Human Genetic Variation of CYP450 Superfamily

Analysis of Functional Diversity in Worldwide Populations

Renato Polimanti; Sara Piacentini; Dario Manfellotto; Maria Fuciarelli


Pharmacogenomics. 2012;13(16):1951-1960. 

In This Article

Abstract and Introduction


Aim: The present study aimed to investigate the human genetic diversity of the CYP450 superfamily in order to identify functional interethnic differences and analyze the role of CYP450 enzymes in human adaptation.

Materials & methods: A computational analysis of genetic and functional differences of the 57 CYP450 genes was performed using the Human Genome Diversity Project and HapMap data; comprising approximately 1694 individuals belonging to 62 human populations.

Results: Twenty-six CYP450 SNPs with F-statistics significantly different than the general distribution were identified. Some showed high differentiation among human populations, suggesting that functional interethnic differences may be present. Indeed, some of these are significantly associated with drug response or disease risk. Furthermore, our data highlighted that TBXAS1 and genes in CYP3A cluster may have a role in some processes of human adaptation.

Conclusion: Our study provided an analysis of genetic diversity of CYP450 superfamily, identifying functional differences among ethnic groups and their related clinical phenotypes.


There is great diversity in individuals' susceptibility to environmental, chemical and drug toxicity. Different components may account for this variability, such as genetic, epigenetic, environmental and pathophysiological factors. Among these, the genetic variation of metabolic enzymes may play a key role in determining individual susceptibility.[1] The detoxification metabolism can be broken down into two phases: phase I (oxidation, reduction and hydrolysis) and phase II (conjugation). Among phase I enzymes, the CYP450 superfamily plays a key role in the metabolism of both endogenous and exogenous molecules, such as steroids, fatty acids, carcinogens, toxins and 90% of drugs currently in use.[2]

In the human genome, 57 genes encoding CYP450 enzymes have currently been identified.[3] The CYP450 genes can be classified into different families according to the amino acid similarities of the encoding proteins.[4] In particular, CYP450 genes in families 1–3 encode for 22 different isoforms, mainly involved in the metabolism of drugs and other xenobiotics, whereas families 4–51 are generally involved in the biosynthesis and metabolism of endogenous compounds.[1] A vast literature details the effects of CYP450 gene variation in different medical care areas, such as disease-causing variants and variants associated with drug response.[5–7] Previous studies have identified the occurrence of defective alleles as having four key phenotypes (poor, intermediate, extensive and ultrarapid metabolizers) that could be used to distinguish the diversity in the human CYP450 system.[1]

Recently, high-throughput experimental methods have provided a large quantity of genetic data that may permit us to improve pharmacogenomic research.[2] Many genetic variants have been identified in humans and different variation classes are recognized (i.e., SNPs, copy-number variants, insertions, deletions and inversions). In particular, much information is available about SNPs that account for the major component of human genome variation. All these new genetic data may allow us to achieve a personalized medicine approach based on individual genomic information. By investigating specific enzymatic systems, it is possible to select the optimal strategies of prevention and therapy for each individual.[8] Although technological developments are continuously increasing and knowledge of the human genome is rapidly accumulating, our ability to analyze these data and the decision whether to use them is still limited.[9] Nevertheless, large-scale human data sets such as the HapMap Project,[10] the Human Genome Diversity Project (HGDP)[11] or, recently, the 1000 Genomes Project[12] can be analyzed to discover sequence variants that affect common disease or drug responses. Furthermore, this available information may be used to identify the health-related aspects most influenced by ethnicity, this particular investigation may have a relevant impact on clinical practice. Physicians may soon be able to understand the relationship between ethnic origin and health-related genetic predisposition in order to select prevention strategies or clinical therapies. Moreover, the analysis of genome diversity may be useful in understanding the genetic basis of human adaptation: in fact, different studies have highlighted that selection signatures may be useful in identifying loci associated with the predisposition of complex diseases.[13]

Among health-related loci, genes belonging to the CYP450 superfamily are widely associated with several biological processes implicated in clinical phenotypes. Therefore, the investigation of ethnic differences in the CYP450 system may be relevant not only to human geneticists but also to physicians. To the best of our knowledge, although several studies have investigated ethnic differences in different CYP450 genes, none has provided an analysis of the entire CYP450 superfamily.[14–16]

Our aim is to investigate the human genetic diversity of the CYP450 superfamily, highlighting the functional differences among worldwide populations. In particular, the strongly differentiated CYP450 SNPs/genes are identified in order to recognize the health aspect most differentiated among ethnic groups, and the analysis of selection signatures in CYP450 genes is performed to understand the role of CYP450 enzymes in human adaptation.