A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration

Abstract

Genetic variants at chromosomes 1q31-32 and 10q26 are strongly associated with susceptibility to age-related macular degeneration (AMD), a common blinding disease of the elderly. We demonstrate, by evaluating 45 tag SNPs spanning HTRA1, PLEKHA1, and predicted gene LOC387715/ARMS2, that rs10490924 SNP alone, or a variant in strong linkage disequilibrium, can explain the bulk of association between the 10q26 chromosomal region and AMD. A previously suggested causal SNP, rs11200638, and other examined SNPs in the region are only indirectly associated with the disease. Contrary to previous reports, we show that rs11200638 SNP has no significant impact on HTRA1 promoter activity in three different cell lines, and HTRA1 mRNA expression exhibits no significant change between control and AMD retinas. However, SNP rs10490924 shows the strongest association with AMD (P ‫؍‬ 5.3 ؋ 10 ؊30 ), revealing an estimated relative risk of 2.66 for GT heterozygotes and 7.05 for TT homozygotes. The rs10490924 SNP results in nonsynonymous A69S alteration in the predicted protein LOC387715/ARMS2, which has a highly conserved ortholog in chimpanzee, but not in other vertebrate sequences. We demonstrate that LOC387715/ARMS2 mRNA is detected in the human retina and various cell lines and encodes a 12-kDa protein, which localizes to the mitochondrial outer membrane when expressed in mammalian cells. We propose that rs10490924 represents a major susceptibility variant for AMD at 10q26. A likely biological mechanism is that the A69S change in the LOC387715/ARMS2 protein affects its presumptive function in mitochondria.aging ͉ genetic association ͉ mitochondria ͉ neurodegeneration ͉ retinal disease

Serum levels of lipid metabolites in age‐related macular degeneration

“…Instead, the profile reproduced observations drawn from the C57BL/6J mouse model wherein there was a correlation between the higher G2 levels and the presence of AMD (OR = 5.8, 95% confidence interval 0.98-34.4) even though prostaglandin G2 levels did not differ between the AMD and control groups. The importance of the Ala 69 →Ser change in ARMS2 mutation in predicting the incidence of AMD was previously described (32). Our finding that addition of this second parameter did not improve our model is not surprising.…”

“…First, we performed a genetic screen for the Ala 69 →Ser change (G→T mutation) in the ARMS2 gene, which is implicated in development of AMD (32). Mass spectrometry analysis of serum lipids indicated that DHA levels in the AMD samples were decreased as compared with those in the non-AMD control group (Fig.…”

“…The mouse model studies then were used to inform the analyses of sera from a group of human volunteers and patients with AMD (with and without the Ala 69 →Ser change in age-related maculopathy susceptibility 2 (ARMS2) gene that was previously associated with AMD) (32) to determine if the molecular markers identified in the mouse models would be indicative of retinal degeneration (a hallmark of AMD). This approach of measuring levels of small molecules in human serum constitutes an unbiased strategy to generate a risk assessment model that may be further verified in longitudinal clinical studies to predict populations at risk of developing AMD.…”

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

“…The high level of LD has made it difficult to determine which of these genes is primarily responsible for the increased risk of AMD (attributable to this region of chromosome 10q26). However, a recent report suggests that a single SNP (rs10490924), which changes the coding sequence of ARMS2, may account for the association between chromosome 10q26 and increased risk for AMD (Kanda et al, 2007). Although the precise role of ARMS2 in AMD disease aetiology has yet to be elucidated, its role in mitochondrial function is thought to be important (Rivera et al, 2005).…”

Variations in five genes and the severity of age-related macular degeneration: results from the Muenster aging and retina study

“…4,6 Common single nucleotide polymorphisms (SNPs) in the complement factor H (CFH) gene on chromosome 1, [7][8][9][10] and in two loci on chromosome 10q26, that is, ARMS2 (formerly labelled as LOC387715) [11][12][13][14][15] and the HtrA serinepeptidase 1 (HtrA1) gene [16][17][18][19] showed strong associations with the risk of advanced AMD. These results have been extensively replicated in studies conducted in various populations and settings (for an overview, see Jakobsdottir et al 20 ).…”