Glutathione S‐transferase theta genotypes and environmental exposures in the risk of canine transitional cell carcinoma

Abstract Introduction Transitional cell carcinoma (TCC) in humans is associated with environmental exposures and variants in glutathione S‐transferase (GST) genes. Scottish Terriers have a high breed risk for TCC, but the relationship between genetic and environmental risk in dogs is not fully understood. Hypotheses Scottish Terriers have a higher frequency of GST‐theta variants compared to lower risk breeds. Dogs with TCC of any breed have a higher frequency of GST‐theta variants along with higher environmental exposures, compared to controls. Animals One hundred and five Scottish Terriers and 68 controls from lower risk breeds; 69 dogs of various breeds with TCC, and 72 breed‐ and sex‐matched unaffected geriatric dogs. Methods In this prospective case‐control study, dogs were genotyped for 3 canine GST‐theta variants: GSTT1 I2+28 G>A, a GSTT1 3′UTR haplotype, and GSTT5 Asp129_Gln130del. Owners of dogs with TCC and unaffected geriatric controls completed a household environmental questionnaire. Results The GSTT1 3′UTR haplotype and GSTT5 Asp129_Gln130del variants were significantly underrepresented in Scottish Terriers (minor allele frequency [MAF] = 0.000 for both), compared to dogs from lower risk breeds (MAF = 0.108 and 0.100; P ≤ .0002). Dogs with TCC did not differ from unaffected geriatric controls across the 3 investigated loci. Transitional cell carcinoma was associated with household insecticide use (odds ratio [OR] = 4.28, 95% confidence interval [CI] = 1.44‐12.33, P = .02), and was negatively associated with proximity to a farm (OR = 0.49, 95% CI = 0.25‐0.99, P = .04). Conclusions and Clinical Importance Low‐activity GST‐theta loci are unlikely contributors to TCC risk in dogs. Increased risk is associated with household insecticide use, and possibly with less rural households.