现在已经很好地确定，不同的人群可能对治疗药物表现出截然不同的反应。但是，这可能在多大程度上受到我们的进化史的影响，鲜为人知。在这个来宾博客中，伦敦大学学院的Ripudaman K Bains概述了为什么了解我们的过去可以帮助我们的未来，并描述她最近的工作published inBMC Geneticswith colleagues from Addis Ababa University, Henry Stewart Group and Uppsala University on molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa.

基因组学革命的最重要成就之一是我们对某些人群为何发展特定疾病的风险升高的理解有所改善。它使我们能够研究多个和以前未表征的人群的多样性，并提高了我们对地理区域中人类遗传多样性的理解，最终帮助我们确定了塑造人口差异的进化过程。现在，某些疾病的遗传易感性存在良好的种族和人口差异。例如1，，，，2)和po的高比例的血液疾病pulations from malaria endemic regions, such as glucose-6-phosphate dehydrogenase deficiency (3）and sickle cell disorder (4，，，，5）。

Genetic variability does not only influence disease phenotype and pathology; it can also influence the safety and efficacy of drug treatment. As such, the results of drug therapy can vary within and between populations. Most patients respond well to drug treatment at standardized dosages, however there are individuals who have minimal or no therapeutic response. Additionally, some patients experience severe adverse drug reactions, which are major contributors to global morbidity and mortality. Once a drug is administered, it is absorbed and distributed to the site of action, where it interacts with targets such as receptors or enzymes. Most drugs undergo metabolism before being excreted. Genetic variation may affect absorption, enzyme activity, cellular uptake, and metabolism, resulting in altered drug activity or half-life. Variation in genes encoding drug metabolizing enzymes, such as those in the Cytochrome P450 (CYP450) super-family, can contribute to sub-optimal clinical outcomes.

Tailored therapy

临床视觉研究的基因编码drug metabolizing enzymes is that genetic variation identified within these genes may one day be used to tailor drug therapies based on an individual’s genotype. However, the implementation of genotype-guided medicine for individuals is not currently in widespread clinical use. Physicians are becoming increasingly aware of clinically relevant genetic polymorphisms. However, a 2006 study by the Federal Drug Administration reported that only ~25% of all prescriptions written in the USA contained pharmacogenetics labeling. The paucity of affordable and efficient testing methods, in addition to the continuous identification of clinically important genetic variants, has delayed the translation of human genetic information into clinical practice and healthcare administration. Population-based studies can go some way towards filling this gap. Studying the distribution of pharmacogenetically relevant variants among populations, instead of individuals, has identified common, medically important, variation. However there are many populations, particularly within Africa, that remain under-represented in population pharmacogenetics studies.

The importance of including African populations within evolutionary and clinical research should not be underestimated. The majority of archaeological and genetic data support a recent African origin model of the evolution of anatomically modern humans ~150,000-200,000 years ago. As a result Africa has extensive inter-ethnic genetic diversity, in addition to considerable inter-ethnic cultural, phenotypic and linguistic differences. From a medical perspective, there are marked differences between African populations and European populations in the response to specific treatments that are administered for diseases. However, over 95% of drug development and clinical trials are carried out in European and North American populations, both with predominantly recent European ancestry. Many developing countries, including those in Africa, rely on FDA and European guidelines for safety levels and optimal therapeutic dosages. There are few large-scale studies examining variation in drug metabolizing enzymes across multiple, geographically and ethnically diverse African populations.

In our recentBMC遗传学出版物我们试图解决这种不平衡。我们使用多学科方法来表征和分析编码药物代谢酶细胞色素P450 3A5（CYP3A5）的基因上的非洲内部变异，该酶涉及所有临床药物中约50％的代谢。但是，CYP3A5的表达可变。个体倾向于以高浓度表达蛋白质，或者蛋白质水平低至不可检测的水平。除了迄今为止是非洲CYP3A5变异的最大研究外，我们的方法与以前的研究不同，因为我们使用了分子和进化方法来了解CYP3A5基因中种群级别的变异。我们的研究发现，CYP3A5可能是非洲最具药理活性的药物代谢酶之一。我们对表达CYP3A5的非洲个人比例（43％）的估计值大大低于以前的独立估计（55-95％）。对于最近的欧洲血统（10％），亚洲（25％）和南美人口（30％）人口的人来说，这要高于独立的估计。我们的发现表明，在不同非洲人群中，可能存在多种与CYP3A5的可变表达有关的药物遗传学概况。

Evolutionary medicine

我们还检查了在进化背景下CYP3A5基因功能变异频率的人群差异。CYP450基因在药物和激素代谢中的作用很大程度上被研究。然而，这些酶代谢药物的能力是被认为是其“本地”作用的副产品，因为CYP450旁产存在于多种原核和真核物种中，并且这些基因被认为存在于星球上的基因，用于超过20亿年。人们认为，CYP450酶代谢外源化合物的能力40亿年前进化而成，使动物能够消化植物中发现的某些有毒化学物质，从而产生易于排泄的水溶性化合物。他们作为药物代谢酶的作用在人类进化史上已经很晚了。

进化原理在医学研究中的应用 - “进化医学”的新兴领域 - 试图了解环境和遗传因素如何影响我们整个人类进化史的疾病和疗法的脆弱性以及对疾病和疗法的反应。我们试图确定可以预测全球区域中CYP3A5表达模式的环境因素，并推断可能塑造了观察到的相关性的进化因素。CYP3A5参与了肾皮质醇的代谢为6-β-羟基皮质醇，这是肾脏钠转运的关键调节剂。从进化的角度来看，盐和水的保留是经常遇到水短缺的人群中的重要特征。先前的一项研究报告说，最容易遭受水短缺的赤道种群更有可能以高浓度表达CYP3A5。在这些区域内，快速盐和水的保留应提供进化优势。

我们通过测试与当今的CYP3A5表达表型与生态数据之间的相关性，对当今的干旱，全新世（最后约10，000年）和晚更新世晚期（〜50,000至10，000年前）之间的相关性进行了进一步的研究。我们发现了重要的基因环境相互作用，这表明生活在干旱和干旱环境中的个体更有可能表达CYP3A5。有趣的是，我们发现高世代和更新世晚期的高CYP3A5表达表型与干旱数据之间存在显着相关性。对于每个时间段的温度数据也可以看到这一点。我们的发现为一个假设提供了进一步的支持：CYP3A5酶可能参与了盐保留和热适应，这解释了我们整个非洲观察到的CYP3A5表达模式的某些差异。

There remains a need for focused studies to establish the relationship between environmental variables, patterns of genetic variation, and clinical outcomes within Africa. This is not limited to studies of CYP450 genes; detailed studies of additional drug metabolizing genes, and genetic markers important in predicting clinical outcomes, will become increasingly necessary as we move towards the era of personalized genomics.

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在本文收藏中探索更多有关进化医学发展的发展BMC Medicine：进化医学：从进化的角度来看临床医学