NUDT15 genotype distributions in the Korean population

Area of Science:

• Pharmacogenetics
• Genetics
• Clinical Pharmacology

Background:

• Thiopurine drugs are essential but have a narrow therapeutic index due to toxicity, partly explained by TPMT polymorphisms.
• NUDT15 genetic variation is increasingly recognized as a key factor influencing thiopurine metabolism and patient response.
• Understanding population-specific NUDT15 allele frequencies is critical for optimizing thiopurine therapy.

Purpose of the Study:

• To investigate the prevalence and spectrum of NUDT15 coding variants in the Korean population.
• To determine the NUDT15 metabolic activity phenotypes in this cohort.
• To compare findings with previous studies and assess implications for thiopurine pharmacogenetics in Koreans.

Main Methods:

• Direct sequencing of the NUDT15 gene in 920 Korean individuals.
• Genotyping of four specific NUDT15 coding variants: p.Arg139Cys, p.Arg139His, p.Val18Ile, and p.Val18_Val19insGlyVal.
• Calculation of allele frequencies and determination of NUDT15 phenotypes (normal, intermediate, low activity) based on diplotypes.

Main Results:

• Identified NUDT15 allele frequencies: NUDT15*1 (86.7%), *2 (4.4%), *3 (6.9%), *4 (0.4%), *5 (1.1%), and *6 (0.5%).
• Phenotype distribution: 75.2% normal activity, 22.7% intermediate activity, and 2.1% low activity.
• Observed a higher prevalence of intermediate or low NUDT15 activity (24.8%) compared to prior Korean studies (19.4%, P<0.05).

Conclusions:

• This is the first study to report diverse NUDT15 variants beyond NUDT15*3 in Koreans.
• The increased prevalence of intermediate/low NUDT15 activity underscores its importance in thiopurine pharmacogenetics within this population.
• Findings provide essential data for future clinical trials and personalized thiopurine dosage adjustments in Korean patients.