Age-related macular degeneration (AMD) is a common cause of severe vision loss. Identification of the genes involved in AMD will lead to a better understanding of this disease at the molecular level, which will eventually lead to early detection, prevention and treatment. Previously, we mapped the ARMD1 gene to 1q25-31 in a large family with AMD. Here, we narrow the ARMD1 locus to 14.9 Mb between LAMB2 and D1S3469, a region containing 50 known genes. Twenty candidate genes within this region were screened for mutations. Only one DNA variation, an A16,263G transition in exon 104 of HEMICENTIN-1, was found to segregate exclusively with the disease haplotype in members of this large family with AMD. This variation produces a non-conservative substitution of arginine for glutamine at amino acid position 5345 (Gln5345Arg). It was also identified in 11 other individuals, all of whom share a haplotype, which envelops HEMICENTIN-1, with the large AMD family. The affected status of all but one of those individuals conforms to the age-dependent penetrance observed in AMD. The amino acid at position 5345 of HEMICENTIN-1 was conserved as glutamine in eight species analyzed. RT-PCR analysis demonstrated that exon 104 of HEMICENTIN-1 is alternatively spliced in various cell types. Exclusive segregation of Gln5345Arg with the disease haplotype in this large family, amino acid conservation of glutamine at this position among mammals, the non-conservative nature of the substitution and similarities to EFEMP1 support the conclusion that HEMICENTIN-1 is the ARMD1 gene.

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Background: Previously, the ⑀4 allele of apolipoprotein E (APOE) was reported to have a significant association with a decreased risk of age-related macular degeneration (AMD). In addition, the ⑀2 allele of APOE was reported to be possibly associated with an increased risk of AMD. Objective: To determine if APOE polymorphisms, previously reported to be associated with AMD, affect its expression in medium to large families, as well as in unrelated patients with AMD. Methods: The APOE genotype was determined by HhaI restriction digests of polymerase chain reactionamplified products in a collection of 259 affected and 207 unaffected individuals from 56 AMD families. Genotypes were determined similarly in a set of 104 unrelated AMD patients and in 113 unaffected control subjects. Diagnosis of AMD was based on clinical examination and evaluation of fundus photographs. Evidence of an association between alleles of APOE and AMD in families was tested by the following 4 statistical methods: 2 analysis of simple allele counting, logistic regression analysis adjusting for age, construction of likelihood ratios of haplotype frequencies, and the pedigree disequilibrium test. Results: None of the statistical methods used showed a significant association between the common alleles of APOE and AMD in our collection of families or in the set of unrelated AMD patients. Conclusions: No evidence was found to support an association between AMD in medium to large families and the ⑀4 or ⑀2 alleles of APOE. Neither was any evidence found for an association of APOE polymorphisms with the set of unrelated patients with AMD. However, a trend for a decreased risk of AMD associated with APOE ⑀4 was observed in the set of unrelated patients with a family history of AMD.

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