Pharmacogenomics
Pharmacogenetic Analysis of Structural Variation in the 1000 Genomes Project using Whole Genome Sequences
While significant strides have been made in understanding pharmacogenetics (PGx) and gene-drug interactions, there remains limited characterization of population-level PGx variation. This study aims to comprehensively profile global star alleles (haplotype patterns) and phenotype frequencies in 58 pharmacogenes associated with drug absorption, distribution, metabolism, and excretion. PyPGx, a star-allele calling tool, was employed to identify star alleles within high-coverage whole genome sequencing (WGS) data from the 1000 Genomes Project (N = 2504; 26 global populations). This process involved detecting structural variants (SVs), such as gene deletions, duplications, hybrids, as well as single nucleotide variants and insertion-deletion variants. The majority of our PyPGx calls for star alleles and phenotype frequencies aligned with the Pharmacogenomics Knowledge Base, although notable population-specific frequencies differed at least twofold. Validation efforts confirmed known SVs while uncovering several novel SVs currently undefined as star alleles. Additionally, we identified 210 small nucleotide variants associated with severe functional consequences that are not defined as star alleles. The study serves as a valuable resource, providing updated population-level star allele and phenotype frequencies while incorporating SVs. It also highlights the burgeoning potential of cost-effective WGS for PGx genotyping, offering invaluable insights to improve tailored drug therapies across diverse populations.
Insights into Pharmacogenetics, Drug-Gene Interactions, and Drug-Drug-Gene Interactions
This review explores genetic contributors to drug interactions, known as drug-gene and drug-drug-gene interactions (DGI and DDGI, respectively). This article is part of a mini-review issue led by the International Society for the Study of Xenobiotics (ISSX) New Investigators Group. Pharmacogenetics (PGx) is the study of the impact of genetic variation on pharmacokinetics (PK), pharmacodynamics (PD), and adverse drug reactions. Genetic variation in pharmacogenes, including drug metabolizing enzymes and drug transporters, is common and can increase the risk of adverse drug events or contribute to reduced efficacy. In this review, we summarize clinically actionable genetic variants, and touch on methodologies such as genotyping patient DNA to identify genetic variation in targeted genes, and deep mutational scanning as a high-throughput in vitro approach to study the impact of genetic variation on protein function and/or expression in vitro. We highlight the utility of physiologically based pharmacokinetic (PBPK) models to integrate genetic and chemical inhibitor and inducer data for more accurate human PK simulations. Additionally, we analyze the limitations of historical ethnic descriptors in pharmacogenomics research. Altogether, the work herein underscores the importance of identifying and understanding complex DGI and DDGIs with the intention to provide better treatment outcomes for patients. We also highlight current barriers to wide-scale implementation of PGx-guided dosing as standard or care in clinical settings.
Nicotine Metabolism and its Association with CYP2A6 Genotype Among Indigenous People in Alaska Who Smoke
Prevalence of smoking is higher in Alaska Native and American Indian (ANAI) populations living in Alaska than the general US population. Genetic factors contribute to smoking and cessation rates. The objective of this study was to compare CYP2A6 genetic variation and CYP2A6 enzyme activity toward nicotine in an ANAI population. ANAI (N = 151) people trying to quit smoking were recruited. DNA samples were genotyped for CYP2A6 variants *1X2A, *1B, *2, *4, *9, *10, *12, and *35. Multiple nicotine metabolites were measured in plasma and urine samples, including cotinine and 3′-hydroxycotinine used to determine CYP2A6 activity (e.g., nicotine metabolite ratio [NMR]). We calculated summary statistics for all of the genotypes and metabolites and assigned CYP2A6 activity scores based on known information. We studied the association of CYP2A6 variants with the NMR and smoking histories. The overall frequency of the CYP2A6*1B gain of function allele was high in the ANAI versus non-ANAI populations in other studies. Both *4 null and *9 decrease of function alleles had frequencies similar to previous studies of ANAI populations. In a multivariate analysis, the genotype-inferred CYP2A6 activity score was associated with both plasma and urine NMR (p value = 8.56E-08 and 4.08E-13, respectively). Plasma NMR was also associated with duration of smoking (p value < 0.01) but not urinary total nicotine equivalents uncorrected for creatinine (TNE9uc) or biological sex. Urine NMR was significantly associated (p value
Bioethics
Indigenous Data Sovereignty in Genomics and Human Genetics: Genomic Equity and Justice for Indigenous Peoples
As the field of genomics and human genetics continues to push our understanding of disease and biodiversity through an ever-increasing pool of genomic data, it is critical to consider the social, ethical, and legal implications of using such data. This is particularly true for genomic data pertaining to Indigenous Peoples, much of which has been collected and (re)used in research without the informed consent of Indigenous communities or without the return of benefits of research discoveries to these communities. Indigenous data sovereignty (IDSov) provides a framework through which Indigenous Peoples can assert their right to control data on or about their communities and lands. Here, we provide a review of IDSov and recommendations for how researchers can integrate it into their genomic research with Indigenous Peoples. Inclusion of IDSov in genomic research design supports meaningful partnerships between researchers and Indigenous communities, ensuring the maximization of benefits and minimization of harms for improved community health and prosperity.
Perspectives on Using Pharmacogenomics to Guide Tobacco Cessation: Survey Results From an American Indian Community
Pharmacogenomics research has predominantly focused on populations of European ancestry, limiting the application to diverse populations such as American Indian and Alaska Native (AIAN) communities. Our community-centric study aims to understand perspectives on utilizing pharmacogenomics to guide tobacco cessation in an AIAN community using a survey with qualitative and quantitative components. We assessed participant (n = 273) tobacco usage and cessation history, pharmacogenomics knowledge, and perceptions of utilizing pharmacogenomics in the context of tobacco cessation. We found that the majority of participants (92%) were aware of the risks associated with tobacco usage and believed it to be a problem within their community (76%). Our results showed that 29% of participants had some level of knowledge regarding pharmacogenomics and only 6% had previously participated in pharmacogenomics research, demonstrating the need for further education and awareness. Community involvement was a priority for participants, with 64% preferring Tribal inclusion in all research stages and 63% favoring partnerships with local health centers. We also found support for future research, with 68% viewing pharmacogenomics as a beneficial tool. Concerns were raised regarding the handling of genetic material and result dissemination, emphasizing the importance of ethical research practices, transparent communication, and community partnership. Our findings serve as a foundation for shaping future research efforts and developing a framework for implementing tobacco cessation interventions. Our community-centered approach addresses the specific needs of this AIAN community and offers insights applicable to research practices within other underserved and marginalized populations, particularly those with a historical distrust of research.
Implementing Community-Engaged Pharmacogenomics in Indigenous Communities
Innovative pharmacogenomic approaches (genetic variation related to medication response) are needed to reduce disease and disparities in Indigenous communities. We support community-based pharmacogenomics research, inclusive of Indigenous values and priorities, to improve the health and well-being of Indigenous peoples.
Evolutionary
Genetics
Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications
Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes—genes responsible for the processing of exogenous substances such as food, pollutants, and medications—as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore 11 key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these 11 CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.
Ethical Guidance in Human Paleogenomics: New and Ongoing Perspectives
Over the past two decades, the study of ancient genomes from Ancestral humans, or human paleogenomic research, has expanded rapidly in both scale and scope. Ethical discourse has subsequently emerged to address issues of social responsibility and scientific robusticity in conducting research. Here, we highlight and contextualize the primary sources of professional ethical guidance aimed at paleogenomic researchers. We describe the tension among existing guidelines, while addressing core issues such as consent, destructive research methods, and data access and management. Currently, there is a dissonance between guidelines that focus on scientific outcomes and those that hold scientists accountable to stakeholder communities,such as descendants. Thus, we provide additional tools to navigate the complexities of ancient DNA research while centering engagement with stakeholder communities in the scientific process.
Fostering Responsible Research on Ancient DNA
Anticipating and addressing the social implications of scientific work is a fundamental responsibility of all scientists. However, expectations for ethically sound practices can evolve over time as the implications of science come to be better understood. Contemporary researchers who work with ancient human remains, including those who conduct ancient DNA research, face precisely this challenge as it becomes clear that practices such as community engagement are needed to address the important social implications of this work. To foster and promote ethical engagement between researchers and communities, we offer five practical recommendations for ancient DNA researchers: (1) formally consult with communities; (2) address cultural and ethical considerations; (3) engage communities and support capacity building; (4) develop plans to report results and manage data; and (5) develop plans for long-term responsibility and stewardship. Ultimately, every member of a research team has an important role in fostering ethical research on ancient DNA.