Towards precision medicine: interrogating the human genome to identify drug pathways associated with potentially functional, population-differentiated polymorphisms

Pharmacogenomics J. 2019 Dec;19(6):516-527. doi: 10.1038/s41397-019-0096-y. Epub 2019 Oct 3.

Abstract

Drug response variations amongst different individuals/populations are influenced by several factors including allele frequency differences of single nucleotide polymorphisms (SNPs) that functionally affect drug-response genes. Here, we aim to identify drugs that potentially exhibit population differences in response using SNP data mining and analytics. Ninety-one pairwise-comparisons of >22,000,000 SNPs from the 1000 Genomes Project, across 14 different populations, were performed to identify 'population-differentiated' SNPs (pdSNPs). Potentially-functional pdSNPs (pf-pdSNPs) were then selected, mapped into genes, and integrated with drug-gene databases to identify 'population-differentiated' drugs enriched with genes carrying pf-pdSNPs. 1191 clinically-approved drugs were found to be significantly enriched (Z > 2.58) with genes carrying SNPs that were differentiated in one or more population-pair comparisons. Thirteen drugs were found to be enriched with such differentiated genes across all 91 population-pairs. Notably, 82% of drugs, which were previously reported in the literature to exhibit population differences in response were also found by this method to contain a significant enrichment of population specific differentiated SNPs. Furthermore, drugs with genetic testing labels, or those suspected to cause adverse reactions, contained a significantly larger number (P < 0.01) of population-pairs with enriched pf-pdSNPs compared with those without these labels. This pioneering effort at harnessing big-data pharmacogenomics to identify 'population differentiated' drugs could help to facilitate data-driven decision-making for a more personalized medicine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Frequency / genetics
  • Genetics, Population / methods
  • Genome, Human / genetics*
  • Humans
  • Pharmaceutical Preparations / metabolism*
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide / genetics*
  • Precision Medicine / methods
  • Signal Transduction / genetics*

Substances

  • Pharmaceutical Preparations