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Identification of genetic loci associated with primary angle-closure glaucoma in the basset hound.

ABSTRACT: Primary angle-closure glaucoma (PACG) in dogs is usually caused by the gradual collapse of the iridocorneal angle and cleft, eventually leading to aqueous humor (AH) outflow obstruction. The condition occurs in several breeds of dogs and the prognosis for affected animals is typically poor. We have identified several basset hound (BH) pedigrees, as well as unrelated cases with characteristic PACG that in many aspects recapitulates PACG in human patients. The goal of this study was to utilize the BH PACG model to characterize the genetics of PACG, and potentially discover genetic factors contributing to PACG in humans and animals.We conducted a genome-wide logistic regression test for association using 37 PACG cases and 41 unaffected controls. Population stratification and cryptic relatedness were assessed using a multidimensional scaling analysis. The expression of two candidate genes within the target tissues of the BH eye was assessed by immunohistochemistry.We report significant associations at two novel loci, specifically BICF2P31912 in COL1A2 on chromosome 14 with a per-allele odds ratio (OR, 95% confidence interval [CI]) of 3.35 (1.73-6.51), P(genome)=3.6×10??; and BICF2P893476 residing in proximity to RAB22A on chromosome 24 with a per-allele OR (95% CI) of 3.93 (1.78-8.66), P(genome)=4.9×10??. COL1A2 and RAB22A demonstrated widespread expression throughout the eye and were prominently noted in the ciliary body (CB), trabecular meshwork (TM), and iris.Our finding of two genetic associations supports the potential segregation of PACG risk-conferring variants in the BH. The genetic associations identified may contribute to mechanisms underlying the pathogenesis of PACG, which remain to be elucidated.

SUBMITTER: Ahram DF

PROVIDER: S-EPMC4000717 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Identification of genetic loci associated with primary angle-closure glaucoma in the basset hound.

Ahram Dina F DF Cook Amy C AC Kecova Helga H Grozdanic Sinisa D SD Kuehn Markus H MH

Molecular vision 20140425

<h4>Purpose</h4>Primary angle-closure glaucoma (PACG) in dogs is usually caused by the gradual collapse of the iridocorneal angle and cleft, eventually leading to aqueous humor (AH) outflow obstruction. The condition occurs in several breeds of dogs and the prognosis for affected animals is typically poor. We have identified several basset hound (BH) pedigrees, as well as unrelated cases with characteristic PACG that in many aspects recapitulates PACG in human patients. The goal of this study wa ...[more]

PMID: 24791135

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Project description:PurposeMutations in ADAMTS10 (CFA20) have previously been associated with primary open angle glaucoma (POAG) in the Beagle and Norwegian Elkhound. The closely related gene, ADAMTS17, has also been associated with several different ocular phenotypes in multiple breeds of dog, including primary lens luxation and POAG. We investigated ADAMTS17 as a candidate gene for POAG in the Basset Hound and Basset Fauve de Bretagne dog breeds.MethodsWe performed ADAMTS17 exon resequencing in three Basset Hounds and three Basset Fauve de Bretagne dogs with POAG. Identified variants were genotyped in additional sample cohorts of both breeds and dogs of other breeds to confirm their association with disease.ResultsAll affected Basset Hounds were homozygous for a 19 bp deletion in exon 2 that alters the reading frame and is predicted to lead to a truncated protein. Fifty clinically unaffected Basset Hounds were genotyped for this mutation and all were either heterozygous or homozygous for the wild type allele. Genotyping of 223 Basset Hounds recruited for a different study revealed a mutation frequency of 0.081 and predicted frequency of affected dogs in the population to be 0.007. Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 1.26 x 10-10. All affected Basset Fauve de Bretagne dogs were homozygous for a missense mutation in exon 11 causing a glycine to serine amino acid substitution (G519S) in the disintegrin-like domain of ADAMTS17 which is predicted to alter protein function. Unaffected Basset Fauve de Bretagne dogs were either heterozygous for the mutation (5/24) or homozygous for the wild type allele (19/24). Based on the entire genotyping dataset the association statistic for the POAG-associated deletion was p = 2.80 x 10-7. Genotyping of 85 dogs of unrelated breeds and 90 dogs of related breeds for this variant was negative.ConclusionThis report documents strong associations between two independent ADAMTS17 mutations and POAG in two different dog breeds.

Project description:PurposePLEKHA7 and COL11A1 were genotyped for single-nucleotide polymorphisms (SNPs) to investigate the possible association of these two genes with primary angle-closure glaucoma (PACG) and disease severity.MethodA total of 51 PACG cases and 51 normal controls were recruited. Twelve SNPs in the PLEKHA7 (rs216489, rs1027617, rs366590, rs11024060, rs6486330, rs11024097, and rs11024102) and COL11A1 (rs1676484, rs3753841, rs12138977, rs2126642, and rs2622848) genes were genotyped by direct Sanger sequencing. Distributions of allele frequencies and genotype frequencies in cases and controls, as well as in mild, moderate, and severe subgroups, were compared based on mean defect (MD ≤ 6.00 dB, 6 dB < MD ≤ 12 dB, and MD > 12 dB were considered mild, moderate, and severe, respectively). Independent Student's t-tests and chi-square tests were used to compare characteristics of PACG cases and controls. Chi-square tests were used to compare the distribution of allele frequencies in cases and controls and in MD-based subgroups with various degrees of glaucoma severity. Binary logistic regression was used to compare the distribution of genotype frequencies and calculate odds ratios (OR) with confidence intervals (CI).ResultThree of the 12 SNPs in COL11A1, rs1676486 (P=0.026, OR = 2.089, 95% CI = 1.092-3.996), rs3753841 (P=0.036, OR = 1.886, 95% CI = 1.038-3.426), and rs12138977 (P=0.024, OR = 2.133, 95% CI = 1.104-4.123) were found to have a significant association with PACG. Furthermore, in the subgroup analysis, rs1676486 (P=0.018, OR = 2.416, 95% CI = 1.284-4.544; P=0.011, OR = 2.119, 95% CI = 1.204-3.729), rs12138977 (P=0.009, OR = 2.158, 95% CI = 1.287-3.618; P=0.006, OR = 1.962, 95% CI = 1.239-3.106), and rs3753841 (P=0.007, OR = 2.550, 95% CI = 1.344-4.839) showed statistically significant differences between moderate/severe groups and controls.ConclusionOur data suggested that COL11A1 rs1676484, rs3753841, and rs12138977 polymorphisms may be of value for further study as potential gene-dependent risk factors for developing PACG. Moreover, COL11A1 rs1676484 and rs12138977 polymorphisms might be associated with PACG disease severity.

Dataset Information

Identification of genetic loci associated with primary angle-closure glaucoma in the basset hound.

Publications

Identification of genetic loci associated with primary angle-closure glaucoma in the basset hound.

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