Assessing Pharmacogenetic Variation in the United States to Enhance Health Equity of Pharmacogenetic Testing

CDC’s Genetic Testing Reference Material program (GeT-RM), in the Division of Laboratory Systems will conduct a 2-year project to test 5000 DNA samples from the population-based National Health and Nutrition Examination Survey (NHANES) to determine the allele frequencies of 970 unique haplotypes in 150 pharmacogenes selected because they have high clinical annotation levels of evidence for variant-drug combinations in the Pharmacogenomics Knowledge Base (PharmGKB).  This work will be accomplished thanks to a funding opportunity from CDC’s Office of Genomics and Precision Public Health in collaboration with CDC’s Office of Advanced Molecular Detection.

Pharmacogenetic testing can help physicians choose the correct drug and dose for each patient

Pharmacogenetic (PGx) tests are used to help predict an individual’s reaction to drugs by interrogating the presence or absence of known genetic variants in genes that encode drug-metabolizing enzymes, drug transporters, drug receptors, or targets of drug action.  Approximately 18% of outpatient prescriptions issued in the United States are for medications that have actionable PGx information available. Physicians use the results of these tests to determine appropriate drugs and doses for their patients to prevent toxic effects or ineffective treatments. PGx data is also important for drug discovery, clinical trials, and development of clinical PGx tests.

Lack of information about PGx allele frequencies in non-European populations

Most population-based genetic studies, including those examining pharmacogenetic loci, have been conducted primarily on individuals of European ancestry.  In addition, databases that aggregate allele frequencies, such as gnomAD are also biased toward European populations and contain very little information from individuals of African or other ancestries. The lack of diverse ethnic representation in these data has created a gap in knowledge about the alleles present in non-White populations and their relative frequencies.  This could cause health inequities because the results of PGx tests that were designed based on allele frequencies of Europeans are being applied to patients of other ethnicities, causing physicians to prescribe drugs and doses that are  ineffective or may cause adverse reactions in non-White patients. In addition, lack of ethnic diversity in PGx data sets can widen health disparities by negatively affecting the outcomes of clinical drug trials and translating genetic research into clinical practice.

Determining PGx allele frequencies in a diverse US population

To obtain a more complete picture of the PGx alleles present in a diverse US population, approximately 5,000 DNA samples from the population-based NHANES will be tested to determine the PGx allele frequencies of 970 unique haplotypes in 150 pharmacogenes. The NHANES sample sets represent the US population and are over-sampled for persons who are aged 60 and older, African American, Asian, and Hispanic to produce reliable statistics. The PGx alleles will be correlated with sample ethnicity to determine the allele frequency of each pharmacogene in the various population groups. Allele frequencies will also be correlated with prescription drug use among the different ethnic groups to study whether drugs prescribed for each are appropriate given the PGx allele frequency determined for the population and how the drugs prescribed could be modified if more comprehensive PGx testing were available. The risks associated with inaccurate drug selections and the potential reduction of this risk based on more accurate ethnicity specific PGx genotype assessment will also be evaluated.

Creation of the comprehensive PGx data set proposed in this project will, for the first time, help to establish the allele frequencies in 150 pharmacogenes across ethnicities in the US population.  This will facilitate development and validation of PGx tests capable of detecting important PGx alleles in African American, Asian, Hispanic, and White populations. The availability of PGx tests that more accurately detect important PGx alleles will greatly improve health equity and patient care and facilitate a more equitable implementation of genomic findings.

The results of this study could be used to promote the uptake of clinical PGx testing to enhance precision medicine, especially in underrepresented populations. The FDA and pharmaceutical developers could use this information when designing clinical drug trials to ensure that the genotypes of the participants are determined properly and utilized when determining drug efficacy and to inform PGx information required on drug labels. This information may also be used to inform guideline development efforts such as the Association for Molecular Pathology’s PGx Standardization project and the Clinical Pharmacogenetics Implementation Consortium (CPIC).