Impact of UGT1A1 variants on longitudinal Bilirubin trajectories in Korean infants with prolonged unconjugated hyperbilirubinemia

초록

Background and aims: Genetic varints of UDPglucuronosyltransferase1A1 gene (UGT1A1) influence susceptibility to neonatal unconjugated hyperbilirubinemia, with ethnic differences noted. We investigated the spectrum of UGT1A1 variants in Korean infants with prolonged jaundice and evaluated their longitudinal effect on the clinical course. Method: This multicenter retrospective study included 65 Korean infants referred for prolonged or severe unconjugated hyperbilirubinemia. Clinical and laboratory data were collected, and UGT1A1 genotyping was performed. Variant frequencies were compared with the Korean Reference Genome Database (KRDGB). Longitudinal total bilirubin (TB) trajectories across predefined postnatal age intervals (2–4, 5–7, 8–10, 11–13 weeks) were assessed using linear mixedeffects models. Multivariable linear regression evaluated independent predictors of TB at presentation and during follow-up. An additive genetic risk score (GRS) was constructed from the variants positively associated with prolonged hyperbilirubinemia. Results: The c.211G>Avariant was the most prevalent polymorphism, with a risk allele frequency of 54.6%, significantly higher compared to the KRDGB (OR = 5.75, p < 0.001). Significant associations were also observed for c.1091C>T, c.1456T>G, and c.-64G>C, while c.-3156G>A showed a reduced risk. Among the 5 variants, c.211G>A was the only variant associated with higher initial TB levels, and GRS positively correlated with initial TB level (ρ = 0.32, p = 0.008). The c.211G>A risk allele number independently predicted higher TB at presentation (β = +1.91 mg/dL per allele, p = 0.043) and at 2–4 weeks (β = +2.80 mg/ dL per allele, p = 0.008); however, this effect attenuated and lost statistical significance after 5 weeks of age. Neither individual variants nor a cumulative UGT1A1 GRS altered the rate of bilirubin decline through 13 weeks of age. Family history of jaundice was also independently associated with hyperbilirubinemia at presentation (β = +3.44, p = 0.025) and remained significant at 5–7 weeks of age (β = +4.06, p = 0.029). Conclusion: The c.211G>A variant is the dominant genetic determinant of higher bilirubin burden, early in the clinical course in Korean infants, but its influence is transient. These findings support genotype-informed risk stratification and counseling in prolonged neonatal jaundice.