Metformin is first-line therapy for type 2 diabetes mellitus (T2DM), yet interindividual variability in glycaemic response and frequent gastrointestinal (GI) intolerance are not fully explained by pharmacogenomics alone. This review synthesised evidence that links baseline gut microbiome composition to metformin effectiveness and tolerability. English-language, open-access Human observational studies from the past decade were identified in PubMed, ScienceDirect, and Google Scholar if they reported stool- or rectal sample–derived microbiome profiles alongside glycaemic outcomes (e.g., HbA1c change) or GI adverse events, dose modification, or discontinuation, with standardised extraction of design, population, -omics methods, and outcome definitions. Few eligible studies met criteria; across prospective and cross-sectional cohorts, higher alpha diversity and specific taxa—including Akkermansia and Streptococcus—were associated with increased GI adverse events to metformin, while distinct microbial signatures differentiated glycaemic responders from non-responders. A small multi-omic analysis suggested that shifts in bile acid–related bacteria together with down-regulation of anti-inflammatory host genes may underlie intolerance. Integrative models combining pharmacogenomic variants with microbiome features were rarely evaluated, and head-to-head comparisons with pharmacogenomics-only models are lacking. Overall, baseline gut microbiome signatures correlate with variability in metformin responses and GI intolerance in T2DM, underscoring the need for larger, standardised multi-omic cohorts to quantify the incremental predictive value of microbiome data for personalised metformin theraphy.

Opioid-Related Pharmacogenomic Variants in a Retrospective Cohort of High-Risk Hospitalized Infants.

Development of a comprehensive cardiovascular disease genetic risk assessment test

Pharmacogenomic (PGx) variants associated with opioid metabolism and reward pathways may influence pain response and risk of opioid dependence. Infants undergoing surgery routinely receive opioids, and prolonged exposure impacts health outcomes. This study evaluated relationships between PGx variants and opioid utilization in infants undergoing surgery for congenital heart disease (CHD). This retrospective cohort study included infants <1 year who underwent CHD surgery and had exome sequencing at a quaternary children's hospital from 2009 to 2020. PGx variants associated with opioid-response (COMT, DRD2/ANKK1, ABCB1, OPRM1, and CYP2D6) were evaluated. Median cumulative morphine milliequivalents (MMEs) administered were calculated over each hospitalization, and median MMEs corresponding with each variant were analyzed using Kruskal-Wallis tests. Overall, 48 infants were identified (54.2% male, 47.9% Hispanic/Latino, and 6.3% preterm). Most (n = 34, 70.8%) underwent open surgery, and 14 (29.2%) underwent minimally invasive procedures. Forty infants (83%) were homozygous for at least one opioid-related PGx variant. Infants who underwent open surgery and were homozygous for OPRM1: rs1799971, COMT: rs4633, rs4680, and ABCB1: rs1045642 demonstrated increased cumulative MMEs compared to wild type. Infants who underwent minimally invasive surgery and were homozygous for ABCB1: rs1045642 also had increased cumulative MMEs. No relationship between CYP2D6 metabolizer phenotypes and MMEs was observed. Most infants undergoing CHD surgery who had exome sequencing were homozygous for an opioid-related PGx variant. Additionally, infants who were homozygous received increased MMEs during hospitalization. Routine reporting of PGx variants could inform future innovation in precision medicine and opioid stewardship efforts.

IntroductionTumor necrosis factor alpha (TNF-α) is an important cytokine that frequently contributes to the pathogenicity of autoimmune diseases. Therefore, TNF inhibitors (TNFi) are used to treat autoimmune diseases. However, around 40% of the patients do not respond to TNFi, with genetic variants being a contributor to this variance. The prevalence of genetic variants affecting TNFi response in Middle Eastern populations is still not understood.MethodsWe assessed the distribution of variants in 111 genes associated with TNFi in 14,387 Qatari individuals using whole genome sequencing data.ResultsOf the 151 known pharmacogenomic variants associated with response to TNFi, approximately half have significantly different allele frequency distribution in the Qatari population compared to other world populations from the gnomAD dataset. High frequency of rs1800629 (TNF), rs1800896 (IL10), and rs1143634 (IL1B) variants are observed, which are known to be associated with responses to Etanercept and Infliximab. Moreover, we identified that PSORS1C1 has the highest CAPLoF (cumulative allele probability) scores for loss-of-function variants, which is associated with response to Etanercept and Adalimumab.DiscussionThe findings of this study will enhance our understanding of the pharmacogenomics of TNF inhibitors in Qatar and beyond, while also supporting the study of genetics in underrepresented populations.

BackgroundGenetics influence medication response yet integrating family health history (FHH) of medication response with pharmacogenomics remains underexplored. The objective of this study was to examine cross-generational medication exposure patterns and assess the utility of FHH for medication response using electronic health records.MethodsGenes & Health (G&H) data from Bangladeshi and Pakistani participants were analysed for parent-offspring trios with medication exposure. Premature discontinuation of amitriptyline was defined as discontinuation within three months. Logistic regression and Fisher’s exact test explored the relationship between parental discontinuation, offspring discontinuation, and CYP2C19 loss-of-function variants.Results13% of offspring prescriptions overlap with parental prescriptions, primarily short-term treatments (antibiotics, vaccines, steroids). In 96 trios, cross-generational amitriptyline exposure is observed. Parental discontinuation does not predict offspring discontinuation (p = 0.275, OR 1.70). However, offspring with two-generation histories of early discontinuation are significantly enriched for CYP2C19 predicted poor metabolizers (38% vs. 10.5%, p = 0.049, OR 4.86).ConclusionsFHH of medication response can highlight individuals enriched for pharmacogenomic variants. This is a clinically useful finding, which may flag psychiatric patients with a two-generation history of early amitriptyline discontinuation or intolerance as a priority for pharmacogenomic testing. This study demonstrates the potential of integrating FHH into clinical pharmacogenomics for actionable insights.

Patient and provider perspectives on the implementation of DPYD testing in oncology care clinics in an academic health system.

BackgroundGenetic polymorphisms in the genes encoding enzymes and proteins in drug metabolism, transport, and response can significantly impact enzymatic activity and overall pharmacokinetics and pharmacodynamics, leading to inter-individual and inter-population differences in drug efficacy and safety. The prevalence of pharmacogenomic variants often differs among populations due to unique evolutionary and demographic factors. By studying the genetic variation within 100 pharmacogenes in the Kinh Vietnamese population, a relatively underexplored group in pharmacogenomic research, we aim to provide insights into the population-specific pharmacogenomic landscape.Materials and Methods100 healthy people were recruited for peripheral blood donation after getting consents. Genomic DNA from participants was sequenced at coding regions of 100 pharmacogenes. Sequence reads were qualified, and variants were called using Genome analysis toolkit (GATK) followed with variant processing. Very important variants were characterized. Genetic distance using pairwise fixation index and allele frequencies comparison between the Kinh population and 25 populations of the 1000 Genome Project were analyzed.Results689 variants were called with 652 SNPs and 37 indels including 371 missense-, 266 synonymous-, 30 frameshift-, 14 stop-gain-, 2 stop-lost-, 3 in-frame insertion-, 2 in-frame deletion- and 1 protein variant. There are 59 novel variants (8.6%) present in 39/100 genes in which 13 variants are labeled with damaging phenotype. 28 VIP variants were obtained from these regions. Allele frequencies of variants are mostly similar with East Asians, but different from Africans. Remarkably, variants rs1801280 and rs1208 (NAT2), rs2231142 (ABCG2), rs2306283 (SCLO1B1) and rs4148323 (UGT1A1) distribute significantly between Kinh people and all other populations.ConclusionThe prevalence of pharmacogenomic variants of 100 pharmacogenes was obtained for Kinh Vietnamese people, in which 28 variants were characterized as very important variants. Kinh Vietnamese shows close genetic distance with East Asians but far from Africans. The variants with distinguished distribution in Kinh people were also highlighted.

Background: Pharmacogenomics offers critical insights into interindividual variability in drug response, especially in complex diseases such as diabetes mellitus. However, most pharmacogenomic evidence is derived from populations of European ancestry, limiting its applicability in admixed and underrepresented populations. In Colombia, the lack of population-specific data hampers the implementation of precision medicine strategies in diabetes care. The aim of this study was to identify pharmacogenomic variants significantly associated with diabetes and exhibiting differential allele frequencies between Colombian populations of African and European ancestry. Methods: We extracted 115 variant annotations related to diabetes from PharmGKB and filtered them for statistical significance and availability of allele frequency data. Fourteen single-nucleotide polymorphisms (SNPs) were compared across five Colombian populations using the CÓDIGO genomic diversity database. Principal component analysis (PCA) was performed to assess genetic clustering, and Pearson correlation coefficients were used to assess pharmacogenomic similarity. Results: PCA revealed distinct genetic clustering patterns that aligned with geographical distribution and ancestral origins. Pharmacogenomic divergence was observed between African and European ancestry groups in Colombia, with certain SNPs (e.g., rs8192675-C for metformin, rs7754840-C for DPP-4 inhibitors) showing 2- to 3-fold higher frequency in African ancestry populations. The bibliometric analysis revealed that 76.1% of studies originated from high-income countries and 68.4% of participants were of European ancestry. No studies originated from Africa or low-income countries. Conclusions: Marked ancestry-based differences in pharmacogenomic variant frequencies in Colombian populations may impact drug efficacy and risk of diabetes. The global literature shows a strong geographic and economic bias, underscoring the need for inclusive, population-specific pharmacogenomic research. These findings offer a foundation for implementing precision diabetes therapies in Latin America and advancing equitable genomic medicine.

Corticosteroids are effective anti‐cancer agents for treating hematologic malignancies in children. However, avascular necrosis (AVN) is a common and debilitating adverse effect, leading to bone death and impacting long‐term quality of life. This study aimed to uncover the genetic factors contributing to corticosteroid‐induced AVN in a well‐characterized cohort of pediatric cancer patients. We conducted a genome‐wide association study (GWAS) on 972 patients, including 108 with AVN grade ≥2 and 864 dose‐matched controls. The GWAS of 6.4 million genetic markers identified four significant AVN‐associated loci (P < 5 × 10−8): WNT7B (OR = 9.2; 95% CI, 3.8‐22.0), POGK (OR = 8.4; 95% CI, 3.6‐19.5), ZNF37A (OR = 6.0; 95% CI, 2.9‐12.5), and a synonymous variant in FAM240C (OR = 5.0; 95% CI, 2.6‐9.5). A multi‐marker predictive model combining single nucleotide polymorphisms (SNPs) and clinical factors showed an area under the ROC curve (AUC) of 78.7%, outperforming SNP‐only (67.8%) and clinical‐only (68.4%) models. The osteogenic processes regulated by WNT7B, part of the Wnt signaling pathway, may contribute to AVN‐related disrupted bone development and repair. Similarly, POGK and ZNF37A, both containing the KRAB domain, are hypothesized to affect osteoblast differentiation and skeletal development in AVN. Developing a predictive model for individual susceptibility to corticosteroid‐induced AVN will enhance the monitoring and management of corticosteroid use in children with cancer.

Background/Objectives: Tramadol is an opioid frequently prescribed for moderate to severe pain and has seen a global increase in use. This presents numerous challenges in clinical management. This study aims to elucidate metabolic signatures associated with tramadol consumption, enhancing predictive capabilities for therapeutic outcomes and optimizing patient-specific treatment plans. Methods: Data were obtained from the Qatar Biobank (QBB), focusing on pharmacogenomic variants associated with tramadol use and prescription trends. A cohort of 27 individuals who were administered daily tramadol doses between 100 and 400 mg with available metabolomic profiles were selected. The pharmacokinetics of tramadol were evaluated in relation to specific CYP2D6 genetic variants. Comparative pharmacometabolomic profiles were generated for tramadol users versus a control group of 54 non-users. Additionally, prescription data encompassing tramadol formulations were collected from the electronic medical records (EMR) system of the major public hospital network in Qatar (Hamad Medical Corporation) to discern prescribing patterns. Results: From January 2019 to December 2022, tramadol prescriptions varied, with chronic pain as the primary indication, followed by acute pain. Pharmacogenomic analysis indicated that CYP2D6 allele variations significantly impacted tramadol and O-desmethyltramadol glucuronide levels, notably in ‘normal metabolizers’. Metabolomic analysis revealed distinct metabolic profiles in tramadol users, with significant variations in phosphatidylcholine, histidine, and lysine pathways compared to controls, highlighting tramadol’s unique biochemical impacts. Conclusions: This study underscores the importance of integrating genetic and omics-based approaches to enhance tramadol’s efficacy and safety. These findings support personalized pain management strategies, enhancing treatment outcomes for both chronic and acute pain.

Abstract Background: Trastuzumab-deruxtecan (T-DXd) has shown an unprecedented clinical benefit in advanced breast cancer. Despite its meaningful anticancer outcomes, around 15-20% of patients have to discontinue T-DXd due to related toxicity (mainly pneumonitis/interstitial lung disease). To date, there is no evidence of the potential impact of pharmacogenomic variants and the risk of treatment-related adverse events (TRAE) in breast cancer patients treated with T-DXd. Methods: The PROCURE project is a translational research study comprising 26 Spanish institutions that aims to analyze pharmacogenomic variants and risk of toxicity in patients with breast cancer treated with T-DXd. Eligible patients had to receive at least one dose of T-DXd for its current approved indications in advanced HER2+/HER2-low breast cancer, with a minimum follow-up of 3 weeks to collect data on early-onset toxicity. Patients who had discontinued the treatment were also eligible. Patients’ demographics and clinical variables were gathered from medical records in an electronic database. Emerging adverse events were registered following CTCAE V.5 guidelines. One blood sample was collected for DNA extraction. Pharmacogenomic analyses included the determination of UGT1A1*28 allele and a massive SNP genotyping array with over 1.9 million genetic markers and enriched in pharmacogenomics variants (Infinium Global Diversity Array with Enhanced PGx, Illumina). Results: A total of 329 female patients were enrolled in the study from July 2022 to March 2024 with available genetic information. At data cut-off (1 July 2024), clinical data was available for 315 (95.7%). The median age was 56 years and the median duration of T-DXd treatment was 12.0 months (95%CI 10.4–14.2). Regarding UGT1A1 genotypes, 36 patients (11.4%) were *28/*28 homozygous (poor metabolizers), 143 (45.3%) were *1/*28 heterozygous (intermediate metabolizers), 1 (0.3%) was *1/*37 and 135 (42.7%) were *1/*1 (wild type). According to UGT1A1 genotypes (in this order: *1/*1, *1/*28, *28/*28) we observed the following TRAE of any grade: neutropenia (14.0%, 15.3%, 8.3%), anemia (13.2%, 7.6%, 11.1%), thrombocytopenia (4.4%, 4.2%, 11.1%), diarrhea (19.9%, 16.7%, 16.7%), vomiting (16.2%, 14.6%, 13.9%), pneumonitis/ILD (10.3%, 8.3%, 8.3%), dose reductions (28.9%, 27.8%, 34.8%), and treatment discontinuation (28.9%, 26.7%, 17.4%). We observed a higher incidence of grade 3 gastrointestinal toxicity in poor metabolizers (*28/*28) compared to the other two genotypes: diarrhea (0.7%, 0.7%, 2.8%), and vomiting (0.7%, 0.0%, 5.6%). The incidence of drug-induced pneumonitis/ILD in our study was 9.2% (29/315). We did not find an association between the UGT1A1 variants and the incidence of pneumonitis. In the SNP array, 314 of 315 samples and &amp;gt;95% of SNVs passed quality control. A logistic regression analysis of pneumonitis/ILD revealed more than 25 markers with unadjusted p-value &amp;lt;5x10-5 (additive model). Detailed pharmacogenomic TRAE analyses will be presented during the conference. Conclusions: Descriptive analyses from the PROCURE project show a similar incidence of all grade TRAE irrespective of UGT1A1 allelic variants. We observed a higher incidence of grade 3 gastrointestinal toxicity in UGT1A1 *28/*28 carriers. Potential pharmacogenomic markers of ILD were identified by a massive SNP genotyping array in unadjusted analysis that warrants further research. Citation Format: Rodrigo Sánchez-Bayona, Javier de Nicolás-Hernández, Cristina Saura, Maria Gion, Juan Miguel Cejalvo, Elisenda Llabrés, Javier Cortés, Alejandro Falcón, Sonia Pernas, Alfonso Lopez de Sa, Maria Vidal, Carmen Hinojo, Teresa Curiel, Josefina Cruz, Virginia Martínez, Blanca Cantos, Maria Jose Echarri, Isabel Gallegos, Coralia Bueno, Ana Milena Vargas, Santiago Escrivá-de-Romaní, Bartomeu Fullana, Maria Angeles Cobos, Alicia Arenas, Laia Joval-Ramentol, Tomás Pascual, Carlos Valdivia, Guillermo Villacampa, Eva Ciruelos, Cristina Rodriguez-Antona. Pharmacogenomic variants and risk of adverse events in breast cancer patients treated with Trastuzumab-deruxtecan: results from the PROCURE project [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-01-16.

Pharmacogenomic variants in the Pumi population from Yunnan, China.

Pharmacogenomic (PGx) variants can significantly impact drug response, but limited data exists on their prevalence in Middle Eastern populations. This study aimed to investigate the inheritance of certain markers in candidate pharmacogenes among healthy Saudis. DNA samples from 95 unrelated healthy Saudi participants were genotyped using the Affymetrix Axiom Precision Medicine Diversity Array. Thirty-eight variants in 15 pharmacogenes were analyzed based on their clinical relevance and lack of previous reporting in Saudi populations. Twenty-six of the 37 tested markers were undetected in the cohort. The selected variants in six genes [DPYD (rs1801268), CACNA1S (rs772226819), EGFR (rs121434568), RYR1 (rs193922816), CYP2B6 (rs3826711), and MT-RNR1 (rs267606617, rs267606618, rs267606619)] were found to be non-existing among Saudis. In contrast, 11 variants and alleles in nine pharmacogenes were detected at varying frequencies. Notable findings included high frequencies of variants in ATIC [rs4673993, minor allele frequency (MAF) = 0.71)] and SLC19A1 (rs1051266, MAF = 0.48) affecting methotrexate efficacy. Three alleles were identified in CYP3A4, including a common (CYP3A4 rs2242480) and two rare alleles (*3 and *22). Another three markers [rs16969968 in CHRNA5, rs11881222 in IFNL3 (IL28B), and SLCO1B1*14] were found to be highly distributed among the participants (MAF = 0.35, 0.30, and 0.14, respectively). Conversely, three rare markers: CYP2A6*2, NAT2*14, and rs115545701 in CFTR, were identified at low-frequency levels (MAF = 0.021, 0.011, 0.005, respectively). Statistically significant differences in allele frequencies were observed for eight variants between Saudi and African populations, five variants compared to East Asians, and two variants compared to Europeans. This study provides novel insights into the distribution of clinically relevant PGx variants in the Saudi population. The findings have implications for personalizing treatments for various conditions, including rheumatoid arthritis, cystic fibrosis, and hepatitis C. These data contribute to the development of population-specific PGx testing panels and treatment guidelines.

BackgroundStatins are essential for managing cardiovascular disease (CVD), but adverse effects often lead to treatment discontinuation and non-adherence, underscoring the need for personalized approaches. This study aimed to evaluate the influence of pharmacogenomic (PGx) variants and demographic factors on statin-associated adverse effects in a multiethnic cohort from the United Arab Emirates (UAE).MethodsThis sub-analysis of the EmHeart Study included 675 patients using rosuvastatin or atorvastatin. Patients were genotyped for SLCO1B1 and ABCG2 actionable variants using real-time PCR. Data on demographics, comorbidities, and statin use were extracted from electronic health records. Adverse events, including statin-associated muscle symptoms (SAMS) and liver enzyme elevation, were tracked over 12 months. Associations were analyzed using chi-square tests and logistic regression.ResultsRosuvastatin users carrying the ABCG2 rs2231142 variant had a threefold increased risk of liver enzyme elevation, particularly among East Asian patients (P < 0.005). Atorvastatin users with the SLCO1B1 rs4149056 variant exhibited a twofold increased risk of SAMS, with higher rates observed in females and Arabs (P < 0.05). The combination of rosuvastatin with ezetimibe further exacerbated risks of SAMS and liver enzyme elevation.ConclusionThis study highlights the importance of genetic testing and demographic factors, such as ethnicity and gender, in tailoring statin therapy to minimize adverse effects. Despite extensive research on PGx-guided statin prescribing, clinical implementation remains limited. Integrating PGx testing into routine practice and enhancing physician awareness of genetic and demographic risk factors can improve the safety, efficacy, and adherence of lipid-lowering therapies in diverse populations.

To identify novel genetic loci associated with differences in serum etonogestrel concentrations among contraceptive implant users. We conducted a cross-sectional analysis in which we enrolled healthy, reproductive-aged (age 18-45 years) participants who had been using etonogestrel implants for 12-48 months. Participants underwent a single-time blood draw for measurement of serum etonogestrel concentrations by liquid chromatography-tandem mass spectrometry and the extraction of DNA from whole blood. We genotyped participants using the Illumina Infinium Global Diversity Array with Enhanced PGx and imputed genotyping results using the TOPMed imputation server. We performed genome-wide complex trait analysis using a linear mixed model leave-one-chromosome-out association analysis to identify genetic variants associated with serum etonogestrel concentrations. We enrolled 900 etonogestrel implant users, with a median age of 22.3 years (range 18.0-41.5 years), median body mass index (BMI) 26.0 (range 18.5-52.0), and median duration of implant use 27 months (range 12-48 months). Most participants self-reported their race as White (49.3%) and ethnicity as Hispanic or Latina (52.9%). Participants had a median serum etonogestrel concentration of 126.9 pg/mL (range 39.4-695.1 pg/mL). Including BMI, duration of implant use, and three principal components as covariates in the genome-wide complex trait analysis, we identified no genetic variants with minor allele frequencies at or above 5% that were associated with serum etonogestrel concentrations at genome-wide significance (P<5.0×10-8). When including rare genetic variants (minor allele frequencies at or above 1%), we discovered 10 genetic loci of interest (RNF114; LINC02405; SYNE1; TSPAN14; CRYZL2P-SEC16B; CHRNA9; RIMS1; CCDC88C; and CBL), all containing genetic variants associated with increased serum etonogestrel concentrations. Among these novel genetic loci associated with serum etonogestrel concentrations, only one (CRYZL2P-SEC16B) has potential, albeit limited, physiologic plausibility. Despite enhanced coverage for known pharmacogenomic variants, we found no significant associations between interindividual variability in contraceptive implant pharmacokinetics and genetic loci directly involved in exogenous steroid hormone metabolism. ClinicalTrials.gov, NCT03092037.

Pharmacogenomics holds significant promise in improving the efficacy and safety of chemotherapy for childhood cancers. However, the field remains underexplored in Africa, where high genetic diversity and substantial disease burdens, including cancers, create unique challenges. This review investigates the current state of pharmacogenomics research in childhood cancer chemotherapies across Africa, focusing on genetic variations influencing chemotherapy efficacy and adverse drug reactions. It also highlights critical gaps, such as limited infrastructure and insufficient healthcare worker knowledge, and emphasizes the importance of capacity-building initiatives in the region. A scoping review was conducted encompassing studies published up to September 2024 that examined pharmacogenomic variations associated with chemotherapies in childhood cancer patients across Africa. The review included laboratory genetic analyses and surveys assessing healthcare workers' knowledge, attitudes, and perceptions regarding pharmacogenomics, particularly in the context of pediatric oncology. A total of 12 genes were identified across eight studies, including TPMT, CYP3A5, MDR1, MAPT, NUDT15, ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3, ABCC4, and MTHFR. The most studied genes were TPMT and CYP3A5, which are involved in the metabolism of 6-mercaptopurine (6-MP) and vincristine, respectively. These studies spanned five African countries, including Kenya, Egypt, Zimbabwe, Nigeria, Tunisia, and Libya, and focused primarily on childhood cancers, particularly acute lymphoblastic leukemia. Chemotherapies frequently studied were 6-MP (reported in five studies), vincristine, cyclophosphamide, and methotrexate. Knowledge of pharmacogenomics among healthcare workers in Africa remains low, though a positive attitude towards its clinical applications was observed. Pharmacogenomic variants, such as TPMT*3A, 3C, and CYP3A53, *6, significantly impact drug metabolism in African children with cancer. However, research remains regionally limited, and gaps in infrastructure and healthcare worker training persist. Expanding research efforts and improving pharmacogenomics capacity through pharmacist training and capacity-building initiatives are essential to advancing personalized medicine in Africa, ultimately improving treatment outcomes for pediatric cancer patients.

BackgroundAnti-infective medicines are crucial for treating infections, but improper dosing can cause toxicity, resistance and treatment failure. Pharmacogenomics can address genetic variations affecting drug efficacy and safety. Despite the high burden of diseases like TB and HIV in Sri Lanka and South Asia, pharmacogenomic data for these populations are limited. This study aims to fill this gap by investigating pharmacogenomic variants in a South Asian population from Sri Lankan.MethodsPharmacogenomic data on anti-infective medicines were obtained from the PharmGKB database, selecting variants with evidence levels 1 A, 1B, 2 A, and 2B. Sri Lankan genetic data were sourced from an anonymized database of 670 Sri Lankans maintained by the Centre for Genetics and Genomics, Faculty of Medicine, University of Colombo. MAFs were compared between Sri Lankan sub-populations and global data from gnomAD, with statistical significance set at p < 0.05.ResultsMAFs of NAT2 gene rs1041983 and rs1799931 variants were, 43.7% (95%CI:41.1–46.4), 7.3% (95%CI:6.0-8.8), respectively. The UGT1A1 rs4148323 variant had a MAF of 3.5% (95%CI:2.6–4.6). In the CYP2B6 gene, 109 individuals were homozygous for the rs3745274 (poor metaboliser) variant, with a MAF of 39.6% (95%CI:37.0-42.3), while the rs34097093 and rs28399499 variants had no individuals homozygous for the variant (MAF: 0.2% [95%CI:0-0.5] (poor/intermediate metaboliser), and 0.1% [95%CI:0-0.4] (poor/intermediate metaboliser), respectively). The MAFs of the CYP2C19 rs12769205 (poor/intermediate metaboliser), rs4244285 (poor/intermediate metaboliser), rs3758581 (poor/intermediate metaboliser), and rs4986893 (poor/intermediate metaboliser) variants were 41.9% (95%CI:39.3–44.6), 41.9% (95%CI:39.2–44.7), 9.7% (95%CI:8.2–11.4), and 0.5% [(95%CI:0.2–1.1), respectively. Most variants showed significant differences compared to global populations, with some exhibiting higher frequencies, particularly when compared to Europeans. CYP2C19 rs12769205 and rs4244285 exhibited higher MAFs in Sri Lankans compared to both other South Asians and Europeans. The NAT2 rs1041983, NAT2 rs1799931, CYP2C19 rs4986893, CYP2C19 rs3758581, and CYP2B6 rs3745274 variants demonstrated significantly higher MAFs than in Europeans but not significantly different from South Asians.ConclusionThis preliminary study identifies variants in NAT2, UGT1A1, CYP2B6, and CYP2C19 genes relevant to the metabolism of anti-TB drugs, antiretrovirals, and voriconazole among Sri Lankans. Several variants, including CYP2C19 rs12769205 and rs4244285, showed higher MAFs, particularly in comparison to European populations, indicating potential differences in drug response. However, the nature of the study limits the ability to explore clinical correlations with the genotypes, therefore further research focusing on clinical correlation and functional validation is required.

Ensuring the efficacy and safety of medicines acting on the central nervous system (CNS) remains a challenge due to their complex pharmacokinetics and inter-individual variability in response. We describe the frequencies of pharmacogenomic variants affecting CNS drug metabolism in a Sri Lankan population. Pharmacogenomic data pertaining to genes of interest were obtained from the Pharmacogenomics Knowledgebase database. Pharmacokinetically relevant cytochrome P450 isoforms were selected. Their frequencies in Sri Lankans were obtained from an anonymized database derived from 690 participants, from the Human Genetics Unit, Faculty of Medicine, University of Colombo. Minor allele frequencies (MAFs) of these variants were calculated and compared with other populations. MAFs of CYP2C19 rs4244285, CYP2D6 rs16947, CYP2D6 rs1058164, CYP2D6 rs1135840, and CYP2B6 rs3745274 were notably high at 40.9% (95%CI:38.3-43.5), 58.0% (95%CI:55.3-60.6), 43.8% (95%CI:41.1-46.4), 44.1% (95%CI:41.5-46.8), and 39.8% (95%CI:37.2-42.4), respectively. MAFs of CYP2C9 rs72558189, CYP2C19 rs4244285, CYP2D6 rs77913725, CYP2D6 rs1135828, and CYP2B6 rs3745274 recorded the highest in Sri Lankans when compared to all other populations. A lower prevalence was noted in MAFs of CYP2D6 rs1065852, CYP2D6 rs16947, and CYP2D6 rs28371706. Sri Lankans exhibit an increased susceptibility to adverse reactions with common antidepressants, antipsychotics, and analgesics and reduced efficacy to opioid analgesics. These findings highlight the need for population-specific pharmacogenomic guidelines.

Clopidogrel exhibits substantial variability in therapeutic response, largely contributed by genetic factors. The pharmacogenomic variants data on clopidogrel metabolism in South Asians have been sparsely studied. This study explores the impact of CYP2C19 and CES1 gene variants on clopidogrel metabolism in Sri Lankans, revealing significant pharmacogenomic insights with broader implications for South Asians. Genotype data were filtered out from an anonymized database of 690 Sri Lankans, and minor allele frequencies (MAFs) were calculated. Five variants of CYP2C19 and one variant of CES1 gene were studied. Among the five CYP2C19 variants studied, rs12769205 (A>G) and rs4244285 (G>A) had the highest MAF of 42.1% and 42.0%, respectively. The CES1 variant rs71647871 (C>T) showed a MAF of 0.2%. Sri Lankans exhibited significantly higher MAFs for key variants compared to populations such as Europeans, African Americans, and East Asians (p < 0.05). Given that South Asians share genetic similarities, these findings suggest that a substantial proportion of the region's population may also be poor responders to clopidogrel, increasing the risk of adverse outcomes. This highlights the importance of genotype-guided antiplatelet therapy, which could improve clinical outcomes across South Asia amidst rising cardiovascular disease rates.