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The shepherds' tale: a genome-wide study across 9 dog breeds implicates two loci in the regulation of fructosamine serum concentration in Belgian shepherds

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Simon K G Forsberg, Marcin Kierczak, Ingrid Ljungvall, Anne-Christine Merveille, Vassiliki Gouni, Maria Wiberg, Jakob Willesen, Sofia Hanås, Anne-Sophie Lequarré, Louise Mejer Sørensen, Laurent Tiret, Kathleen McEntee, Eija Seppälä, Jørgen Koch, Géraldine Battaille, Hannes Lohi, Merete Fredholm, Valerie Chetboul, Jens Häggström, Örjan Carlborg & 2 andre Kerstin Lindblad-Toh, Katja Höglund

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.

OriginalsprogEngelsk
Artikelnummere0123173
TidsskriftPLOS ONE
Vol/bind10
Udgave nummer5
Antal sider17
ISSN1932-6203
DOI
StatusUdgivet - 2015

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