Variants in UGT1A1 and SLCO1B1 increase the risk of neonatal hyperbilirubinemia: a case-control study in subtropical China.

OBJECTIVE: The genetic architecture underlying susceptibility to neonatal hyperbilirubinemia in specific subtropical populations remains poorly defined. This study aimed to evaluate the association between polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1(UGT1A1) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) genes and the risk of neonatal hyperbilirubinemia within the Haikou population, and to explore potential cumulative genetic effects.

METHODS: A retrospective case-control study was conducted involving 210 neonates diagnosed with hyperbilirubinemia (case group) and 195 healthy neonates (control group) admitted to the Haikou Maternal and Child Health Hospital between January 2024 and January 2025. Serum levels of total bilirubin (TBIL), indirect bilirubin (IBIL),and alkaline phosphatase (ALP) were quantified. Seven target single nucleotide polymorphisms (SNPs) were genotyped, including four UGT1A1 loci (rs4148323, rs3771341, rs34946978, rs35350960) and three SLCO1B1 loci (rs4149056, rs2306283, rs4149015). Genotype-phenotype correlations, disease risk associations,gene-gene interactions, cumulative risk allele analyses, and combined genotype analyses were statistically evaluated. Stratified and sensitivity analyses were performed to assess the robustness of the findings.

RESULTS: The case group exhibited a significantly higher prevalence of preterm births compared to the control group (16.9% vs. 9.5%, P = 0.04). Allele frequencies for UGT1A1 rs4148323 (22.14% vs. 11.79%), SLCO1B1 rs4149056 (19.05% vs. 10.26%), and rs4149015 (21.43% vs. 11.79%) were significantly elevated in the case group (P < 0.05). Possession of the UGT1A1 rs4148323 GA genotype (OR = 2.370, 95% CI: 1.499-3.805), SLCO1B1 rs4149056 TC genotype (OR = 1.594, 95% CI: 1.006-2.545), and rs4149015 AG genotype (OR = 2.247, 95% CI: 1.429-3.576) was associated with a significantly increased risk of hyperbilirubinemia. In multivariate analysis adjusting for gestational age, birth weight, and feeding modality, these associations remained robust (adjusted ORs: 2.338, 1.481, and 2.233, respectively; all P < 0.05). No statistically significant multiplicative interaction was detected between UGT1A1 and SLCO1B1 variants (P-interaction > 0.05). However, a cumulative risk allele analysis demonstrated a significant dose-response relationship: neonates carrying 3-4 risk alleles across UGT1A1 rs4148323and SLCO1B1 rs4149056/rs4149015 exhibited a markedly elevated risk compared to those with 0-1 risk alleles (adjusted OR = 3.412, 95% CI: 1.892-6.154, P < 0.001). Combined genotype analysis further revealed that carriers of concurrent UGT1A1 rs4148323 variant(GA/AA) and SLCO1B1 rs4149056/rs4149015 variant (TC + CC/AG + AA) genotypes had significantly higher TBIL levels than carriers of single-gene variants (P < 0.01), consistent with an additive genetic burden. The primary stratified analysis restricted to term neonates (>=37 weeks) confirmed that the main genetic associations remained robust; late-preterm (35-36 weeks) subgroup analyses were underpowered and are presented in Supplementary Materials.

CONCLUSION: Neonatal hyperbilirubinemia is a multifactorial condition; our findings underscore that UGT1A1 and SLCO1B1 variants-specifically rs4148323, rs4149056, and rs4149015-are potent genetic biomarkers for predicting disease susceptibility in the Haikou population. The significant additive cumulative effect supports the clinical value of multi-locus genetic profiling. Future large-scale studies incorporating multi-gene panels and formal additive burden testing are warranted to elucidate complex gene-gene relationships and facilitate personalized neonatal care.