In the era of precision medicine, pharmacogenetics has substantial potential for addressing inter-individual variability in drug responses. Although pharmacogenetics has been a research focus for many years, resulting in the establishment of several formal guidelines, its clinical implementation remains limited to several gene–drug combinations in most countries, including Korea. The main causes of delayed implementation are technical challenges in genotyping and knowledge gaps among healthcare providers; therefore, clinical laboratories play a critical role in the timely implementation of pharmacogenetics. This paper presents an update of the Clinical Pharmacogenetic Testing and Application guidelines issued by the Korean Society for Laboratory Medicine and aims to provide the necessary information for clinical laboratories planning to implement or expand their pharmacogenetic testing. Current knowledge regarding nomenclature, gene–drug relationships, genotyping technologies, testing strategies, methods for clinically relevant information delivery, QC, and reimbursements has been curated and described in this guideline.

Background: Korea National Health and Nutrition Examination Survey (KNHANES) triglyceride testing changed from the glycerol blanking method (2005–2021) to the glycerol nonblanking method (2022). We converted triglyceride data from 2005–2021 to that obtained since 2022 with different analytical methods. Methods: To develop a conversion equation, 98 fresh serum specimen pairs were compared using Passing–Bablok regression analysis. Implications of the conversion equation on epidemiological data were evaluated using KNHANES data from 2019–2021. Bias estimations determined using the Lipid Standardization Program (LSP) of the United States Centers for Disease Control and Prevention (CDC) enhanced the accuracy and comparability of the triglyceride results. Results: Triglyceride concentrations measured via the glycerol non-blanking method were 10.7 mg/dL (0.12 mmol/L, 10.0%) higher than those from the glycerol blanking method, with a 9.9 mg/dL (0.11 mmol/L, 5.0%) difference at a concentration of 200 mg/dL (2.26 mmol/L, N = 98). The conversion equation y (glycerol non-blanking, 2022) = 11.94+0.99x (glycerol blanking, 2005–2021) changed the mean triglyceride concentrations of the KNHANES 2019–2021 data (N = 16,015) from 123.7 mg/dL (1.40 mmol/L, 95% confidence interval [CI]: 122.2–125.1 mg/dL [1.38–1.41 mmol/L]) to 134.3 mg/dL (1.52 mmol/L, 95% CI: 132.9–135.8 mg/dL [1.50–1.53 mmol/L]). Since 2022, bias monitoring using the CDC’s LSP has remained within a 5.0% limit. Conclusions KNHANES triglyceride values in 2022 (non-blanking) were substantially higher than those from 2005–2021 (blanking). Conversion equations helped effectively adjust 2005–2021 data. Researchers should consider adjusting the KNHANES triglyceride data based on their study characteristics.

Background: We developed an assay to measure DNA-incorporated 6-thioguanine (DNATG) and validated its clinical applicability in Korean pediatric patients with acute lymphoblastic leukemia (ALL) in order to improve individualized thiopurine treatment and reduce the life-threatening cytotoxicity. Methods: The DNA-TG assay was developed based on liquid chromatography-tandem mass spectrometry, with isotope-labeled TG-d3 and guanine-d3 as internal standards.This method was applied to 257 samples of pediatric ALL patients. The DNA-TG level was compared with erythrocyte TG nucleotide (RBC-TGN) level in relation to the TPMT and NUDT15 genotypes, which affect thiopurine metabolism, using Spearman’s rank test and repeated measure ANOVA. Results: For DNA-TG quantification, a linearity range of 10.0-5,000.0 fmol TG/µg DNA;bias for accuracy of –10.4% –3.5%; coefficient of variation for intra- and inter-day precision of 3.4% and 5.8% at 80 fmol TG/µg DNA and of 4.9% and 5.3% at 800 fmol TG/µg DNA, respectively; and recovery of 85.7%–116.2% were achieved without matrix effects or carry-over. The median DNA-TG level in the 257 samples was 106.0 fmol TG/µg DNA (interquartile range, 75.8–150.9). There was a strong correlation between DNA-TG and RBC-TGN levels (ρ = 0.68,ρ < 0.0001). The DNA-TG/RBC-TGN ratio was significantly higher in NUDT15 intermediate metabolizers (*1/*2 and *1/*3) than in patients with wildtype alleles (ρ < 0.0001). Conclusions This simple and sensitive method for measuring DNA-TG level can improve therapeutic drug monitoring for thiopurine treatment.

Background: Because there is limited recent information on this topic, this study investigated the seroprevalence of anti-hepatitis A virus (HAV) immunoglobulin G (IgG) in the South Korean population in 2015–2017. Methods: Anti-HAV IgG seroprevalence data were obtained from the laboratory information system of Green Cross Laboratories, one of the largest referral laboratories in South Korea. Results: During the three-year study period, we obtained test results from 240,840 individuals (124,353 men and 116,487 women) from 1,348 hospitals and local clinics throughout South Korea. The median (range) age of subjects was 38.0 (18.0–97.2) years. The annual seroprevalence of anti-HAV IgG was 53.3%, 53.0%, and 53.1% in 2015, 2016, and 2017, respectively. The median age differed among geographic regions and anti-HAV seroprevalence differed among age groups and geographic regions (P<0.0001). Subjects in their 20’s had a significantly lower rate of anti-HAV IgG-positivity than subjects in their 10’s (odds ratio, [OR] 0.74, 95% CI, 0.69–0.78, P<0.0001), while other age groups had higher rates. Multivariable-adjusted logistic regression analysis showed that women and subjects living in Inchoen, Sejong city, Gangwon province, Gwangju, and North Jeolla province were more likely to be immune to HAV compared to subjects living in Seoul (OR >1.0, P<0.05). Conclusions This study provides basic information about the recent seroprevalence of anti-HAV IgG in the Korean population and contributes to identifying groups at high risk of an HAV epidemic.

BACKGROUND: Differences in the performance of suggested warfarin dosing algorithms among different ethnicities and genotypes have been reported; this necessitates the development of an algorithm with enhanced performance for specific population groups. Previous warfarin dosing algorithms underestimated warfarin doses in VKORC1 1173C carriers. We aimed to develop and validate a new warfarin dosing algorithm for Korean patients with VKORC1 1173C. METHODS: A total of 109 patients carrying VKORC1 1173CT (N=105) or 1173CC (N=4) were included in this study. Multiple regression analysis was performed to deduce a new dosing algorithm. Following literature searches for genotype-guided warfarin dosing algorithms, 21 algorithms were selected and evaluated using the correlation coefficient (ρ) of actual dose and estimated dose, mean error, and root mean square error. RESULTS: The developed algorithm is as follows: maintenance dose (mg/week)=exp [3.223−0.009×(age)+0.577×(body surface area [BSA])+0.178×(sex)−0.481×(CYP2C9 genotype)+0.227×(VKORC1 genotype)]. Integrated variables explained 44% of the variance in the maintenance dose. The predicted and actual doses showed moderate correlation (ρ=0.641) with the best performance with a mean error of −1.30 mg/week. The proportion of underestimated groups was 17%, which was lower than with the other algorithms. CONCLUSIONS This is the first study to develop and validate a warfarin dosing algorithm based on data from VKORC1 1173C carriers; it showed superior predictive performance compared with previously published algorithms.

PURPOSE: We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. RESULTS: A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group. CONCLUSION: NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.
6-Mercaptopurine ; Blood Cell Count ; Child* ; Humans ; Leukemia ; Leukopenia ; Precursor Cell Lymphoblastic Leukemia-Lymphoma* ; Thioguanine

BACKGROUND: This study aimed to investigate the current statuses of eight hormone tests (testosterone, estradiol, prolactin, progesterone, luteinizing hormone, follicle-stimulating hormone, parathyroid hormone, and thyroglobulin) used by clinical laboratories in Korea. METHODS: From November 1 to December 31, 2016, we surveyed 300 laboratories that participated in the regular proficiency survey program administered by the Korean Association of Quality Assurance for Clinical Laboratory. The survey comprised a questionnaire designed to address factors related to these hormone tests, including the measurement methods, instruments, test numbers per month, turnaround times, reporting units and ranges, reference ranges, and internal or external quality control methods. RESULTS: Fifty-four (18.0%) of 300 laboratories replied to the survey questionnaire. Each laboratory performed hormone analyses that used variable instruments, commercial kits, and calibrators. The test numbers per month, turnaround times, and reporting units (particularly for testosterone) varied among laboratories. Most laboratories used reference intervals that had been transferred from other references and were verified using in-house samples. Many laboratories that assessed luteinizing hormone, follicle-stimulating hormone, and parathyroid hormone levels did not participate in the proficiency survey program conducted by The Korean Association of Quality Assurance for Clinical Laboratory. CONCLUSIONS: We hope that the results of this study, which investigated the status of hormone testing at Korean diagnostic laboratories, will facilitate improvements in the quality of hormone testing and promote the development of guidelines for testing.
Clinical Laboratory Services ; Estradiol ; Follicle Stimulating Hormone ; Hope ; Korea* ; Laboratory Proficiency Testing ; Luteinizing Hormone ; Parathyroid Hormone ; Progesterone ; Prolactin ; Quality Control ; Reference Values ; Surveys and Questionnaires

No abstract available.
Coronavirus Infections/*diagnosis/virology ; Humans ; Middle East Respiratory Syndrome Coronavirus/genetics/isolation & purification ; Nasopharynx/virology ; RNA, Viral/genetics/metabolism ; Real-Time Polymerase Chain Reaction ; Viral Envelope Proteins/genetics

Diagnosis of the urea cycle disorder (USD) carbamoyl-phosphate synthetase 1 (CPS1) deficiency (CPS1D) based on only the measurements of biochemical intermediary metabolites is not sufficient to properly exclude other UCDs with similar symptoms. We report the first Korean CPS1D patient using whole exome sequencing (WES). A four-day-old female neonate presented with respiratory failure due to severe metabolic encephalopathy with hyperammonemia (1,690 µmol/L; reference range, 11.2-48.2 µmol/L). Plasma amino acid analysis revealed markedly elevated levels of alanine (2,923 µmol/L; reference range, 131-710 µmol/L) and glutamine (5,777 µmol/L; reference range, 376-709 µmol/L), whereas that of citrulline was decreased (2 µmol/L; reference range, 10-45 µmol/L). WES revealed compound heterozygous pathogenic variants in the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which was previously reported in Japanese patients with CPS1D. We successfully applied WES to molecularly diagnose the first Korean patient with CPS1D in a clinical setting. This result supports the clinical applicability of WES for cost-effective molecular diagnosis of UCDs.
Base Sequence ; Carbamoyl-Phosphate Synthase (Ammonia)/chemistry/*genetics ; Carbamoyl-Phosphate Synthase I Deficiency Disease/diagnosis/*genetics ; Codon, Nonsense ; Exons ; Female ; Frameshift Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Infant, Newborn ; Republic of Korea ; Sequence Analysis, DNA ; Urea Cycle Disorders, Inborn/diagnosis

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.
Antitubercular Agents/blood/*therapeutic use ; Arylamine N-Acetyltransferase/genetics ; Chromatography, High Pressure Liquid ; Drug Monitoring ; Humans ; Nutritional Status ; Pharmacogenetics ; Tandem Mass Spectrometry ; Tuberculosis/*drug therapy