A Variant of the <i>HTRA1</i> Gene Increases Susceptibility to Age-Related Macular Degeneration

TLDR

Age‑related macular degeneration is the leading cause of irreversible vision loss in the developed world, has a strong genetic component, and a risk locus at chromosome 10q26 has been identified, though the causal gene was unknown until HTRA1 was implicated. The authors genotyped 581 AMD cases and 309 normal controls in a Caucasian Utah cohort. A SNP rs11200638 in the HTRA1 promoter is the most likely causal variant at 10q26, conferring a 49.3 % population attributable risk; the risk allele increases HTRA1 mRNA and protein expression in lymphocytes and retinal pigment epithelium, and drusen are strongly immunolabeled with HTRA1, supporting a key role for HTRA1 in AMD susceptibility and a new pathogenic pathway.

Abstract

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.