Identification of Genetic Susceptibility Factors Associated with Canine Gastric Dilatation-Volvulus.

Canine gastric dilatation-volvulus (GDV) is a common life-threatening condition occurring primarily in large and giant breeds with a 3.9% to 36.7% lifetime risk. The genetic correlates of GDV have not previously been systematically explored. We undertook an inter-breed genome-wide association analysis (GWAS) of 253 dogs from ten breeds including 106 healthy dogs and 147 dogs with at least one GDV episode. SNP array genotyping followed by imputation was conducted on 241 samples to identify GDV-associated single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs). A subset of 33 dogs (15 healthy dogs and 18 GDV patients from the three most represented breeds) was characterized by whole genome sequencing (WGS). After genome-wide Bonferroni correction, we identified a significant putatively protective intergenic SNP (rs851737064) across all breeds. The signal was most significant in Collies, German Shorthaired Pointers, and Great Danes. Subsequent focused analysis across these three breeds identified 12 significant additional putatively protective or deleterious SNPs. Notable significant SNPs included those occurring in genes involved in gastric tone and motility including VHL, NALCN, and PRKCZ. These data provide important new clues to canine GDV risk factors and facilitate generation of hypotheses regarding the genetic and molecular underpinnings this syndrome.

The canine gut microbiome is associated with higher risk of gastric dilatation-volvulus and high risk genetic variants of the immune system.

BACKGROUND: Large and giant dog breeds have a high risk for gastric dilatation-volvulus (GDV) which is an acute, life-threatening condition. Previous work by our group identified a strong risk of GDV linked to specific alleles in innate and adaptive immune genes. We hypothesize that variation in the genes of the immune system act through modulation of the gut microbiome, or through autoimmune mechanisms, or both, to predispose dogs to this condition. Here, we investigate whether differences in the canine fecal microbiome are associated with GDV and are linked to previously identified risk alleles. METHODOLOGY/PRINCIPLE FINDINGS: Fecal samples from healthy Great Danes (n = 38), and dogs with at least one occurrence of GDV (n = 37) were collected and analyzed by paired-end sequencing of the 16S rRNA gene. Dietary intake and temperament were estimated from a study-specific dietary and temperament questionnaire. Dogs with GDV had significantly more diverse fecal microbiomes than healthy control dogs. Alpha diversity was significantly increased in dogs with GDV, as well as dogs with at least one risk allele for DRB1 and TRL5. We found no significant association of dietary intake and GDV. Dogs with GDV showed a significant expansion of the rare lineage Actinobacteria (p = 0.004), as well as a significantly greater abundance of Firmicutes (p = 0.004) and a significantly lower abundance of Bacteroidetes (p<0.004). There was a significant difference in the abundance of 10 genera but after correction for multiple comparisons, none were significant. Bacterial phyla were significantly different between controls and dogs with GDV and at least one risk allele for DRB1 and TRL5. Actinobacteria were significantly higher in dogs with GDV and with one risk allele for DRB1 and TLR5 but not DLA88 genes. Furthermore, Collinsella was significantly increased in dogs with at least one risk allele for DRB1 and TLR5. Logistic regression showed that a model which included Actinobacteria, at least one risk allele,and temperament, explained 29% of the variation in risk of GDV in Great Danes. CONCLUSIONS: The microbiome in GDV was altered by an expansion of a minor lineage and was associated with specific alleles of both innate and adaptive immunity genes. These associations are consistent with our hypothesis that immune genes may play a role in predisposition to GDV by altering the gut microbiome. Further research will be required to directly test the causal relationships of immune genes, the gut microbiome and GDV.

Associations between gastric dilatation-volvulus in Great Danes and specific alleles of the canine immune-system genes DLA88, DRB1, and TLR5.

OBJECTIVE To determine whether specific alleles of candidate genes of the major histocompatibility complex (MHC) and innate immune system were associated with gastric dilatation-volvulus (GDV) in Great Danes. ANIMALS 42 healthy Great Danes (control group) and 39 Great Danes with ≥ 1 GDV episode. PROCEDURES Variable regions of the 2 most polymorphic MHC genes (DLA88 and DRB1) were amplified and sequenced from the dogs in each group. Similarly, regions of 3 genes associated with the innate immune system (TLR5, NOD2, and ATG16L1), which have been linked to inflammatory bowel disease, were amplified and sequenced. Alleles were evaluated for associations with GDV, controlling for age and dog family. RESULTS Specific alleles of genes DLA88, DRB1, and TLR5 were significantly associated with GDV. One allele of each gene had an OR > 2 in the unadjusted univariate analyses and retained a hazard ratio > 2 after controlling for temperament, age, and familial association in the multivariate analysis. CONCLUSIONS AND CLINICAL RELEVANCE The 3 GDV-associated alleles identified in this study may serve as diagnostic markers for identification of Great Danes at risk for GDV. Additional research is needed to determine whether other dog breeds have the same genetic associations. These findings also provided a new target for research into the etiology of, and potential treatments for, GDV in dogs.

Inherited and predisposing factors in the development of gastric dilatation volvulus in dogs.

This review article summarizes what is known as well as what is undetermined concerning the inherited and environmental pathogenesis of gastric dilatation volvulus in dogs. The disorder primarily affects large and giant, deep-chested breeds. A concise description of a typical dog affected with gastric dilatation volvulus is presented.

A retrospective study of gastric dilatation and gastric dilatation and volvulus in working farm dogs in New Zealand.

AIMS: To present findings from a case series of gastric dilatation (GD) or gastric dilatation and volvulus (GDV) in working farm dogs in New Zealand that were examined at veterinary clinics, and to identify possible risk factors for GD or GDV in working farm dogs in New Zealand using a case-control study. METHODS: This retrospective study included a case-series and a case-control study. The case series analysed information from 62 case records of GD or GDV in working farm dogs seen between August 2004 and September 2009 at 13 veterinary clinics throughout New Zealand. Cases were classified as GD or GDV if the diagnosis was confirmed by radiography, surgery or post-mortem examination. Details of history and treatment, as well as outcomes, were obtained for each case. For the case-control study, records of 41 working farm dogs with GD or GDV (cases) seen between April 2008 and April 2009, and 82 working farm dogs examined because of trauma over the same period and in the same 13 clinics (controls), were used to model the risk factors for GD or GDV. RESULTS: From the case-series study, 40/62 (65%) cases of GD or GDV that were examined and treated at the veterinary clinics returned to work. Of the 41 dogs where the gastric contents were recorded, 25 (61%) had predominantly food or bones in the stomach, and 26/27 dogs had a history of having eaten meat, bones or scavenged a carcass. The case-control study showed that the significant risk factors for GD or GDV, compared with control dogs presenting with trauma, were breed, age and season. The odds that a case of GD or GDV was a Huntaway, after adjusting for age and season, was 19 times higher than the odds a control was a Huntaway. Gender and bodyweight were not identified as risk factors. CONCLUSIONS AND CLINICAL RELEVANCE: A high proportion of farm working dogs with GD or GDV were successfully treated by veterinarians. The risk of a case of GD or GDV being a Huntaway was significantly higher than for a dog presenting as a trauma case. However the influences of the season of the year, climatic factors and nutritional factors on the pathogenesis need to be identified before adequate preventative measures can be recommended.

Predisposition to gastric dilatation-volvulus in relation to genetics of thoracic conformation in Irish setters.

Thoracic depth/width ratios (TDWRs) were calculated from measurements of the parents (i.e., common dam and two sires) and puppies in two litters of Irish setters. The TDWRs of the parents, distribution of TDWRs in the litters, and comparisons with earlier population studies suggest that an incompletely dominant major gene and a background of minor genes and environmental factors are responsible for the TDWR. A history of gastric dilatation-volvulus (GDV) (i.e., bloat) was correlated with high TDWRs in this family as it was for Irish setters and certain other breeds studied earlier. It may be possible to reduce the incidence of GDV by selective breeding of dogs with lower TDWRs.

Familial occurrence of intrathoracic gastric volvulus.

This report describes the first documented familial occurrence of gastric volvulus in two consecutive generations. Consideration is given to familial transmission of other foregut disorders. The report reviews the different types of gastric volvulus and considers their pathogenesis, clinical presentation, and treatment.

Gastric dilatation-volvulus in the dog, with emphasis on cardiac arrhythmias.

Gastric dilatation was diagnosed in 156 dogs during a 5-year period. The recurrence rate was 10% and the overall mortality was 43%. Large-breed dogs of either sex and ranging in age from 2 months to 15 years (mean age, 5.2 +/- 2.9 years) were found to be susceptible to the problem. Cardiac arrhythmias were diagnosed in 48 of 115 (42%) affected dogs. Cardiac arrhythmias occurred most frequently between 12 and 36 hours after the onset of gastric dilatation-volvulus and were generally ventricular in origin.