Age-related macular degeneration (AMD) is a major cause of visual loss in the elderly in developed countries. Neovascular AMD (nAMD), a subtype of advanced AMD, is responsible for almost 90% of severe visual loss due to AMD.
1 Age-related macular degeneration, including nAMD, is a multifactorial disease whose pathogenesis has been linked to numerous environmental and genetic factors.
1 Through genome-wide linkage and association, two major loci have been described as being associated with an increased risk of AMD: the complement factor H (
CFH) gene at 1q31 and the age-related maculopathy susceptibility 2 (ARMS2)/high-temperature requirement factor A1 (
HTRA1) locus at 10q26.
2–5 In particular, single nucleotide polymorphisms (SNPs) of
HTRA1 have been associated with increased risk of nAMD in various ethnic groups.
4–7 Some studies have related specific
HTRA1 alleles with neovascular lesion size
8 and with the response to intravitreal anti-VEGF therapy in AMD patients,
9 although this association was not confirmed by others.
10 Additionally, overexpression of HTRA1 in the retinal pigment epithelium of transgenic mice induces the exudative form of AMD.
11,12 Nevertheless, the intraocular concentration of HTRA1 protein in human patients affected by nAMD has, to our knowledge, never been tested, and it remains to be elucidated whether the SNPs of
HTRA1 identified are causally linked to aberrant gene expression or whether they are simply genetic markers.
13 In fact, the overexpression of HTRA1 protein and mRNA associated with the
HTRA1 risk allele
rs11200638, initially documented in human retinas from ex vivo studies,
14–16 was subsequently negated in multiple ex vivo and in vitro studies.
17–20