Evaluation of the ABCR and glutathione peroxidase-3 genes in familial and sporadic cases of exudative age-related macular degeneration.

Age-related macular degeneration (ARMD) is the most common cause of blindness in older patients and is a major health care epidemic in developed countries. The exact cause of ARMD is not known. It has been recently reported that heterozygous missense ABCR mutations are associated with age-related macular degeneration. In addition, one of the susceptible loci for maculopathy is on chromosome 5 that is very close to the plasma glutathione peroxidase (GPX) gene. Since the retina is highly sensitive to peroxidation and the GPX gene product protects cells from oxidative damage, and the fact that the ABCR gene is considered as a major disease gene in macular degeneration we reasoned that they might serve as candidate genes in a subset of ARMD cases. To test our hypothesis, we have carried out a pilot study by analyzing 8 exudative ARMD patients for allelic variations in the GPX gene and three statistically significant mutations in the ABCR gene (R943Q, G1961E and D2177N). Our analysis failed to identify the above three major alterations in the ABCR gene as well as mutations in the coding sequence of the GPX gene. However, we have been able to identify two polymorphic heterozygous mutations in the promoter region of the GPX gene in one sporadic patient. These mutations have not been seen in any other patients. On the other hand, when 28 individuals from 6 different ethnic backgrounds with no evidence of ARMD were analyzed, four of them showed the same alterations in the GPX promoter region. Although we cannot completely exclude the possibility of alterations in the coding regions of the GPX gene, the promoter mutation identified in the present study statistically may not be associated with this disease. However, it may be associated with other additive factors as might be expected for a complex disorder.