PPM 03-0314-190024

In order to fully realize the promise of personalized medicine in Qatar, an understanding of population-specific genetic variation in drug metabolism (DM) genes is important, as it enables precise dosing for individuals that are fast or slow metabolizers of a prescribed drug, as well as identification of individuals at risk for adverse reactions. Pharmacogenetics (Pgx) is the study of human genetic variation that alters DM, and Pgx variants are known for over 500 drugs. The long-term goal of the proposed project is pharmacogenomics precision medicine (PgxPM) in Qatar, where physicians and patients will know a priori if the patient requires a custom dosage of a prescribed drug (or alternate drug) based on Pgx variants in the patient genome. The specific unmet need to be addressed in this project is Pgx screening in the intensive care unit (ICU), where an overdose, underdose, or adverse drug reaction can have dire consequences, and knowledge of a patient’s Pgx profile must be available prior to ICU admission, a strong argument for preventative Pgx screening of the complete Qatari population given the relatively long turnaround time of genomic analysis (>4 days). Pgx screening is currently not provided by Hamad Medical Corporation (HMC) ICU, despite the fact that 52% of drugs (n=91 among n=173) utilized by the HMC ICU have one or more known Pgx variants. The problem for implementation of PgxPM in Qatar is that the prevalence of Pgx variants in Qatar is unknown, and studies by the PIs and others suggest that Pgx variants are population-specific, such as a CYP2C19 variant observed in 20% of East Asians. The central hypothesis of the proposed research is that the Pgx variants common in Qatar are different from those common elsewhere, and may be undiscovered. This project aims to overcome key scientific and technological barriers to progress towards the long-term goal of PgxPM in Qatar using a strategic approach of (1) developing a database of Pgx variants in Qatar; (2) quantifying the impact of Pgx screening on ICU care in Qatar; (3) identifying novel variants in Qatar of interest for future Pgx research, and (4) designing a custom genotyping array for PgxPM in Qatar (QChip2Pgx). The proposal will achieve these objectives through computational analysis of Qatar Genome Project (QGP) data of n>12,000 genomes and by validation of QGP variants in the Weill Cornell Medicine in Qatar (WCMQ) cohort of n>3400 genomes. Furthermore, a cohort of n=300 Qatari HMC ICU patients will be recruited in order to quantify by whole genome sequencing (WGS) the prevalence of known Pgx variants in ICU-prescribed medications in this cohort. The PIs are uniquely qualified for completing this project, having published analysis of over n=1376 Qatari genomes and having led the design of QChip1, which focused on variants of interest for rare genetic disease screening and research. As part of the design process, the PIs identified potential Pgx variants in QGP and WCMQ data in n=77 DM genes, a preliminary analysis of these variants is presented below. The scientific and technical objectives of the project will be achieved through completion of the specific research aims. Aim 1. Prevalence in Qatar of known pharmacogenomics variants. The prevalence in Qatar of Pgx variants is unknown. In order to test the hypothesis that common Pgx variants exist in Qatar, the prevalence of known Pgx variants will be quantified in WGS data for QGP and WCMQ cohorts. Comparison of variant prevalence between Qataris and non-Qataris will be conducted to identify Pgx variants at unexpectedly high or low allele frequency in Qatar. Variants will be prioritized for inclusion in the QChip2Pgx design based on the allele frequency in Qataris, the allele frequency in non-Qataris, and presence in one or both cohorts. Aim 2. The impact of pharmacogenomics on ICU care in Qatar. Currently the HMC ICU does not screen for known Pgx variants in n=91 commonly prescribed drugs. In order to test the hypothesis that Pgx screening will have an impact on ICU care, WGS will be conducted on n=300 Qatari recruited at HMC ICU, and the prevalence of known Pgx variants relevant to ICU-prescribed drugs will be quantified. In order to determine if existing WGS cohorts are an adequate model for ICU patients, comparison of genomic data across three cohorts (ICU, QGP, WCMQ) will be conducted. Variants will be prioritized for inclusion in the QChip2Pgx design based on relevance to ICU. Aim 3. Computational discovery of novel pharmacogenomics variants in Qatar. Based on preliminary data, we hypothesize that Qataris have novel and undiscovered population-specific Pgx variants. In order to advance PgxPM research in Qatar, a computational analysis algorithm developed by the PIs will be used to identify potential Pgx variants in known DM genes computationally-predicted high likelihood to affect DM present in ICU, QGP and WMCQ cohorts. Variants will be prioritized for inclusion in the QChip2Pgx design based on frequency in the cohorts and computationally-predicted likelihood to affect DM. The expected outcomes of the proposed research will be both scientific discoveries and technological innovations. The expected scientific discovery outcomes will be (1) identification of Pgx variants common in Qatar; (2) demonstration of the potential impact of Pgx screening on ICU care; and (3) discovery of novel Pgx variants in Qatar of interest for research. The technological innovation outcomes will be (1) a database of the prevalence of known and novel Pgx variants in Qatar; and (2) a design for the QChip2Pgx array based on prioritization of the known and novel Pgx variants in Qatar. The potential impact of reaching the proposed objectives of this study is advancement of the state-of-the-art of PM in Qatar and regional leadership in Pgx.