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Abstract
Both safety and efficacy of medical treatment can vary depending on the ethnogeographic background of the patient. One of the reasons underlying this variability is differences in pharmacogenetic polymorphisms in genes involved in drug disposition, as well as in drug targets. Knowledge and appreciation of these differences is thus essential to optimize population-stratified care. Here, we provide an extensive updated analysis of population pharmacogenomics in ten pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in drug hypersensitivity (HLA-A, HLA-B) or drug-induced acute hemolytic anemia (G6PD). Combined, polymorphisms in the analyzed genes affect the pharmacology, efficacy or safety of 141 different drugs and therapeutic regimens. The data reveal pronounced differences in the genetic landscape, complexity and variant frequencies between ethnogeographic groups. Reduced function alleles of CYP2D6, SLC22A1 and CFTR were most prevalent in individuals of European descent, whereas DPYD and TPMT deficiencies were most common in Sub-Saharan Africa. Oceanian populations showed the highest frequencies of CYP2C19 loss-of-function alleles while their inferred CYP2D6 activity was among the highest worldwide. Frequencies of HLA-B*15:02 and HLA-B*58:01 were highest across Asia, which has important implications for the risk of severe cutaneous adverse reactions upon treatment with carbamazepine and allopurinol. G6PD deficiencies were most frequent in Africa, the Middle East and Southeast Asia with pronounced differences in variant composition. These variability data provide an important resource to inform cost-effectiveness modeling and guide population-specific genotyping strategies with the goal of optimizing the implementation of precision public health.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00439-021-02385-x.
Highlights
Interindividual differences in drug response are a common phenomenon in pharmacological therapy
We provide an updated overview of population pharmacogenomics of ten important pharmacokinetic genes (CYP2D6, CYP2C19, DPYD, TPMT, NUDT15 and SLC22A1), drug targets (CFTR) and genes involved in adverse event risk independent of drug pharmacokinetics or target (HLA-A, human leukocyte antigen (HLA)-B and G6PD)
We provide a detailed overview of ethnogeographic differences in allele frequencies, infer functional consequences and discuss implications and relevance for the implementation of population-specific precision public health
Summary
Interindividual differences in drug response are a common phenomenon in pharmacological therapy. Interindividual differences can give rise to sometimes severe adverse drug reactions (ADRs) in a subset of patients that overall account for approximately 7% of all hospitalizations and 0.3% of death among all hospitalized patients (Lazarou et al 1998; Pirmohamed et al 2004). Many of these pharmacogenes are among the most polymorphic genes in the human genome and harbor thousands of genetic variants, which can change enzyme activity or disrupt drug-target interactions, thereby eventually altering drug effects (Lauschke et al 2017; Zhou et al 2021a). Much effort has been made to identify actionable associations between genetic variants and differential drug response. As of 2021, > 310 drugs have received pharmacogenomic information in their labels or have received guidelines by pharmacogenomic expert working groups, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG), that can guide drug selection or posology (Lauschke et al 2019; Shekhani et al 2020)
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