Impact of population-specific pharmacogenomic variants on drug dosing in ICU patients

Intensive care units (ICU) patients are highly vulnerable to inaccurate drug dosing. Pharmacogenomics (PGx) studies the role of inherited genetic variation in drug metabolism and dose efficacy. To assess the prevalence of PGx variants that may influence therapeutic effect in the ICU, we carried out whole genome sequencing (WGS) of 210 Qataris in ICU care at Hamad Medical Corporation (HMC), Doha, Qatar and assessed the WGS for predicted deleterious variants of genes that metabolize 30 drugs commonly prescribed in the ICU. PGx variation was evaluated using two complementary approaches. First, variants with established functional interpretation were assessed using CPIC guidelines and star-allele haplotypes inferred by PharmCAT to estimate the prevalence of alleles associated with abnormal drug metabolism. Second, a broader exploratory analysis examined computationally predicted deleterious single-nucleotide variants in pharmacogenes that currently lack CPIC guidelines or defined star alleles, with these findings interpreted as descriptive of genomic variation rather than clinical metabolizer phenotypes.Of the ICU patients that received the 5 most commonly prescribed drugs (warfarin, phenytoin, midazolam, vancomycin, levetiracetam), 93% had deleterious metabolism-related variants. Ninety-one % of ICU patients carried at least one variant in a gene with known PGx relevance that could potentially impact the metabolism or activity of at least one medication they received. Most patients had ≥14 deleterious variants of genes that affect the metabolism of administered drugs. Comparison of the deleterious variants related to metabolism of ICU drugs with African/African American and European populations revealed significant population specificity in ICU related PGx variants. Together, these data suggest that population specific, PGx based on the individual's genome likely plays a significant role in effective, safe dosing in the ICU setting.