Exploring Pharmacogenetic Factors Influencing Hydroxyurea Response in Tanzanian Sickle Cell Disease Patients: A Genomic Medicine Approach
Siana NkyaCollin NzundaEmmanuel SaukiwaFrida KaywangaEliud BuchardDavid A. SolomonHeavenlight ChristopherDoreen NgowiJulieth JohansenFlorence UrioJosephine MgayaChristina KindoleMbonea YonaziSalman KarimMohamed Zahir AlimohamedRaphael Zozimus SangedaClara ChambaCollet DandaraEnrico M. NovelliEmile R. ChimusaJulie Makani
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Abstract Sickle cell disease (SCD) continues to pose a significant public health challenge, particularly in sub-Saharan Africa. Despite its discovery over a century ago, the progress in developing and accessing effective interventions has been notably restricted. Currently, hydroxyurea stands as the primary drug in widespread use, and has been associated with elevated levels of fetal hemoglobin (HbF) and enhanced clinical outcomes. Notably, a substantial proportion, up to 30%, of patients do not exhibit a positive response to hydroxyurea treatment. There is compelling evidence suggesting that genetic factors play a crucial role in influencing the effectiveness of hydroxyurea. In this study, we present findings on the investigation of genetic variants influencing hydroxyurea response in 13 genetic loci associated with HbF synthesis and hydroxyurea drug metabolism focusing on MYB , HBB , HBG1 , HBG2 , BCL11A , KLF10 , HAO2 , NOS1 , ARG2 , SAR1A , CYP2C9 , CYP2E1 . We report remarkable genetic associations with CYP2C9 , CYP2E1, KLF10 , BCL11A , ARG2 , HBG1 , SAR1A , MYB , and NOS1 loci with hydroxyurea response. We also highlight associated pathway’s enrichment and gene-gene interactions analysis in the context of hydroxyurea treatment response.Keywords:
Drug response
Pharmacogenetics (PGx) studies the influence of genetic variation on drug response. Clinically actionable associations inform guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), but the broad impact of genetic variation on entire populations is not well understood. We analyzed PGx allele and phenotype frequencies for 487,409 participants in the UK Biobank, the largest PGx study to date. For 14 CPIC pharmacogenes known to influence human drug response, we find that 99.5% of individuals may have an atypical response to at least 1 drug; on average they may have an atypical response to 10.3 drugs. Nearly 24% of participants have been prescribed a drug for which they are predicted to have an atypical response. Non‐European populations carry a greater frequency of variants that are predicted to be functionally deleterious; many of these are not captured by current PGx allele definitions. Strategies for detecting and interpreting rare variation will be critical for enabling broad application of pharmacogenetics.
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Pharmacogenetics explores the genetic determination of drug response (therapeutic as well as side-effects). Starting point is the marked interindividual variation in response to drugs, and the lack of valid clinical predictors of drug response. Some reasons argue for the impact of interindividual genetic variation on differential drug response. On the other hand, there is some evidence of familial similarities in drug response; we also know that most of the targets of drugs are under genetic variation.
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Drug response shows significant interpatient variability and evidence that genetics influences outcome of drug therapy has been known for more than five decades. However, the translation of this knowledge to clinical practice remains slow. Using examples from clinical practice six considerations about the implementation of pharmacogenetics (PGx) into routine care are discussed: the need for PGx biomarkers; the sources of genetic variability in drug response; the amount of variability explained by PGx; whether PGx test results are actionable; the level of evidence needed for implementation of PGx and the sources of information regarding interpretation of PGx data.
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Vogel in 1959 first proposed the term “Pharmacogenetics” and in 1962, Kalow wrote the first monograph for the same. The field of pharmacogenetics was stimulated in 1970s when Vesell and Colleagues demonstrated that plasma half-lives of many drugs are less divergent among monozygotic twin pairs than among dizygotic twin pairs. Over 50 years down the lane examples of exaggerated responses to drugs, novel drug effects, or lack of effectiveness of drugs as a manifestation of inherited individual traits have been observed.
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Pharmacogenetics is the inherited basis of differences among individuals in their response to drugs. Genetic polymorphisms of drug-metabolizing enzymes may account for as much as 30% of interindividual differences in drug disposition and response. An increasing number of drug target polymorphisms have also been linked to differences in drug response. This chapter reviews some examples of the use of pharmacogenetics in clinical practice. Despite the increasing number of examples of genetic polymorphisms affecting drug response in the literature, pharmacogenetic data are rarely used in current clinical practice. The limitations that have prevented the use of pharmacogenetic testing in clinical practice are reviewed.
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As genotyping and genetic testing become more sophisticated, accessible, and costeffective, these tools hold great promise for predicting and improving responses to medications.
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Genetics has given a real boost to personalized and precision medicine, providing data used either for precise diagnostics, prediction of the course of illness, or for selecting therapy and tailoring it. Pharmacogenetics, as a discipline researching connection between genetic background of an individual and the effect of a certain drug, has created new possibilities in medicine. One of the most researched drugs in pharmacogenetics is certainly clopidogrel.
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Abstract Pharmacogenetics (PGx) studies the influence of genetic variation on drug response. Clinically actionable associations inform guidelines created by the Clinical Pharmacogenetics Implementation Consortium (CPIC), but the broad impact of genetic variation on entire populations is not well-understood. We analyzed PGx allele and phenotype frequencies for 487,409 participants in the U.K. Biobank, the largest PGx study to date. For fourteen CPIC pharmacogenes known to influence human drug response, we find that 99.5% of individuals may have an atypical response to at least one drug; on average they may have an atypical response to 12 drugs. Non-European populations carry a greater frequency of variants that are predicted to be functionally deleterious; many of these are not captured by current PGx allele definitions. Strategies for detecting and interpreting rare variation will be critical for enabling broad application of pharmacogenetics.
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