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Kaylie D. Webb, Ashley G. Anderson, Dianna K. Wheaton; Analysis Of CFH, LOC387715/ARMS2, And HTRA1 Gene Polymorphisms In Stargardt Patients With ABCA4 Mutations. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4556.
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© ARVO (1962-2015); The Authors (2016-present)
Several genetic factors are linked to increased risk of developing macular degeneration. Mutations in ABCA4 are known to cause Stargardt disease; additionally individuals who are heterozygous for an ABCA4 mutation are predisposed to develop age-related macular degeneration (AMD). Other variants, specifically in complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), also known as LOC387715, and high-temperature requirement factor A1 (HTRA1), are associated with increased risk of AMD development and disease severity, but these risk alleles have not been investigated in patients with Stargardt disease. Here we report the frequency of common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715/ARMS2, and HTRA1 in Stargardt macular dystrophy patients with at least one allelic mutation in the ABCA4 gene.
Twenty three unrelated subjects diagnosed with Stargardt disease (10 males and 13 females) ranging in age from 7 to 62 (mean 37 ± 17 yrs) with one (n=12) or two (n=11) ABCA4 mutations along with 47 unrelated control subjects participated in this pilot study. Genomic DNA was extracted from venous blood, genotyping of the three risk alleles (CFH, LOC387715/ARMS2, and HTRA1) was performed using polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion and further verified by direct sequencing (Xu, et al Molecular Vision 2008). Hardy Weinberg equilibrium was confirmed; genotype and allele frequencies were compared using the Χ2 test.
Genotypes were determined successfully by restriction enzyme digestion in all participants. The genotype frequencies for CFH in Stargardt subjects were 65.2% wild-type, 30.4% heterozygous and 4.3% homozygous which was not significantly different from controls (p=0.744, Χ2 test). Allele frequencies for the risk C allele at Y204H in CFH were 19.6% in Stargardt cases and 25.5% in controls (p=0.435, Χ2 test). Genotype frequencies for both LOC387715/ARMS2, and HTRA1 were 47.8% wild-type, 47.8% heterozygous and 4.3% homozygous which was not significantly different from controls (p=0.824, Χ2 test). Allele frequencies for SNPrs10490924:G>T in LOC387715/ARMS2 and SNPrs11200638:G>A in the promoter of HTRA1 were 28.3% in affected subjects and 28.7% in controls (p=0.955; Χ2 test).
Low observed frequencies of CFH Y402H, LOC387715/ARMS2, and HTRA1 SNPs in Stargardt patients suggest that these genetic risk factors are unlikely to influence development of Stargardt disease in patients with one or more ABCA4 mutations. Further studies should be conducted with larger populations to assess whether these risk alleles may act as genetic modifiers of phenotype severity in Stargardt disease.
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