Dogs and Humans Share a Common Susceptibility Gene SRBD1 for Glaucoma Risk

Abstract

Glaucoma is a degenerative optic neuropathy that is associated with elevated intraocular pressure. Primary open angle glaucoma is the most common type of glaucoma in canines, and its highest incidence among dog breeds has been reported in Shiba-Inus, followed by Shih-Tzus. These breeds are known to have an abnormal iridocorneal angle and dysplastic prectinate ligament. However, the hereditary and genetic backgrounds of these dogs have not yet been clarified. In this study, we investigated the association between polymorphisms of the glaucoma candidate genes, SRBD1, ELOVL5, and ADAMTS10, and glaucoma in Shiba-Inus and Shih-Tzus. We analyzed 11 polymorphisms in these three genes using direct DNA sequencing. Three SRBD1 SNPs, rs8655283, rs22018514 and rs22018513 were significantly associated with glaucoma in Shiba-Inus, while rs22018513, a synonymous SNP in exon 4, showed the strongest association (P = 0.00039, OR = 3.03). Conditional analysis revealed that rs22018513 could account for most of the association of these SNPs with glaucoma in Shiba-Inus. In Shih-Tzus, only rs9172407 in the SRBD1 intron 1 was significantly associated with glaucoma (P = 0.0014, OR = 5.25). There were no significant associations between the ELOVL5 or ADAMTS10 polymorphisms and glaucoma in Shiba-Inus and Shih-Tzus. The results showed that SRBD1 polymorphisms play an important role in glaucoma pathology in both Shiba-Inus and Shih-Tzus. SRBD1 polymorphisms have also been associated with normal- and high-tension glaucomas in humans. Therefore, SRBD1 may be a common susceptibility gene for glaucoma in humans and dogs. We anticipate that the nucleotide sequencing data from this study can be used in genetic testing to determine for the first time, the genetic status and susceptibility of glaucoma in dogs, with high precision. Moreover, canine glaucoma resulting from SRBD1 polymorphisms could be a useful animal model to study human glaucoma.

Genetic and Biochemical Biomarkers in Canine Glaucoma

“…A significant association of SRBD1 polymorphisms and glaucoma was identified in Shiba Inus and Shih Tzus. 48 In Shiba Inus, the strongest association with glaucoma in SRBD1 was observed at rs22018513, which is a synonymous SNP in exon 4. Two other SNPs, rs8655283 and rs22018514, were also significantly associated with glaucoma; however, these significant associations were calculated only secondarily from a strong linkage disequilibrium with rs22018513.…”

Major review: Molecular genetics of primary open-angle glaucoma

“…SRBD1 variants have been associated with POAG, especially NTG, in multiple studies (Gibson et al, 2012; Kanemaki et al, 2013; Mabuchi et al, 2011, 2015; Meguro et al, 2010). LRP12/ZFPM2 variants have been associated with NTG in multiple studies (Bailey et al, 2016; Wiggs et al, 2012).…”

Genetics of Canine Primary Glaucomas

“…Although this candidate gene approach was initially not successful in the study of canine primary glaucomas, [17][18][19][20] it led to the discovery of the SRBD1 glaucoma susceptibility gene in the Shiba inu and Shih Tzu ( Table 2). 21 With the availability of improved canine genomic resources, approaches for discovering disease-causing mutations have evolved from a candidate gene approach, which focuses only on small genomic regions, to whole-genome linkage analyses and genome-wide association studies (GWAS). 14,15,22,23 With the latter methods, the whole genome is evaluated using genetic markers such as microsatellites or single-nucleotide polymorphisms (SNPs) to look for markers correlated to the disease status and therefore closely linked to the disease mutations.…”

“…1,3,134,139,145 The disease has been studied most thoroughly in American and English cocker spaniels, 128,129,[146][147][148][149][150][151][152] basset hound, 26,27,[127][128][129]146,[150][151][152][153][154] English and Welsh springer spaniels, 9,131 Bouvier des Flandres, 142,149 Chow Chow, 152,155 Siberian husky, 152 Great Dane, 132 flat-coated retriever, 143,156,157 Samoyed, [11][12][13] Shiba inu, 19,21,130,145 Shih Tzu, 21,145 Eurasier dog (created from Chow Chow and Samoyed), 141 Dandie Dinmont terrier, 28 and golden retriever. 158 Despite the proposed autosomal-dominant and autosomal-recessive inheritance of PACG in the Welsh springer spaniel 131 and Siberian husky, …”

“…27 SRBD1 was identified as a PACG risk gene in Shiba inus and Shih Tzus. 21 Its function remains unknown; the gene encodes for S1 RNA-binding domain and also has been associated with primary glaucoma in human patients. [161][162][163] Another susceptibility locus for canine PACG was mapped to a 9.5-Mb region on canine chromosome 8 in the Dandie Dinmont terriers, but no specific disease gene could be identified by screening positional candidate genes.…”