Genetics of breed susceptibility to canine diabetes mellitus and insulinoma: From one extreme to the other

犬糖尿病和胰岛素瘤品种易感性的遗传学：从一个极端到另一个极端

• 批准号: 1902557
• 金额: --
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1902557
• 关键词: Genetics; breed; susceptibility; canine; diabetes

Pet dogs exhibit tremendous diversity across different breeds, not only in physical appearance but also in disease susceptibility. Diabetes mellitus (DM), affects 1 in 300 dogs and results from destruction of pancreatic beta-cells, leading to insulin deficiency. Samoyed dogs are highly susceptible to DM (OR = 21.7), whereas Boxer dogs are resistant (OR =0.06), suggesting that beta-cells in the former breed are more 'fragile'. However, Boxers are susceptible to developing insulinomas (INSA), implying that the price paid for improved beta-cell survival is the potential for malignant transformation and tumour formation. The genetic risk associated with these two disease syndromes is likely to be 'fixed' within each breed. We propose an approach whereby we compare whole genome sequences (WGS) in dogs at the extremes of the pancreatic beta cell phenotype.HYPOTHESISWe hypothesise that comparison of the Boxer genome to the Samoyed genome will reveal unique variations in genes critical for beta-cell health and survival. Such variants may protect from DM, but predispose to INSA and vice versa. Identification of genes and mechanisms involved in beta-cell health and resilience will reveal new pathways for intervention in prevention or treatment of DM and INSA.AIMSTo undertake WGS (Illumina HiSeqX) of at least 10 Samoyeds and 10 Boxers (10x to 30x coverage, dependent on pilot work), with a focus on cases of DM and INSA. Labrador retrievers will be used as a reference breed, with a neutral risk of both diseases. To identify breed-specific variants with relevance to pancreatic beta-cell biology and investigate these in a larger cohort of dogs (n=100) affected with DM and INSA across a range of breeds METHODSDNA samples for this project are already available. A bespoke bioinformatic pathway will be used for analysis, utilising the high-performance computer cluster at the Wellcome Trust Centre for Human Genetics, University of Oxford.

不同品种的宠物狗表现出巨大的多样性，不仅在外表上，而且在疾病易感性上。糖尿病 (DM) 影响每 300 只狗中就有 1 只，其原因是胰腺 β 细胞遭到破坏，导致胰岛素缺乏。萨摩耶犬对 DM 高度敏感（OR = 21.7），而拳师犬则具有抵抗力（OR = 0.06），这表明前一个品种的 β 细胞更加“脆弱”。然而，拳击手很容易患上胰岛素瘤 (INSA)，这意味着为提高 β 细胞存活率而付出的代价是可能发生恶性转化和肿瘤形成。与这两种疾病综合症相关的遗传风险可能在每个品种中都是“固定的”。我们提出了一种方法，可以比较处于胰腺β细胞表型极端的狗的全基因组序列（WGS）。假设我们假设，将拳击手基因组与萨摩耶基因组进行比较将揭示对β细胞健康和生存至关重要的基因的独特变异。这些变异可以预防 DM，但容易患 INSA，反之亦然。鉴定与 β 细胞健康和恢复力相关的基因和机制将揭示干预预防或治疗 DM 和 INSA 的新途径。目的对至少 10 只萨摩耶犬和 10 只拳师犬进行全基因组测序 (Illumina HiSeqX)（覆盖范围为 10 倍到 30 倍，取决于试点工作），重点关注 DM 和 INSA 病例。拉布拉多猎犬将被用作参考品种，两种疾病的风险均为中性。为了识别与胰腺 β 细胞生物学相关的品种特异性变异，并在更大的一组受 DM 和 INSA 影响的各种品种的狗 (n=100) 中研究这些变异，本项目的 DNA 样本已经可用。将利用牛津大学威康人类遗传学信托中心的高性能计算机集群，使用定制的生物信息学途径进行分析。

项目成果

Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds.

• DOI: 10.1186/s40575-020-00093-9
• 发表时间: 2020-10-31
• 期刊: Canine medicine and genetics
• 作者: Denyer AL;Massey JP;Davison LJ;Ollier WER;Catchpole B;Kennedy LJ
• 通讯作者: Kennedy LJ

Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked?

• DOI: 10.2337/db16-1551
• 发表时间: 2017-06
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: O'Kell AL;Wasserfall C;Catchpole B;Davison LJ;Hess RS;Kushner JA;Atkinson MA
• 通讯作者: Atkinson MA