Forsberg Simon K G, Kierczak Marcin, Ljungvall Ingrid, Merveille Anne-Christine, Gouni Vassiliki, Wiberg Maria, Lundgren Willesen Jakob, Hanås Sofia, Lequarré Anne-Sophie, Mejer Sørensen Louise, Tiret Laurent, McEntee Kathleen, Seppälä Eija, Koch Jørgen, Battaille Géraldine, Lohi Hannes, Fredholm Merete, Chetboul Valerie, Häggström Jens, Carlborg Örjan, Lindblad-Toh Kerstin, Höglund Katja
Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Computational Genetics Section, Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden; Science for Life Laboratory & Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
PLoS One. 2015 May 13;10(5):e0123173. doi: 10.1371/journal.pone.0123173. eCollection 2015.
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.
糖尿病在犬类和人类中都是严重的健康问题。某些犬种该疾病的患病率很高，而其他犬种患病风险较低。果糖胺和糖化血红蛋白（HbA1c）是血糖的两个主要生物标志物，其血清浓度反映了过去几周至几个月内的葡萄糖代谢情况。在本研究中，我们利用来自9个犬种的数据，寻找影响健康犬血清果糖胺浓度变化的遗传因素。综合考虑所有犬种，我们未发现与果糖胺血清浓度存在全基因组显著关联。然而，通过进行特定犬种分析，我们在马里努阿犬亚型的比利时牧羊犬中发现了3号染色体上的一个关联（p校正≈1.68×10-6）。相关区域及其附近区域含有一些有趣的候选基因，如LETM1和GAPDH，它们在葡萄糖代谢中很重要，且先前已被认为与糖尿病的病因有关。为了进一步探究这种犬种特异性的遗传学机制，我们在基因组中筛选了比利时牧羊犬特有的杂合性降低区域。这揭示了一个杂合性降低的区域，该区域与3号染色体上的关联区域存在统计学上显著的相互作用（p = 0.025）。该区域也含有一些有趣的候选基因和调控区域，但相互作用背后的确切机制仍不清楚。尽管如此，这一发现为犬类复杂性状的犬种特异性遗传效应提供了一个合理的解释。牧羊犬种患糖尿病的风险较低。比利时牧羊犬的研究结果可能与针对该疾病的一种保护机制有关。对葡萄糖代谢调控的进一步了解可能会改善糖尿病的诊断和治疗方法。
