Analysis of polymorphisms of canine Cytochrome P 450-CYP2D15.

Cytochrome P450 (CYP) proteins constitute a large ancient family of oxidative enzymes essential for the efficient elimination of a wide variety of clinically used drugs. Polymorphic variants of human CYP2D6 are associated with the conversion rate and efficacy of several drugs such as antidepressants. Polymorphisms of the canine orthologue CYP2D15 are of interest because these antidepressants are also used in dogs with behavioral problems and the outcome of the treatment is variable. However, the annotated CYP2D15 gene is incomplete and inaccurately assembled in CanFam3.1, hampering DNA sequence analysis of the gene in individual dogs. We elucidated the complete exon-intron structure of CYP2D15 to enable comprehensive genotyping of the gene using genomic DNA. We surveyed variations of the gene in four diverse dog breeds and identified novel polymorphisms in exon 2 in border collies. Further investigation to establish the impact of these canine CYP2D15 polymorphisms on interindividual variability in expression and function of this metabolizing enzyme is now feasible. Further knowledge of CYP pharmacogenetics will help individualize therapy and thereby increase therapeutic efficacy, especially in the use of antidepressants in veterinary behavioral medicine.

Life expectancy in a birth cohort of Boxers followed up from weaning to 10 years of age.

OBJECTIVE: To determine mortality rate over time, risk factors for death, and heritability of life expectancy in Boxers. ANIMALS: 1,733 purebred Boxers born in The Netherlands between January 1994 and March 1995. PROCEDURE: Dogs were followed up from weaning (ie, 49 days of age) to 10 years of age through use of a written questionnaire sent to owners every 6 months. Mortality rate over time, risk factors potentially associated with death, and heritability of life expectancy were examined by use of a proportional hazards model based on the Weibull distribution. RESULTS: stimated mortality rate during the 10-year study period for this birth cohort of Boxers was 45%. The probability of surviving to 5 years of age was 88%; the probability of surviving to 10 years of age was 55%. Estimated effective heritability of life expectancy was 0.076, meaning that in this population, an estimated 76% of the observed variation in life expectancy could be attributed to genetic differences among dogs that were passed from parents to their offspring. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cumulative incidence of death from weaning to 10 years of age among this birth cohort of Boxers was 45%. The estimated heritability of life expectancy suggested that life expectancy can be improved by use of selective breeding.

Incidence, risk factors, and heritability estimates of hind limb lameness caused by hip dysplasia in a birth cohort of boxers.

OBJECTIVE: To determine incidence, risk factors, and heritability estimates of hind limb lameness caused by hip dysplasia in a birth cohort of Boxers. ANIMALS: 1733 Boxers from 325 litters. PROCEDURE: Status of Boxers with respect to clinical signs of canine hip dysplasia (cCHD) was registered during an 8-year period. Survival analysis accounted for dogs lost to follow-up. Effective heritability for developing cCHD was estimated by use of a proportional hazard model on the basis of the Weibull distribution. Parametric survival models were developed to identify the influence of potential risk factors. RESULTS: Cumulative hazard rate for cCHD from 7 weeks to 8 years of age was 8.5%. Dogs that were kept on a floor covered with a slippery material were 1.6 times as likely to develop cCHD, compared with dogs kept on a nonslippery floor. Risk of cCHD doubled in dogs from litters with a high preweaning mortality rate. Dogs that were neutered at 6 months prior to a diagnosis of CHD were 1.5 times as likely to develop cCHD, compared with sexually intact dogs. Dogs >5 years of age were 1.8 times as likely to develop cCHD, compared with younger dogs. Estimated effective heritability of cCHD was 0.11. In terms of the risk of cCHD in progeny, mean estimated breeding value (EBV) of the 10 best and 10 worst sires was -0.32 and 0.42, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Registration of Boxers that develop cCHD may provide a strategy for disease prevention. In addition to diagnostic evaluation of radiographs, sire EBVs provide useful information for breeding selection decisions.

The use of a genetic-counselling program by Dutch breeders for four hereditary health problems in boxer dogs.

Our group developed a genetic-counselling program for boxer-dog breeders in The Netherlands, using data for cryptorchidism (uni- and/or bilateral), epilepsy, knee-problems (including ligament rupture, fractured or ruptured meniscus, severe osteo-arthrosis of the knee, or a combination of these disorders), and schisis (including cheiloschisis, palatoschisis, or cheilopalatoschisis). We transformed the estimated breeding values (EBVs) into odds ratios (ORs), to enable the breeder to compare the risk for each of the traits for a certain dam-sire combination with the average population risk (set at 1). The goal of the study was to evaluate the use of our genetic-counselling program by Dutch breeders of boxer dogs. We asked breeders of the Dutch Boxer Club to send in an application form for genetic-counselling from June 1 to December 1, 2000. Breeders indicated on this application form three desirable sires for their dam (sire 1, sire 2, sire 3) in random order. On the basis of this information, a counselling report was produced which included ORs for the four diseases in litters of the dam-sire combinations indicated on the application form. Together with the counselling report, the breeders received an evaluation form. We received 129 application forms from 70 breeders, and collected 125 evaluations. Of these evaluations, 96 were informative about the influence of the counselling report on sire choice. The most-important criteria used by breeders to select sires were: the exterior characteristics (60%) and known progeny (52%). Although it was the first time breeders could make use of genetic-counselling, 32% of the breeders indicated that the genetic-counselling played a major role in their sire selection. Breeders expressed little difference in importance for the four genetic traits, but there was a tendency to consider epilepsy more than the others. Breeders hesitated to put long-term population interest above short-term personal interest. Nevertheless, the general conclusion of this study is that breeders acknowledge the value of counselling, especially to reduce the frequency of a threatening disease such as epilepsy.