Population genetic structure of variable drug response

  title={Population genetic structure of variable drug response},
  author={James F. Wilson and Michael E. Weale and Alice Smith and Fiona Gratrix and Benjamin Fletcher and Mark George Thomas and Neil Bradman and David B. Goldstein},
  journal={Nature Genetics},
Geographic patterns of genetic variation, including variation at drug metabolizing enzyme (DME) loci and drug targets, indicate that geographic structuring of inter-individual variation in drug response may occur frequently. This raises two questions: how to represent human population genetic structure in the evaluation of drug safety and efficacy, and how to relate this structure to drug response. We address these by (i) inferring the genetic structure present in a heterogeneous sample and (ii… 

Human loci involved in drug biotransformation: worldwide genetic variation, population structure, and pharmacogenetic implications

The global distribution of PGx variation is infers and its structure is defined, and it is shown that intergenic, synonymous and non-synonymous SNPs show similar levels of genetic variation across the globe, while loci coding for Cytochrome P450s show significantly higher levels of Genetic diversity between populations than the other gene categories.

Global patterns of genetic diversity and signals of natural selection for human ADME genes.

It is found that ADME genes show significantly greater variation in levels of population differentiation, and numerous signals of recent positive selection onADME genes are found, suggesting that genetic differentiation at ADme genes could contribute to population heterogeneity in drug responses.

Theoretical Basis for the Identification of Allelic Variants That Encode Drug Efficacy and Toxicity

This model is incorporated by mathematical functions of drug response to varying doses or concentrations and the statistical device used to model the correlated structure of the residual (co)variance matrix is used.

Drug pathways: moving beyond single gene pharmacogenetics.

  • H. McLeod
  • Biology, Medicine
  • 2004
There is enormous potential for pharmacogenetics to yield a powerful set of molecular diagnostics that will become routine tools by which clinicians select medications and drug doses for individual patients.

Human population genetic structure and inference of group membership.

These results set a minimum for the number of markers that must be tested to make strong inferences about detecting population structure among Old World populations under ideal experimental conditions and note that, whereas some proxies correspond crudely, if at all, to population structure, the heuristic value of others is much higher.

Multiple Advantageous Amino Acid Variants in the NAT2 Gene in Human Populations

The diminished dietary availability of folates resulting from the nutritional shift, as the possible cause of the fitness increase associated to haplotypes carrying mutations that reduce enzymatic activity, is suggested.

Genetic variation and pharmacogenomics: concepts, facts, and challenges

Future approaches to the identification, evaluation, and prioritization of drug targets, the optimization of clinical trials, and the development of efficient therapies must be based on in-depth knowledge of candidate gene variation as an essential prerequisite.

Large-scale SNP analysis reveals clustered and continuous patterns of human genetic variation

Analysis of 11,555 single nucleotide polymorphisms in 203 individuals from 12 diverse human populations provides a valuable resource for the definition of marker panels to detect and control for population stratification in population-based gene identification studies.

CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure

The CYP2D6 diversity is far greater within than between populations and groups thereof, null or low-activity variants occur at high frequencies in various areas of the world, and linkage disequilibrium is lowest in Africa and highest in the Americas.

Geographic structure of human genetic variation: medical and evolutionary implications

The geographic structure of human populations can be summarized by two numbers: 85 and 15, and two keywords: Continuous Genetic Change (CGC), and outliers, which characterizes most of the differences between groups at different geographic scales.



Molecular mechanisms of genetic polymorphisms of drug metabolism.

Analysis of allele frequencies in different populations revealed major differences, thereby tracing the molecular history and evolution of these polymorphisms.

Inference of population structure using multilocus genotype data.

A model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations that can be applied to most of the commonly used genetic markers, provided that they are not closely linked.

Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data.

A polymerase chain reaction (PCR)/restriction fragment length polymorphism-based genotyping strategy to detect 'key' mutations linked to extensive metabolizer or poor metabolizer associated alleles in combination with extra-long PCR (XL-PCR).

Molecular mechanism of slow acetylation of drugs and carcinogens in humans.

A simple DNA amplification assay is developed that allows the predictive genotyping of more than 95% of slow and rapid acetylator alleles and the identification of individuals at risk.

Identification of the primary gene defect at the cytochrome P450 CYP2D locus

The identification of the primary mutation responsible for this metabolic defect and the development of a simple DNA-based genetic assay are reported to allow both the identification of most individuals at risk of drug side-effects and clarification of the conflicting reports on the association of this polymorphism with cancer susceptibility.

Consistent long-range linkage disequilibrium generated by admixture in a Bantu-Semitic hybrid population.

This study provides the first conclusive demonstration that the diverse demographic histories of human populations have produced dramatic differences in genomewide patterns of LD, and suggests that demographic history has such a profound effect on LD that it will not be possible to predict patterns a priori but thatIt will be necessary to empirically evaluate the patterns in all populations of interest.

Genetic evidence for a higher female migration rate in humans

It is found that Y chromosome variants tend to be more localized geographically than those of mtDNA and the autosomes, and the reduction of variation within populations for Y chromosome single nucleotide polymorphisms (SNPs) is of such magnitude that differences in the effective population sizes of the sexes alone are insufficient to produce the observation.

A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin.

A new allele is identified in Caucasian PMs which contains an A-->G mutation in the initiation codon which indicates that CYP2C19*4 represents a new PM allele.