Polymorphisms in the canine glucocorticoid receptor alpha gene (NR3C1α)
Polymorphisms in the canine glucocorticoid receptor alpha gene (NR3C1α)
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DOI：
10.1111/jvp.12241
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发表时间：
2016-02-01
影响因子：
1.3
通讯作者：
Mealey, K. L.
中科院分区：
文献类型：
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作者：
Costa, A.;Sellon, R. K.;Mealey, K. L.
皮质类固醇是犬中使用最广泛的一类治疗药物之一。在人类患者中，对皮质类固醇治疗的反应与糖皮质激素受体基因（NR 3C 1）的某些多态性的存在相关。根据存在的多态性，患者可能表现出对糖皮质激素诱导的不良反应的敏感性增加或对其治疗效果的抵抗。因为狗对皮质类固醇治疗的反应也是可变的和不可预测的，我们假设狗NR 3C 1基因存在遗传变异。本研究的目的是测序犬NR 3C 1基因的编码区在一个有代表性的样品的狗。对来自先前确定的四个家养品种（亚洲/古代、放牧、狩猎和獒）遗传分组的97只狗的样本进行测序和评价。4个外显子存在多态性，4个外显子与参考序列无差异。共鉴定出6个单核苷酸多态性（SNPs），包括4个同义SNPs和2个非同义SNPs（c.811A>T和c.2111T>C）。没有狗是纯合子的任何一个变异等位基因，而23只狗是杂合子的c.811A>T等位基因和2个杂合子的c.2111T>C等位基因。由c.811A>T（丝氨酸变为半胱氨酸）和c.2111T>C（异亮氨酸变为苏氨酸）引起的氨基酸变化均通过计算机分析预测为对所得蛋白质的结构和功能“可能有损害”。我们得出结论，NR 3C 1多态性发生在狗，并可能导致个体差异，在皮质类固醇治疗。
Corticosteroids are one of the most extensively used class of therapeutic agents in dogs. In human patients, response to corticosteroid therapy has been correlated with the presence of certain polymorphisms of the glucocorticoid receptor gene (NR3C1). Depending on the polymorphism present, patients may show either increased sensitivity to glucocorticoid-induced adverse effects or resistance to their therapeutic effects. Because response to corticosteroid therapy in dogs can also be variable and unpredictable, we hypothesized that genetic variability exists in the canine NR3C1 gene. The aim of this study was to sequence the coding regions of the canine NR3C1 gene in a representative sample of dogs. Samples from 97 dogs from four previously identified genetic groupings of domestic breeds (Asian/Ancient, Herding, Hunting, and Mastiff) were sequenced and evaluated. Four exons contained polymorphisms and four exons showed no variation from the reference sequence. A total of six single nucleotide polymorphisms (SNPs) were identified including four synonymous SNPs and two nonsynonymous SNPs (c.811A>T and c.2111T>C). No dogs were homozygous for either variant allele, while 23 dogs were heterozygous for the c.811A>T allele and 2 were heterozygous for c.2111T>C allele. The amino acid changes caused by c.811A>T (serine to cysteine) and c.2111T>C (isoleucine to threonine) were both predicted by in silico analysis to be 'probably damaging' to structure and function of the resulting protein. We conclude that NR3C1 polymorphisms occur in dogs and may cause individual variation in response to corticosteroid therapy.