Pharmacogenetics and genomics最新文献

Objectives: Pharmacogenomic testing is rapidly becoming the standard of care in treating pediatric acute lymphoblastic leukemia (ALL). Risk classification of ALL can be performed through whole transcriptome sequencing (WTS) of diagnostic tumor samples. We evaluated the feasibility of inferring germline pharmacogenomic genotypes from the tumor transcriptome in ALL.

Methods: Transcriptome and paired tumor-germline genome sequencing data were collected from clinical testing at St. Jude Children's Research Hospital. Genotypes for pharmacogenes that are actionable for medications used in the management of pediatric ALL ( TPMT, NUDT15 , and G6PD ) were determined using a rule-based algorithm from transcriptome data. WTS-derived genotype calls were compared with germline genotypes obtained from whole genome sequencing (WGS) and clinical genotyping assays.

Results: Among 650 patients with ALL, 36 (5.5%) patients had somatic copy number loss on chromosomes 6, 13, or X, where TPMT , NUDT15 , and G6PD are located, respectively. For the remaining 614 patients, WTS provided thiopurine dosing guidance by calling both TPMT and NUDT15 diplotypes in 545 patients (83.8%). For G6PD , accurate genotyping was called for 367 male patients. We observed a greater than 99% concordance between tumor WTS and germline WGS diplotypes for all three genes.

Conclusion: The leukemia transcriptome can be used to provide accurate genotyping calls for select germline pharmacogenes actionable in the treatment of pediatric ALL.

In Canada, access to pharmacogenetic (PGx) testing remains limited, particularly outside of research institutions, and commercial testing is often cost-prohibitive. To address access challenges, several Canadian insurance providers have begun offering PGx test coverage; however, the extent and nature of this coverage remain unclear. This study systematically reviewed publicly available PGx coverage policies from Canadian insurance companies to evaluate eligibility requirements, affiliated laboratories, and clinical actionability of test panels. Ten Canadian insurers were identified with publicly accessible PGx testing policies. Six offered partial reimbursement or discounted pricing to all members, while four restricted full coverage to individuals meeting specific criteria, such as being on disability leave or having a physician's diagnosis. Eligibility requirements varied considerably, with some insurers requiring multiple conditions to be met. Four commercial laboratories were affiliated with insurers, but these labs differed substantially in the number of actionable genes and drugs tested. Our findings highlight substantial heterogeneity in insurer eligibility criteria and affiliate lab test comprehensiveness that may create inequities in access and quality of care. Furthermore, variability in insurance coverage may influence clinicians' willingness to recommend testing and patients' ability to access personalized therapy. These findings underscore the need for standardized PGx testing coverage policies and harmonized testing panels. Collaboration among insurers, researchers, and clinicians is essential to generating Canadian-specific evidence to guide equitable and clinically effective PGx implementation.

Background: Large consortia link variants in SLC22A1 , SLC47A1 , and GLP1R to antidiabetic response, yet few data confirm these effects in small real-world cohorts. We tested whether three common polymorphisms translate into measurable 3-month metabolic changes.

Methods: Twenty-seven Bulgarian adults with type 2 diabetes [BMI ≥ 25 kg/m²; mean glycated hemoglobin (HbA1c): 8.3 ± 0.9%] received metformin XR 2000 mg ( n  = 17) or oral semaglutide 14 mg ( n  = 10). Sanger sequencing identified SLC22A1 rs628031, SLC47A1 rs2252281, and GLP1R rs6923761. Primary endpoints were 3-month changes (Δ) in weight and HbA1c; analysis of variance and ordinary least squares regression assessed genotype and treatment effects, as well as covariate-adjusted linear models of 3-month change (Δ).

Results: Semaglutide produced greater weight loss than metformin [-6.5 ± 3.6 vs. -1.6 ± 2.5 kg; 95% confidence interval (CI) -7.6 to -2.2; P  = 0.001] and larger BMI reduction (-2.0 ± 1.2 vs. -0.3 ± 0.9 kg/m²; P  = 0.001). At an exploratory 10% FDR, only OCT1 rs34130495 dosage was associated with high-density lipoprotein (HDL) change in metformin-treated participants ( β = +0.340 mmol/L per minor allele; P  = 0.0026; q  = 0.063; N  = 16). GLP1R rs6923761 showed nominal trends for weight and BMI change in semaglutide users that did not survive FDR ( P  ≈ 0.06-0.07; q  ≈ 0.29; N  = 10).

Conclusion: Semaglutide outperformed metformin for short-term weight loss. An HDL signal for OCT1 rs34130495 at an exploratory 10% FDR warrants replication. These hypothesis-generating data support the feasibility of genotype-guided studies in local clinical settings.

Background: Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic drug-metabolizing enzyme involved in the metabolism of many clinically important medications. CYP2D6 is affected by genetic variation as well as drug interactions; however, this does not account for all the variability seen in CYP2D6. Previously, a single-nucleotide variant in the nuclear factor 1-B (NFIB), rs28379954 T>C, was linked to increased CYP2D6 activity and metabolism of CYP2D6 substrates. Thus, we investigated the effect of NFIB rs28379954 on the metabolism of CYP2D6 substrates, solanidine and tamoxifen.

Methods: Patients (N = 759) were genotyped for CYP2D6 genetic variants and NFIB rs28379954. Solanidine, tamoxifen, and their metabolites were measured with ultra-HPLC-tandem mass spectrometry.

Results: NFIB rs28379954 genotype (T/T versus T/C) was not associated with metabolism of solanidine to its CYP2D6-generated metabolites, 4-OH-solanidine or SSDA irrespective of CYP2D6 phenotype (poor metabolizer, intermediate metabolizer, or normal metabolizer; P > 0.05). Similarly, the ratio of endoxifen to tamoxifen was not affected by NFIB rs28379954 genotype in any CYP2D6 phenotypic group (P > 0.05). Multivariable linear regression modeling demonstrated that CYP2D6 phenotypes were associated with solanidine metabolic ratios as well endoxifen to tamoxifen ratios. However, the addition of NFIB genotype to the model did not significantly improve the predictability of solanidine or tamoxifen metabolites in plasma.

Conclusion: In conclusion, we did not observe any significant impact of NFIB rs28379954 genetic variation on CYP2D6 activity in vivo, when assessed using tamoxifen or solanidine metabolites as prototypical CYP2D6 substrates.

Objectives: Dyslipidemia is a crucial risk factor for atherosclerotic cardiovascular disease. Although rosuvastatin is widely used, treatment response varies significantly due to genetic variation. This study investigated the pharmacogenomic impact of low-density lipoprotein receptor (LDLR) 3' untranslated region (UTR) variants on rosuvastatin efficacy in a Chinese Han adult cohort with dyslipidemia.

Methods: A cohort of 113 Chinese participants receiving 10 mg rosuvastatin daily was sequenced for LDLR 3'UTR variants. Haploview was used to assess linkage disequilibrium (LD) patterns and haplotype structures. Multivariate regression modeling was employed to assess the influence of genetic variants on therapeutic outcomes.

Results: Seventeen LDLR 3'UTR variants were identified. A crosspopulation comparative assessment revealed significant variation in allele frequencies across distinct ethnic groups. Five variants (rs14158, rs2738466, rs5742911, rs17249057, and rs17249064) were in complete LD ( D ' = 1 and r2  = 1). CHANGE analysis revealed that rosuvastatin efficacy was significantly influenced by rs2738465, rs55903358, rs186461273, and rs751672818, while ANCOVA indicated that baseline triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and patient age, alongside rs2738467, rs143587805, and rs751672818 significantly impacted treatment response. Given the bias correction properties and well-established efficiency, results derived from ANCOVA were preferred. These findings were first reported, highlighting LDLR variants can be used as predictive markers for precision medicine for rosuvastatin in the Chinese population.

Conclusions: These findings highlight the role of LDLR 3'UTR as a critical pharmacogenomic locus. Our results advance understanding of genetic predictors for personalized statin therapy.

Objectives: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, shaped by both environmental and genetic factors. While genome-wide association studies have identified several IPF risk loci, the genetic basis remains incomplete, especially in non-European populations.

Methods: We performed an exome-wide association study in 186 Korean IPF patients and 262 healthy controls using the Illumina HumanExome v1.1 BeadChip to discover novel exonic variants linked to IPF susceptibility. Logistic regression was used to test associations, adjusting for age, sex, and smoking history. Functional implications were evaluated through structural modeling and protein stability predictions.

Results: After quality control, 23 737 single-nucleotide polymorphisms (SNPs) were analyzed. The variant rs1047406 (T>C) in the PEBP4 gene was significantly associated with IPF under a codominant model (odds ratio = 1.94, 95% confidence interval = 1.42-2.65, P < 0.05 after correction). Haplotype analysis, including three nearby SNPs, further supported this association. In-silico analyses predicted that the E11G substitution caused by rs1047406 reduces protein stability and may disrupt proper folding. GTEx eQTL data showed that the minor allele is linked to altered PEBP4 expression in several tissues. PEBP4 is known to regulate phosphoinositide 3-kinase/protein kinase B and nuclear factor kappa B pathways, both implicated in fibrotic remodeling.

Conclusion: A novel PEBP4 variant associated with IPF was identified in a Korean population, likely affecting protein function and expression. These findings underscore the importance of ethnic-specific studies and support PEBP4 as a candidate gene in IPF, meriting further validation.

It is unknown how many people in the US have had pharmacogenetic (PGx) testing and whether people want to be tested. We conducted a nationally representative survey of the general US adult population to determine the prevalence of adults that have had PGx testing using a validated confidential online survey, the Non-Medical Use of Prescription Drugs Program. A weighted logistic regression was used to test health characteristics associated with PGx testing and determine those who desire to be tested. The analysis included 29 146 individuals who completed the survey, which represents approximately 260 000 000 adults in the US. The prevalence of US adults who have been PGx tested is 6.6% [95% confidence interval (CI): 6.2-7.0]. Only 32.2% (95% CI: 31.5-32.9), an estimated 79 million individuals, desired PGx testing. Adults who had or want PGx testing were more likely to be female, have higher education, be students, current or former members of the military, use medications, and have a mental health disorder. The prevalence of adults who have been PGx tested remains low in the US. There are knowledge gaps about the benefits of PGx testing that must be bridged to increase implementation.

Irinotecan treatment is often complicated by gastrointestinal, hematological, and infusion-related toxicities, the latter of which typically presents as acute cholinergic syndrome (ACS). While genetic variation in UGT1A1 increases toxicity risk, fewer studies have investigated variation in other genes. This study aimed to assess the impact of variation in other genes involved in irinotecan pharmacokinetics with irinotecan-related toxicity. This was a retrospective study of patients receiving standard irinotecan doses (180 mg/m2) with available genetic and clinical data. The primary analysis was to investigate the impact of carboxylesterase (CES) genetic variation on irinotecan infusion-related ACS. Exploratory secondary analyses evaluated variation in CES1, CES2, UGT1A7, UGT1A9, ABCB1, ABCG2, ABCC2, and SLCO1B1 with severe toxicity, treatment modification, diarrhea, and neutropenia. Univariate associations with P less than 0.05 were adjusted for UGT1A1*28 and UGT1A1*6 genotype. A total of 93 patients were included in this analysis. CES1 variants were not associated with infusion-related ACS. In the exploratory analysis, CES1 rs3785161 AA was associated with an increased likelihood of severe irinotecan toxicity (37 vs. 16%; P = 0.034), and ABCG2 rs2231142 AA/AC was associated with an increased likelihood of severe neutropenia (33 vs. 8%; P = 0.017). CES1 and ABCG2 variants may increase the risk of irinotecan toxicity. Further studies are needed to validate these associations to justify prospective studies investigating the clinical benefits of genetics-guided irinotecan dosing.