Bilirubin metabolism is predominantly mediated by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), which aids in glucuronidation and thereby facilitates bilirubin’s removal from the body. UGT1A1, located on chromosome 2 (2q37), covers an area of approximately 160 kbp[11–14]. Multiple genetic polymorphisms within the UGT1A1 gene, such as rs8175347, rs4124874, rs4148323, and rs10929302 are known to influence gene expression, the function of enzymes, and the concentration of bilirubin in the serum.[15–17]. We noted statistically significant disparities in the distribution of the alleles and genotypes of rs11888492 and rs4148325 of UGT1A1 between the control and NHB groups. However, no clear relationship was observed between other variants and neonatal hyperbilirubinemia.
For rs11888492, our findings revealed that the frequencies of the CC genotype and C allele were more prevalent within the NHB cohort than in control subjects (P = 0.001 and P = 0.023, respectively). The G allele was linked to a decreased likelihood of NHB incidence (OR = 0.363; 95% CI: 0.169–0.777), while allele C increased the risk. Neonates carrying the GG genotype had significantly lower total bilirubin levels than those carrying the CC genotype. However, Zhai et al.[14] previously observed no correlation between rs11888492 and serum TBIL levels in patients with sepsis.
For rs4148325, our investigation revealed that the genotype CC and allele C frequencies were more prevalent within the NHB cohort than in the control group (P = 0.001 and P = 0.002, respectively). When comparing neonates with the CC genotype to those with the CT genotype, there is a notably reduced risk associated with the CT genotype for the development of NHB (OR = 0.242; 95% CI: 0.102–0.574). Newborns carrying the CT genotype exhibited significantly lower bilirubin levels than those with the CC genotype. However, our findings differ from those reported in other studies that found that rs4148325 was closely linked to the highest levels of bilirubin elevation in patients receiving sarilumab treatment, likely indicating Gilbert syndrome or disorders of bilirubin excretion[18, 19]. The observed inconsistency could be due to the limited size of our sample group and the failure to consider the cumulative effects of numerous genetic variations in our analytical approach.
As far as we are aware, our research is pioneering in examining the interactive influence of UGT1A1 genetic variants rs11888492 and rs4148325 on neonatal hyperbilirubinemia. We found that these variants were protective factors against the development of neonatal hyperbilirubinemia, with total bilirubin levels decreasing with an increase in the number of genetic variations.
BLVRA is another important bilirubin metabolism gene responsible for the transformation of biliverdin into bilirubin. Genetic variations within the BLVRA gene may also affect TBIL levels[20]. Although genetic variations in BLVRA have been associated with unconjugated hyperbilirubinemia in adults[21], the variant rs699512 did not show a substantial impact hyperbilirubinemia in our findings. Similarly, the correlation between rs7738 and hyperbilirubinemia remains controversial. One study demonstrated an association between rs7738 in the BLVRA and TBIL levels in coronary artery disease cases within the Chinese population[22]. However, Chiddarwar et al.[23] observed an increased frequency in the rs7738 variant allele among individuals with hyperbilirubinemia in comparison with the control cohort, although this discrepancy lacked statistical significance (P < 0.14). Our study yielded results similar to those reported by Chiddarwar et al.[23] regarding rs7738. Additionally, we observed that other variants, including rs10486752, rs1181576, and rs2730625, had no discernible effect on neonatal hyperbilirubinemia. Notably, our study marks an initial inquiry into the effects of rs1181576 and rs2730625 on neonatal hyperbilirubinemia.
This study is subject to certain constraints, including a relatively limited sample size and assessment of only 14 gene loci that potentially affect bilirubin metabolism. Neonatal hyperbilirubinemia is a complex issue influenced by multiple factors, and additional research with larger sample sizes is necessary to investigate gene–gene interactions and offer a more thorough understanding of its pathogenesis.