Rhesus monkeys and humans share common susceptibility genes for age-related macular disease

Abstract

Age-related macular degeneration (AMD), a complex multigenic disorder and the most common cause of vision loss in the elderly, is associated with polymorphisms in the LOC387715/ARMS2 and HTRA1 genes on 10q26. Like humans, macaque monkeys possess a macula and develop age-related macular pathologies including drusen, the phenotypic hallmark of AMD. We genotyped a cohort of 137 unrelated rhesus macaques with and without macular drusen. As in humans, one variant within LOC387715/ARMS2 and one in HTRA1 were significantly associated with affected status. HTRA1 and the predicted LOC387715/ARMS2 gene were both transcribed in rhesus and human retina and retinal pigment epithelium. Among several primate species, orthologous exons for the human LOC387715/ARMS2 gene were present only in Old World monkeys and apes. In functional analyses, the disease-associated HTRA1 polymorphism resulted in a 2-fold increase in gene expression, supporting a role in pathogenesis. These results demonstrate that two genes associated with AMD in humans are also associated with macular disease in rhesus macaques and that one of these genes is specific to higher primates. This is the first evidence that humans and macaques share the same genetic susceptibility factors for a common complex disease.

Figure 1.

Age-related maculopathy in rhesus primates. Left image shows color photograph of retina with normal macula. Middle and right images show age-related macular drusen (yellow–white subretinal deposits).

Figure 2.

A schematic of the LOC387715/ARMS2 locus and the HTRA1 promoter region, situated 6102 bp apart in humans. The positions of the AMD-associated human SNPs within exon 1 of LOC387715/ARMS2 (rs1049024) and within the HTRA1 promoter (rs11200638) are indicated with blue boxes. The position of the new SNPs identified in all rhesus (Chinese- and Indian origin), and in the Indian-origin population only, is indicated with yellow and green highlighted boxes, respectively. The two new SNPs that are associated with drusen development in rhesus are indicated with a highlighted box outlined with a brown line.

Figure 3.

LOC387715/ARMS2 and HTRA1 transcripts are present within human and rhesus tissue. RT–PCR was performed using intron-spanning primers designed to consensus human and rhesus (A) LOC387715/ARMS2 and (B) HTRA1 exonic sequence; (C) β-actin was used as a positive control.

Figure 4.

An alignment of human and rhesus (A) exon 1 LOC387715/ARMS2 sequence and (B) HTRA1 promoter. The position of maculopathy-associated SNPs in rhesus monkeys (↓) compared with humans (⇓) is shown.

Figure 5.

A schematic indicating the evolution and appearance of LOC387715/ARMS2 exons within the primate lineage. Exon 1 sequence with a putative ATG start codon arose about 43 million years ago after the split from prosimians; it was maintained in apes but not in Old World monkeys. Exon 2 appeared within Old World monkeys after the split from New World monkeys; a putative TGA termination codon in exon 2 arose within the hominid group, i.e. it is present only in apes and humans.