Association of HLA polymorphisms in Age–related macular degeneration

Abstract

Abstract: : Purpose:Age–related macular degeneration (AMD) is the commonest cause of blindness in the elderly in the western world. Recent research suggests that inflammation may play an important role in its development. This evidence includes the presence of inflammatory molecules within drusen and the association of choroidal macrophages with choroidal neovascularization. HLA molecules are critical for regulation of the immune response. Various HLA alleles are associated with a variety of chronic inflammatory diseases. The strongest HLA association known is for the retinal disease, birdshot choroidopathy. We therefore hypothesised that specific HLA genotypes may be a risk factor for AMD, supporting an immune mediated aetiology for this disease. Methods:101 subjects with a diagnosis of AMD were recruited from the ophthalmology clinics of the Southampton Eye Unit and research clinics on the Island of Guernsey. Genotyping of HLA class I A, B and Cw and class II DRB1 and DQB1 loci for principal allele groups was performed by polymerase chain reaction and sequence specific primers (PCR–SSP). Genotype frequencies were compared in patients and controls by 2x2 contingency tables and two–tailed P values calculated using Fisher’s exact test. A P value of less than 0.05 was considered significant. Results:HLA Genotype frequencies for both class I (n=101) and class II (n=60) alleles were compared with published data from UK Caucasian population controls (n=1943 for class I & n=786 for class II). The frequencies of HLA class I genotypes A*03(0.3645 vs. 0.2475; P=0.015), Cw*02 (0.1458 vs. 0.0700; P=0.024) and Cw*07 (0.6875 vs. 0.5742; P=0.047) were all significantly higher in AMD patients. Similarly HLA class II DQB1*06 genotype (0.233 vs. 0.3926; P=0.018) and DRB3 haplotype (0.6833 vs. 0.4758; P=0.002) frequencies were significantly higher in AMD patients. Conclusions:Our preliminary data indicate significant associations of HLA–A*03, Cw*02, Cw*07 and DQB1*06 genotypes and DRB3 haplotypes in AMD patients. This suggests that HLA polymorphisms may influence the development of AMD by genetic modulation of the immune response. This association, however, has only been demonstrated in comparison to population controls. HLA genotyping is being currently performed in a larger cohort of AMD cases and age–matched controls from the same clinic population to confirm this association.

Keywords: age–related macular degeneration • immunomodulation/immunoregulation • genetics