Abstract
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.
Highlights
Diabetes mellitus constitutes a major human public health problem [1] and is a growing problem in dogs [2,3,4]
The distribution by breed is shown in S1 Fig. As expected, after initial analyses, we found the study population to be highly genetically stratified (S2 Fig), with strata that closely corresponded to the included breeds
While no influence of sex or age on fructosamine concentration has been shown in dogs [31], since our Belgian shepherd (BS) study population consisted of only males, we cannot be entirely sure that the association we found is not male-specific
Summary
Diabetes mellitus constitutes a major human public health problem [1] and is a growing problem in dogs [2,3,4]. Diabetes mellitus is a group of metabolic diseases characterised by chronic excess of blood glucose (hyperglycaemia), as a result of defects in insulin secretion, insulin action, or both. The lifespan of the erythrocyte is 100–120 days, and HbA1c reliably represents the glycemic control over the last 2–3 months. It cannot determine short-term changes in a patient’s glucose control [5]. A second biomarker of glycaemia is fructosamine, which is formed in a non-enzymatic, irreversible reaction between glucose and free amino groups on serum proteins [6]. It can be used to determine more short-term changes in a patient’s glucose control [6]
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