Mouse Models

“… 119 , 128 , 129 An important issue to consider is that AMD-associated variants at chromosome 10q26 loci, where HTRA1 is located, have been shown to decrease HTRA1 expression, suggesting HTRA1 -overexpressing mice may not represent the role of HTRA1 in AMD pathobiology. 130 This is further supported by a recent article from the Hageman group showing that HtrA1 is specifically reduced as much as 50% in the RPE of humans with the ARMS2 risk allele. 130 This appears to be due to disruption of a cis-acting regulatory element within the ARMS2 locus further supporting that augmentation, not inhibition, of HTRA1 is a rational therapeutic approach for AMD patients with the 10q26 risk allele.…”

“… 130 This is further supported by a recent article from the Hageman group showing that HtrA1 is specifically reduced as much as 50% in the RPE of humans with the ARMS2 risk allele. 130 This appears to be due to disruption of a cis-acting regulatory element within the ARMS2 locus further supporting that augmentation, not inhibition, of HTRA1 is a rational therapeutic approach for AMD patients with the 10q26 risk allele. 130 …”

“… 130 This appears to be due to disruption of a cis-acting regulatory element within the ARMS2 locus further supporting that augmentation, not inhibition, of HTRA1 is a rational therapeutic approach for AMD patients with the 10q26 risk allele. 130 …”

Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci

“…The HtrA1 protein functions as both a secreted serine protease and an extracellular chaperone [ 70 ], and cleaves a variety of extracellular matrix (ECM) proteins, proteoglycans and growth factors [ 71 , 72 ]. Evidence suggests that the biological and disease initiation events associated with AMD driven by risk at Chr10 are distinct from Chr1-directed AMD [ 51 , 73 ]. However, the observed mitigating effect of protective CFH-CFHR5 on ARMS2/HTRA1 risk indicates that therapeutic interventions targeting the complement system may potentially modulate risk on Chr10.…”