Towards precision medicine: interrogating the human genome to identify drug pathways associated with potentially functional, population-differentiated polymorphisms.,The Pharmacogenomics Journal

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Towards precision medicine: interrogating the human genome to identify drug pathways associated with potentially functional, population-differentiated polymorphisms.
The Pharmacogenomics Journal ( IF 2.9 ) Pub Date : 2019-10-03 , DOI: 10.1038/s41397-019-0096-y
Maulana Bachtiar _{1,

2} , Brandon Nick Sern Ooi ₁ , Jingbo Wang ₁ , Yu Jin ₂ , Tin Wee Tan _{1,

3} , Samuel S Chong ₄ , Caroline G L Lee _{1,

2,

5}

Affiliation

Drug response variations amongst different individuals/populations are influenced by several factors including allele frequency differences of single nucleotide polymorphisms (SNPs) that functionally affect drug-response genes. Here, we aim to identify drugs that potentially exhibit population differences in response using SNP data mining and analytics. Ninety-one pairwise-comparisons of >22,000,000 SNPs from the 1000 Genomes Project, across 14 different populations, were performed to identify 'population-differentiated' SNPs (pdSNPs). Potentially-functional pdSNPs (pf-pdSNPs) were then selected, mapped into genes, and integrated with drug-gene databases to identify 'population-differentiated' drugs enriched with genes carrying pf-pdSNPs. 1191 clinically-approved drugs were found to be significantly enriched (Z > 2.58) with genes carrying SNPs that were differentiated in one or more population-pair comparisons. Thirteen drugs were found to be enriched with such differentiated genes across all 91 population-pairs. Notably, 82% of drugs, which were previously reported in the literature to exhibit population differences in response were also found by this method to contain a significant enrichment of population specific differentiated SNPs. Furthermore, drugs with genetic testing labels, or those suspected to cause adverse reactions, contained a significantly larger number (P < 0.01) of population-pairs with enriched pf-pdSNPs compared with those without these labels. This pioneering effort at harnessing big-data pharmacogenomics to identify 'population differentiated' drugs could help to facilitate data-driven decision-making for a more personalized medicine.

中文翻译：

迈向精准医学：询问人类基因组以识别与潜在功能性、群体分化多态性相关的药物途径。

不同个体/人群之间的药物反应变化受几个因素的影响，包括在功能上影响药物反应基因的单核苷酸多态性 (SNP) 的等位基因频率差异。在这里，我们的目标是使用 SNP 数据挖掘和分析来识别可能表现出群体反应差异的药物。对来自 14 个不同群体的 1000 个基因组计划的 >22,000,000 个 SNP 进行了 91 次成对比较，以确定“群体分化”的 SNP (pdSNP)。然后选择具有潜在功能的 pdSNP (pf-pdSNP)，将其映射到基因中，并与药物基因数据库整合，以识别富含携带 pf-pdSNP 基因的“人群分化”药物。1191 种临床批准的药物被发现显着富集（Z > 2. 58）带有携带在一个或多个群体对比较中分化的SNP的基因。发现 13 种药物在所有 91 个群体对中都富含这种分化基因。值得注意的是，82% 的药物（之前在文献中报道过的表现出群体反应差异）也通过这种方法发现含有显着富集的群体特异性分化 SNP。此外，与没有这些标签的药物相比，带有基因检测标签的药物或疑似引起不良反应的药物含有大量（P < 0.01）具有丰富 pf-pdSNP 的群体对。这项利用大数据药物基因组学识别“人群差异化”的开创性努力

更新日期：2020-01-16

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