Age-related macular degeneration (ARMD) is a common complex disorder that affects the central region of the retina (macula) and is the leading cause of legal bli...
Age-related macular degeneration (ARMD) is a common complex disorder that affects the central region of the retina (macula) and is the leading cause of legal blindness in white Americans over age 65. Contributions of environmental factors and genetic susceptibility have been identified. The strongest nongenetic risk factor for ARMD is cigarette smoking.
For a general phenotypic description and a discussion of genetic heterogeneity of ARMD, see 603075.
Several studies 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
Using a combination of family-based and case-control analyses, Jakobsdottir et al. (2005) implicated PLEKHA1 (607772) and LOC387715 within the 10q26 region. Rivera et al. (2005) concluded that the A69S single-nucleotide polymorphism (rs10490924) in exon 1 of the LOC387715 gene (611313.0001) was the most likely susceptibility allele in this region. Given a previous report on the effect of cigarette smoking on the linkage findings in the 10q26 region (Weeks et al., 2004), Schmidt et al. (2006) tested whether smoking modifies this association. To incorporate the 2 most important known ARMD risk factors, smoking and the Y402H variant of the CFH gene (134370.0008), Schmidt et al. (2006) used logistic regression modeling to test for gene-gene and gene-environment interactions in a case-control data set and used the ordered subset analysis to account for genetic linkage heterogeneity in a family-based data set. Their results strongly implicated the A69S coding change in the LOC387715 gene as the second major identified ARMD susceptibility allele, confirming earlier suggestions. This variant's effect on ARMD was statistically independent of CFH and was of similar magnitude to the effect of the Y402H allele of CFH. The overall effect was driven primarily by a strong association in smokers, since Schmidt et al. (2006) observed significant evidence for a statistical interaction between the LOC387715 variant and a history of cigarette smoking. This gene-environment interaction was supported by statistically independent family-based and case-control analysis methods. They estimated that CFH, LOC387715, and cigarette smoking together explained 61% of the population-attributable risk (PAR) of ARMD. The adjusted PAR percentage estimates were 20% for smoking, 36% for LOC387715, and 43% for CFH. This was the first demonstration that a genetic susceptibility coupled with a modifiable lifestyle factor, namely cigarette smoking, confers a significantly higher risk of ARMD than either factor alone.
Schaumberg et al. (2007) studied the associations between the CFH Y402H and the LOC387715 A69S variants with ARMD in a prospective, nested case-control study and investigated whether these variants interacted with modifiable risk factors. Participants with 1 or 2 copies of the Y402H variant were, respectively, 1.98 and 3.92 times more likely to develop ARMD, whereas the incidence rate ratios for 1 or 2 copies of A69S were 2.38 and 5.66, respectively. The fraction of ARMD cases attributable to these 2 variants was 63%. Subjects homozygous for both risk alleles had a 50-fold increased risk of ARMD, and cigarette smoking and obesity multiplied the risks associated with these variants.
To identify genetic factors that modify the risk of exudative ARMD in the Japanese population, Arakawa et al. (2011) conducted a genomewide association study and a replication study using a total of 1,536 individuals with exudative ARMD and 18,894 controls. Arakawa et al. (2011) confirmed the association of ARMS2 with ARMD (rs3750847, p = 8.67 x 10(-29)).
Fritsche et al. (2013) identified association of the T allele of rs10490924 with increased risk of ARMD (OR 2.76, 95% CI 2.72-2.80, combined p = 4 x 10(-540)).
▼ Animal Model
Francis et al. (2008) genotyped 137 unrelated rhesus macaques, 81 with and 56 without macular drusen, and identified a variant in the Loc387715 gene that was significantly associated with affected status. Among several primate species, orthologous exons for the human LOC387715 gene were present only in Old World monkeys and apes. 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.