印度人群中与非胰岛素抗糖尿病药物相关的药物基因变异情况。

IF 3.7 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Ambily Sivadas, S Sahana, Bani Jolly, Rahul C Bhoyar, Abhinav Jain, Disha Sharma, Mohamed Imran, Vigneshwar Senthivel, Mohit Kumar Divakar, Anushree Mishra, Arpita Mukhopadhyay, Greg Gibson, Km Venkat Narayan, Sridhar Sivasubbu, Vinod Scaria, Anura V Kurpad
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引用次数: 0

摘要

简介:基因变异会导致对非胰岛素抗糖尿病药物(NIADs)的不同反应,进而导致不同的血浆葡萄糖控制。血浆葡萄糖的最佳控制对于最大限度地减少与 2 型糖尿病相关的长期并发症至关重要。印度独特的基因结构和不断增加的 2 型糖尿病负担,需要对 NIAD 相关的药物基因(PGx)变异进行特定人群调查。最近从印度人群中获得的大规模全基因组为绘制特定人群的 NIAD 相关 PGx 变异图谱提供了一个独特的机会:我们在1029个印度全基因组中挖掘了与44种NIAD相关的PGx变异、药物-药物相互作用(DDI)和药物-药物-基因相互作用(DDGI)。使用费雪精确检验估算并比较了人群等位基因频率:结果:总的来说,我们在印度人中发现了 76 个已知的和 52 个预测的与 2 型糖尿病治疗反应相关的有害常见 PGx 变异。我们报告了在不同 NIAD 类别中,反应相关等位基因减少和增加的相对累积数量存在明显的种族间差异。与全球其他人群相比,印度人和南亚人中二甲双胍反应相关等位基因减少的比例明显偏高。共享 PGx 基因的网络分析预测了 NIAD 与其他代谢性疾病药物联合用药时的高 DDI 风险。我们还预测,CYP3A4/3A5代谢的NIADs、沙格列汀、利纳列汀和甘布肽与质子泵抑制剂(PPIs)联合用药时,CYP2C19介导的DDGI风险会增加:印度人和南亚人在服用抗糖尿病药物时具有独特的 PGx 特征,其特点是各种 NIAD 类药物的不良治疗反应相关等位基因过多。这表明,至少在某些 NIADs 中,存在人群特异性药物反应降低的可能性。此外,我们的研究结果还为加快未来在印度人和南亚人中开展糖尿病 PGx 研究以及重新考虑 NIAD 剂量指南提供了可操作的资源,以确保在人群中实现最大疗效和安全性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population.

Introduction: Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India's distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants.

Research design and methods: We mined 1029 Indian whole genomes for PGx variants, drug-drug interaction (DDI) and drug-drug-gene interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies were estimated and compared using Fisher's exact test.

Results: Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to type 2 diabetes therapy among Indians. We report remarkable interethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared with other global populations. Network analysis of shared PGx genes predicts high DDI risk during coadministration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when coadministered with proton-pump inhibitors (PPIs).

Conclusions: Indians and South Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of poor treatment response-associated alleles for various NIAD classes. This suggests the possibility of a population-specific reduced drug response in atleast some NIADs. In addition, our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and South Asians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population.

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来源期刊
BMJ Open Diabetes Research & Care
BMJ Open Diabetes Research & Care Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
9.30
自引率
2.40%
发文量
123
审稿时长
18 weeks
期刊介绍: BMJ Open Diabetes Research & Care is an open access journal committed to publishing high-quality, basic and clinical research articles regarding type 1 and type 2 diabetes, and associated complications. Only original content will be accepted, and submissions are subject to rigorous peer review to ensure the publication of high-quality — and evidence-based — original research articles.
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