Association of HTRA1 and ARMS2 gene variation with drusen formation in rhesus macaques
Introduction
Age-related macular degeneration (AMD) is a clinically heterogeneous disease and constitutes the major cause of visual impairment in the elderly population worldwide (Bird, 2003, Friedman et al., 2004). Early symptoms of AMD include drusen formation. Rhesus macaques (Macaca mulatta) provide a natural model of retinal drusen (Stafford, 1974, El-Mofty et al., 1978, Dawson et al., 1989, Dawson et al., 2008) that closely resembles the human pathology both clinically and ultra-structurally (Ishibashi et al., 1968, Olin et al., 1995, Dawson et al., 2008). Susceptibility to AMD and drusen formation is caused by both environmental and genetic factors, and a genomic region orthologous to human chromosome 6q has been shown before to be associated with drusen in rhesus macaques (Singh et al., 2005). Recently, it was demonstrated that rhesus and humans share common susceptibility genes for AMD, based upon an observed association between drusen formation and variation in the ARMS2 gene (alias: LOC387715) and in the HTRA1 (high-temperature requirement A1) gene, both located on human chromosome 10q26 and rhesus chromosome 9. The two genes are transcribed in the retinal pigment epithelium of rhesus and humans (Francis et al., 2008). In order to corroborate the association between drusen formation and variation in the ARMS2 and HTRA1 genes of rhesus macaques, we genotyped animals from the Sebana Seca facility of the Caribbean Primate Research Centre (CPRC) and from the German Primate Centre (DPZ, Gottingen, Germany). One polymorphism in each gene was found to be significantly associated with drusen formation at the genotype level. Subsequent haplotype analysis revealed, however, that these associations were entirely attributable to a single promoter polymorphism in the HTRA1 gene. In addition to confirming previous disease–gene association findings for AMD, our data provide another example of how humans and rhesus macaques may share genetic susceptibility factors for a common complex disease.
Section snippets
Animals
The study group comprised 116 rhesus macaques, aged 5–22 years. 52 monkeys were randomly selected from social group M, originally derived from Cayo Santiago and currently maintained at the Sebana Seca field station of the CPRC on mainland Puerto Rico. The history of these monkeys has been described elsewhere (Singh et al., 2005). Another 64 rhesus macaques were selected from the German Primate Research Centre (Deutsche Primatenzentrum, DPZ) in Göttingen, Germany. These animals also originated
Results
The drusen prevalence in CPRC and DPZ monkeys has been reported upon before (Singh et al., 2005, Singh et al., 2007). Our study group comprised 52 animals from the CPRC (38 affected, 14 unaffected) and 64 animals from the DPZ (34 affected, 30 unaffected). Sequence analysis of the ARMS2 gene identified two known and three novel exonic variants, together with a novel intronic polymorphism (Table 2). Whilst exonic variations c.88C>T (P30S) and c.110G>A (R37H) have been observed before in macaques
Discussion
Rhesus macaques appear to provide an excellent animal model for human age-related macular drusen (AMD), not only in terms of pathology but also with regard to the discovery of genetic risk factors. Thus, we have been able to map a macular drusen susceptibility locus in rhesus macaques to the homologue of human chromosome 6q14–15, following a positional candidate approach (Singh et al., 2005). Since then, a strong association has been established through multiple studies in humans between AMD
Acknowledgements
This work was supported by NCRR (NIH) grant P40 RR03640, awarded to the Caribbean Primate Research Center, Puerto Rico, and by a grant of the Deutsche Forschungsgemeinschaft to J. S.
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