Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. It is a multifactorial disease involving both genetic and environmental effects, although the precise etiology of AMD remains elusive. A number of candidate gene associations have been reported with AMD, but few have been confirmed in subsequent studies, according to Nobuo Fuse, MD, and colleagues from the Department of Ophthalmology, Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan.

Reporting in the American Journal of Ophthalmology,1 Dr. Fuse said that at least nine independent studies have shown that complement factor H (CFH) coding variant, Tyr402His, significantly increases the risk for AMD in North American and European populations, and earlier a Gln5345Arg variant in the hemicentin-1 gene was reported in a large AMD family in the United States. The CFH and Hemicentin-1 genes, however, do not seem to be involved in a statistically significant fraction of dry AMD cases in the Japanese population.

Dr. Fuse and colleagues recruited 80 unrelated Japanese AMD patients with dry/geographic atrophy (GA) (grade 4; mean age: 73.3 ± 8.2 years), who had multiple large, soft drusen and/or GA with adjacent soft drusen. The frequency of the previously reported Tyr402His variant for the CFH gene was not significantly higher in 80 unrelated Japanese patients with dry AMD than in 196 Japanese control patients (P=.31). And the frequencies of the other coding single nucleotide polymorphism (SNP) Val62Ile was not significantly higher in the AMD group than in the controls (P=.50).

Among the hereditary retinal dystrophies, polymorphisms Gly1961Glu and Asp2177Asn in the ABCA4 gene have been reported to enhance the susceptibility of eyes to AMD, the authors wrote. A Met299Val polymorphism in the elongation of very long chain fatty acid-like 4 gene (ELOVL4) with AMD has been identified in white populations in the United States. To date, at least nine genome-wide linkage studies in AMD have been published and a large number of candidate regions for susceptibility genes have been suggested, Dr. Fuse said. AMD genome scan results reveal that the most replicated linkage findings have been on chromosomes 1q25-31 and 10q26. “The ARMD1 locus was mapped to chromosome 1q25-31 in a large family, and other studies have confirmed the association of AMD with this locus, including the Hemicentin-1 (Fibl6) gene at the ARMD1 locus,” Dr. Fuse and colleagues wrote.

Previous studies have shown that the CFH coding variant Tyr402His increases the risk for AMD in the North American and European populations, according to the report. The allele frequency of Tyr402His polymorphism in CFH has an ethnic variation, with much lower 1277C frequency in Asian than in white patients.

“Phenotypic and genetic heterogeneity complicate the analysis of the etiology of AMD. In the United States and Europe, dry AMD is more common than the wet type, with about 85% to 90% of AMD patients diagnosed with dry AMD. Wet AMD is more common in Japanese people. There are substantial differences in the disease phenotype and different frequencies of SNPs between the two ethnic groups. In the [white] populations, the Tyr402His polymorphism of CFH is associated with AMD. In Japanese, however, this polymorphism does not seem to predispose [patients] to AMD,” the investigators wrote. Ethnic differences in disease-susceptible genetic variants and diversity in phenotypes would be suggested in AMD.

Nobuo Fuse, MD, is from the Department of Ophthalmology, Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan. He may be reached at fusen@oph.med.tohoku.ac.jp.

1. Fuse N, Miyazawa A, Mengkegale M, et al. Polymorphisms in Complement Factor H and Hemicentin-1 genes in a Japanese population with dry-type age-related macular degeneration. Am J Ophthalmol. 2006;142:1074-1076.