Genome wide association study of 40 clinical measurements in eight dog breeds.

The domestic dog represents an ideal model for identifying susceptibility genes, many of which are shared with humans. In this study, we investigated the genetic contribution to individual differences in 40 clinically important measurements by a genome-wide association study (GWAS) in a multinational cohort of 472 healthy dogs from eight breeds. Meta-analysis using the binary effects model after breed-specific GWAS, identified 13 genome-wide significant associations, three of them showed experimental-wide significant associations. We detected a signal at chromosome 13 for the serum concentration of alanine aminotransferase (ALT) in which we detected four breed-specific signals. A large proportion of the variance of ALT (18.1-47.7%) was explained by this locus. Similarly, a single SNP was also responsible for a large proportion of the variance (6.8-78.4%) for other measurements such as fructosamine, stress during physical exam, glucose, and morphometric measurements. The genetic contribution of single variant was much larger than in humans. These findings illustrate the importance of performing meta-analysis after breed-specific GWAS to reveal the genetic contribution to individual differences in clinically important measurements, which would lead to improvement of veterinary medicine.

The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds.

Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

Gln27Glu polymorphism of the beta2 adrenergic receptor gene in healthy Japanese men is associated with the change of fructosamine level caused by exercise.

Adrenaline plays a major role in the maintenance of blood glucose level by promoting glycogenolysis during prolonged exercise predominantly via the beta2 adrenergic receptor (beta2AR). Because beta2ARs are mainly present in the muscle and liver, beta2AR gene polymorphism may affect changes in glucose metabolism caused by exercise. We, therefore, investigated the effect of beta2AR gene polymorphism on glucose metabolism in healthy Japanese men. The study group consisted of 124 unrelated healthy Japanese men who were aged 21-69 years (mean +/- S.D.: 45.3+/-11.7). They participated in an exercise program which was defined as low-moderate intensity at 20-60min per day, 2-3 days per week for 3 months. The genotype of Gln27Gln was detected in 109 subjects (87.9%), of Gln27Glu in 15 subjects (12.1%) and of Glu27Glu in none, and that of Arg16Arg, Arg16Gly and Gly16Gly in 32 (25.8%), 79 (63.7%) and 13 subjects (10.5%), respectively. There was no association between these polymorphisms and the metabolic characteristics at baseline. The change in fructosamine level as a result of exercise showed that the carrier of the Glu allele had a better response to exercise than the non-carrier. In conclusion, Gln27Glu polymorphism was associated with the change in fructosamine level resulting from exercise, but not Arg16Gly polymorphism.