Macular Degeneration, Age-Related, 7

A number sign (#) is used with this entry because of evidence that susceptibility to age-related macular degeneration-7 (ARMD7) is conferred by variation in the HTRA1 gene (602194) on chromosome 10q26.

See also ARMD8 (613778) for a discussion of the relationship of another gene in the 10q26 region, ARMS2 (611313; also known as LOC387715), and susceptibility to ARMD.

For a phenotypic description and a discussion of genetic heterogeneity of age-related macular degeneration, see 603075.

Mapping

Several studies had suggested specific ARMD susceptibility genes in the 10q26 region (e.g., Majewski et al. (2003), Seddon et al. (2003), Kenealy et al. (2004), Fisher et al. (2005)).

Molecular Genetics

The neovascular, or wet, type of ARMD is more prevalent among Asians than among Caucasians, and the soft indistinct drusen characteristic of dry, or nonneovascular, ARMD are rarely seen in Asian individuals. To identify novel genetic variants that predispose individuals to the wet ARMD phenotype, DeWan et al. (2006) studied 96 patients with wet ARMD from a cohort of Southeast Asians identified in Hong Kong and 130 age-matched control individuals who were ARMD-free. The ARMD cases and controls had a mean age of 74. Within this population DeWan et al. (2006) identified a 10-fold increased risk for wet ARMD for individuals homozygous for the risk genotype (AA) of a single-nucleotide polymorphism, rs11200638, located 512 basepairs upstream of the putative transcriptional start site of the HTRA1 gene (-512G-A; 602194.0001). Transfection studies suggested that the sequence change associated with the SNP enhances transcription of HTRA1 in individuals homozygous for the risk allele.

Yang et al. (2006) genotyped 581 ARMD cases and 309 normal controls in a Caucasian cohort in Utah and found that rs11200638 was the most likely causal variant for ARMD at the 10q26 locus. They estimated that the variant confers a population-attributable risk of 49.3%. Preliminary analysis of lymphocytes and retinal pigment epithelium from 4 ARMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein.

Mori et al. (2007) found a significant association between the -512A allele and ARMD among 123 Japanese patients and 133 Japanese controls. The frequency of the risk A allele was 0.577 and 0.380 in patients and controls, respectively, yielding an odds ratio of 2.23 (p = 7.75 x 10(-6)). The results were more significant in a subset of 104 Japanese patients with wet ARMD (p = 5.96 x 10(-7)). The association was significant in both nonsmokers and smokers, and was more significant in nonsmokers.

In a discussion of studies of the 10q26 ARMD locus, Allikmets and Dean (2008) commented on the studies of Yang et al. (2006) and DeWan et al. (2006), which suggested that the rs11200638 variant of HTRA1 was the sought-after functional variant and claimed that HTRA1 was the wet ARMD gene. They found 3 key problems arising from these 2 studies: (1) As the variant encoding A69S in the LOC387715 gene (rs10490924; 611313.0001) is in almost complete linkage disequilibrium with rs11200638 (D-prime = 0.99) (Dewan et al., 2006), it is impossible to assign causality on the basis of allele frequencies alone; (2) the 10q26 locus does not harbor a wet ARMD gene, but rather a late ARMD, including both wet and dry subtypes, as shown by Rivera et al. (2005); and (3) subsequent studies failed to replicate the functional (gene expression) data (Kanda et al., 2007, Fritsche et al., 2008).

Animal Model

Francis et al. (2008) genotyped 137 unrelated rhesus macaques, 81 with and 56 without macular drusen, and identified a variant in the Htra1 gene that was significantly associated with affected status. Functional analysis of the polymorphic variant showed a 2-fold increase in gene expression, supporting a role in pathogenesis. Francis et al. (2008) stated that this was the first evidence that humans and macaques share the same genetic susceptibility factors for common complex disease.