Population pharmacogenomics: an update on ethnogeographic differences and opportunities for precision public health

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.

Genetic Variations of the DPYD Gene and Its Relationship with Ancestry Proportions in Different Ecuadorian Trihybrid Populations

“…The genetic variability reported in DPYD is heterogeneous and has a close relationship with biogeographical ancestry [ 75 , 76 , 77 , 78 ]. The estimation of ancestry developed in the Ecuadorian ethnic groups allowed us to establish a relationship between the frequency of the minor alleles found in the different molecular variants of DPYD and the proportion of ancestry with ancestral reference populations, especially with NAM and AFR populations.…”

A paradigm shift in pharmacogenomics: From candidate polymorphisms to comprehensive sequencing

“…Evaluation of pharmacogenomic variability between human populations is receiving increasing interest. Over the last two decades, studies have pinpointed numerous clinically relevant single‐nucleotide polymorphisms (SNPs) and CNVs with distinct ethnogeographic frequency profiles 24 . Some well‐studied population‐specific variations in CYP2D6 , CYP2C19 and HLA‐B are illustrated below.…”

The genetic landscape of major drug metabolizing cytochrome P450 genes—an updated analysis of population-scale sequencing data

“…With the exception of CYP3A4, these enzymes lack important endogeneous substrates and, consequently, these CYP genes are extremely polymorphic with a plethora of single nucleotide variations (SNVs) and structural variants [ 5 , 6 ]. Genetic drift, population admixture and isolation compound the genetic complexity and result in substantial ethnogeographic differences in CYP gene variability across human populations [ 7 ].…”