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Rachel W. Kuchtey, Jessica Wenzler, Jason Gibson, Yutao Liu, Michael Hauser, R R. Allingham, John Kuchtey; Sequencing ADAMTS10 in Ghanaian POAG patients. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4505.
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Previously we identified ADAMTS10 as the candidate disease-causing gene in the beagle canine model of inherited primary open angle glaucoma (POAG). The aim of this study is to investigate involvement of ADAMTS10 in human POAG. A West African study population was chosen since intraocular pressure (IOP) elevation occurs relatively early in this population, similar to the beagle POAG model.
DNA samples from 157 unrelated POAG patients and 108 unaffected individuals of West African ancestry were collected in Ghana. All coding exons and proximal intronic sequence of ADAMTS10 were amplified by PCR and sequenced by conventional Sanger sequencing. To assess novelty, identified variants were compared with dbSNP 135, 1,000 Genomes and the NHLBI Exome Sequencing Project. Statistical significance was assessed by Fisher’s Exact Test.
Sequencing ADAMTS10 revealed non-synonymous (NS) variants in the POAG group that were not found in unaffected controls; R62Q, R93H, R119Q, G604D and R977G, all of which were SNPs either not previously identified or with minor allele frequency < 0.01. Of the NS SNPs only in the POAG group, R93H was found in 2 POAG patients, while the others were singletons (found in one patient). In the controls, 2 singleton NS variants were found, a 3 base pair deletion resulting in deletion of an amino acid (F56del) and a di-nucleotide variant resulting in an amino acid substitution (R814Q). None of the NS SNPs were predicted to have a deleterious effect by the SNPs3D program. Two synonomous SNPs had minor allele frequencies (MAF) significantly different than controls (p<0.05). In addition, a 7 base pair insertion near exon 25 potentially affecting mRNA splicing was found with a MAF of 0.122 in POAG patients, significantly higher than in controls (0.056, p<0.05). Also statistically significant (p<0.05), a non-coding SNP near the stop codon of exon 26, which may affect mRNA splicing, was found in 9 of 157 POAG patients but none of 108 controls.
This is the first screening of ADAMTS10 in human POAG patients. Two non-coding variants with potential effects on mRNA splicing were identified with MAF significantly greater than controls, suggesting possible risk alleles for POAG. These preliminary results will be extended by sequencing ADAMTS10 in additional Ghanaian patients and controls.
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