UGT1A1 Gene Polymorphisms in North Indian Neonates Presenting with Unconjugated Hyperbilirubinemia

Abstract

Genetic factors are implicated in pathogenesis of neonatal hyperbilirubinemia. In this nested case-control study, we determined 1) frequency of thymine-adenine (TA) n promoter polymorphism and Gly71Arg mutation in uridine diphosphoglucuronateglucuronosyltransferase 1A1 (UGT1A1) gene in neonates Ն35-wk gestation presenting with bilirubin levels Ն18 mg/dL and controls, 2) interaction among (TA) n promoter polymorphism, glucose-6-phosphate dehydrogenase (G6PD) gene mutations, and peak bilirubin. The number of TA repeats was assessed by PCR-single-strand conformation polymorphism (SSCP) analysis and Gly71Arg mutation by PCR-RFLP. Fifty samples of both mutations were verified with DNA sequencing. One hundred twenty-seven neonates were enrolled (77 hyperbilirubinemics, 50 controls). The incidence of (TA) n polymorphism was higher in babies with hyperbilirubinemia [89.6% vs. 50%, OR 8.63 (95% CI, 3.2-24.1)]. Gly71Arg mutation was not found either in hyperbilirubinemics or controls. A novel polymorphism (Ala72Pro) at codon position 72 of exon 1 was detected in all 50 samples (21 hyperbilirubinemics, 29 controls), which were sequenced. Presence of variant (TA) n promoter (adjusted OR, 10.6; 95% CI, 3.3-34.2), G6PD deficiency (adjusted OR, 20.6; 95% CI, 3.6 -117.3), and history of jaundice in sibling requiring phototherapy (adjusted OR, 12.6; 95% CI, 1.1-141.6) were independent risk factors for bilirubin levels Ն18 mg/dL. (Pediatr Res 65: 675-680, 2009) T he incidence and severity of neonatal hyperbilirubinemia is significantly higher in Asians, more so in North Indians, than in Caucasians (1,2). Despite all standard investigations, no cause is identified in 48 -58% of these cases (2,3). Genetic factors have been implicated in such situations; however, their contribution in Indian population has not been reported. Genetic variants involving red blood cell enzyme glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G6PD) and bilirubin conjugating enzyme uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (EC 2.4.1.17; UGT1A1) have been commonly associated with neonatal hyperbilirubinemia (4,5). The usual polymorphism described in Caucasians is additional thymine-adenine (TA) insertions in the normal sequence A(TA) 6 TAA of the TATAA box promoter of the UGT1A1 gene (6). However, in East Asians, missence mutations in the coding area of the UGT1A1 gene, especially G3 A transition at nucleotide position 211 of exon 1 (Gly71Arg) are the most common (7). The types, prevalence, and importance of various mutations of UGT1A1 gene vary across different regions of world.Hence, this study was conducted with the primary objective of determining the frequency of (TA) n promoter polymorphism and Gly71Arg mutation in the UGT1A1 gene in North Indian neonates Ն35-wk gestation presenting with serum total bilirubin (STB) Ն18 mg/dL. The secondary objective was to study the interaction among the presence of UGT1A1 gene polymorphisms, G6PD gene mutations, and peak STB levels. PATIENTS AND METHODSThis was a hospital-based nested case-co...

G71R mutation of the UGT1A1 gene is not associated with neonatal hyperbilirubinemia in India

“…This finding is in agreement with those reported among the Japanese neonates [4] but discordant with the results on Gilbert's syndrome patients from the eastern part of India [5]. On the other hand, a complete absence of this mutation was observed among the neonates with or without hyperbilirubinemia from north India [6]. Thus, our study indicates that the development of hyperbilirubinemia among our neonates was influenced by the TA insertion rather than the G71R mutation of the UGT1A1 gene.…”

UGT1A1 gene mutations and neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations

“…Among the four mutations, 211G>A was the most common as shown above, and resulted in a change of glycine to arginine at position 71 (G71R). The A allele frequency in the case group was 20.4%, which is higher than data from Turkish (4.3%) (13) and North India (0%) (14), but lower than values in Korean (32%) (15) and Japan (34%) (16), and close to our previous study (23.3%) (17). The frequency of the 211G>A mutation was significantly higher in hyperbilirubinemia infants than controls in this study, indicating its close relationship to neonatal hyperbilirubinemia in Guangxi Heiyi Zhuang and Han populations.…”

“…However, discrepant conclusions were reached for Caucasians. Indeed, (TA)7 insertion is the most common mutation causing Gilbert syndrome in Caucasians (6,7), and multiple studies have revealed its relationship with neonatal hyperbilirubinemia in Caucasians (14,(24)(25)(26)(27)(28)(29)(30). Roy-Chowdhury et al (24) reported that the (TA)7 allele may be associated with high TSB levels.…”

“…Roy-Chowdhury et al (24) reported that the (TA)7 allele may be associated with high TSB levels. Agrawal et al (14) reported that (TA)n promoter variations are significantly associated with neonatal hyperbilirubinemia in North India. However, the majority of studies assessing Caucasians, including two recent ones, have shown that (TA)7 insertion alone does not necessarily cause neonatal hyperbilirubinemia (20,(25)(26)(27), in agreement with Asian studies.…”

211 G to A Variation of UDP-Glucuronosyl Transferase 1A1 Gene and Neonatal Breastfeeding Jaundice

“…Recently, homozygous A(TA) 7 TAA variation in promoter region of UGT1A1 gene was found to be associated with neonatal hyperbilirubinemia in western people (7)(8)(9)(10)(11)(12)(13)(14). However, in Japanese, Koreans, and Taiwanese studies, the high allele-frequency of Gly71Arg, but not promoter polymorphism, in UGT1A1 gene was found to be responsible for neonatal hyperbilirubinemia (15)(16)(17)(18)(19).…”