Abstract
Purpose :
To determine whether age-related macular degeneration SNPs cause the extreme variable expressivity seen amongst affected subjects with North Carolina Macular Dystrophy.
Methods :
Sixty affected NCMD subjects with the V1 (chr 6: 99593030G>T) or V2 (chr 6: 99593111G>C) mutations were genotyped. Subjects were selected based on DNA quality and quantity. Samples were genotyped for 15 AMD-associated SNPs (single nucleotide polymorphisms: CFH, ARMS2, APOE2, APOE4, C3, TIMP3, C2, CFB, LIPC, ABCA1, CETP, COL8A1, CFI). Genotype calls were converted to “number of AMD risk alleles.” A chi square analysis was used to determine if there was a difference in distribution between the number of risk allele categories between NCMD grade groups. Each SNP was analyzed individually against disease severity.
Results :
Chi square analysis results:
1-way Anova p-value = 0.307926
Chi Square on APOE2 (rs429358) p-value = 0.118
Chi Square on APOE4 (rs7412) p-value = 0.2203
Chi Square on CFH (rs3766405) p-value = 0.04134
Chi Square on CFH (rs412852) p-value = 0.6772
Chi Square on CFH (rs1048663) p-value = 0.02417
Chi Square on ARMS2 (del443ins54) p-value = 0.159
Chi Square on C3 (rs2230199) p-value = 0.04879
Chi Square TIMP3 (rs9621532) p-value = 0.05322
Chi Square on C2 (rs9332739) p-value = 0.007876
Chi Square on CFB (rs541862) p-value = 0.1486
Chi Square on LIPC (rs10468017) p-value = 0.8663
Chi Square on ABCA1 (rs1883025) p-value = 0.4475
Chi Square on CETP (rs3764261) p-value = 0.8826
Chi Square on COL8A1(rs13095226) p-value = 0.004832
Chi Square on CFI (rs10033900) p-value = 0.2143
There was no significant distribution difference in any alleles measured. There was no association between disease severity and SNP frequency found.
Conclusions :
Variable expressivity is a trait seen in most monogenic autosomal dominant Mendelian diseases. NCMD has more marked variable expressivity than most Mendelian macular dystrophies which has been unexplained to date. To our knowledge, this is the first study evaluating the major AMD SNPs as gene modifiers of a monogenic autosomal dominant Mendelian disease.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.