Abstract
PURPOSE: The SIX6 gene is a major susceptibility gene for human glaucoma, and its variants have been implicated in structural and functional alterations of the retina, such as nerve fiber layer thinning and retinal ganglion cell degeneration, which contribute to glaucoma development. This study investigated whether SIX6 polymorphisms are associated with glaucoma in dogs, focusing on the Shiba-Inu and Shih-Tzu breeds. METHODS: We genotyped 19 single nucleotide polymorphisms within the SIX6 gene region in 109 Shiba-Inus (49 cases and 60 controls) and 57 Shih-Tzus (18 cases and 39 controls), followed by association analyses. Comparative sequence analysis of canine and human SIX6 was performed to assess evolutionary conservation. RESULTS: In Shiba-Inus, rs851962234, located in the 3'-untranslated region of SIX6, was significantly associated with glaucoma (P = 0.0047; Pc = 0.038), with the minor A allele showing a frequency of 17.3% in cases and 4.2% in controls, and conferring an increased risk (odds ratio, 3.56). In contrast, rs851962234 showed no association in Shih-Tzus, likely owing to the rarity of the A allele in this breed. No other single nucleotide polymorphisms were associated with glaucoma in either breed. A comparative analysis showed a 98.4% amino acid identity between canine and human SIX6 across the coding regions. CONCLUSIONS: This study identifies rs851962234 in canine SIX6 as being significantly associated with glaucoma in Shiba-Inus, suggesting its potential role in modulating SIX6 expression and retinal ganglion cell vulnerability. These findings offer new insight into the genetic basis of canine glaucoma and highlight parallels and distinctions with human disease.