目的：探讨尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）Gly71Arg、TATA盒基因突变和葡萄糖-6-磷酸脱氢酶（G6PD）基因突变与新生儿高未结合胆红素血症的关系。方法：UGT1A1 TATA盒、外显子1、外显子5和G6PD基因外显子12经PCR扩增和测序，构建突变样本的克隆，对其进行验证。分析病例组及对照组UGT1A1 Gly71Arg和TATA盒基因多态性频率的差异，应用logistic回归分析基因突变对新生儿高未结合胆红素血症发生的影响。结果：病例组UGT1A1 Gly71Arg基因多态性的基因型分布与对照组比较差异有统计学意义（P0.05）。Logistic回归分析显示UGT1A1 Gly71Arg、TATA盒基因和G6PD基因突变对新生儿高未结合胆红素血症发生的OR值（95％CI）分别为5.468（2.274，12.818）、0.688（0.266，1.778）和5.081（1.070，24.133）。结论：UGT1A1 Gly71Arg和G6PD基因突变可能是新生儿高未结合胆红素血症发生的原因。
Abstract
OBJECTIVE: To study association of uridine-diphosphate-glucuronosyltransferase1A1 (UGT1A1) Gly71Arg, UGT1A1 promoter TATA-box and glucose-6-phosphate dehydrogenase (G6PD) gene mutations with the occurrence of neonatal unconjugated hyperbilirubinemia. METHODS: The TATA-box, exon 1 and exon 5 of the UGT1A1 gene and the exon 12 of G6PD gene were amplified by PCR. The products of PCR were analyzed by direct DNA sequencing. Clones for the mutations of the UGT1A1 gene and the G6PD gene were constructed in order to identify the results of the products of PCR. Seventy-two neonates with unconjugated hyperbilirubinemia (case group) and 65 healthy neonates (control group) were enrolled. The genotypes and allele frequencies of the polymorphisms of UGT1A1 Gly71Arg and UGT1A1 TATA-box were compared between the two groups. The effects of UGT1A1 Gly71Arg, UGT1A1 promoter TATA-box and G6PD gene mutations on the development of neonatal unconjugated hyperbilirubinemia were estimated using logistic regression models. RESULTS: There were significant differences in the genotype distribution of Gly71Arg polymorphism of UGT1A1 gene between the case and control groups (P0.05). The OR and 95%CI values of UGT1A1 Gly71Arg, UGT1A1 TATA-box and G6PD gene mutations associated with the development of neonatal unconjugated hyperbilirubinemia were 5.468 (2.274, 12.818), 0.688 (0.266, 1.778) and 5.081 (1.070, 24.133) respectively. CONCLUSIONS: UGT1A1 Gly71Arg and G6PD gene mutations may be involved in the development of neonatal unconjugated hyperbilirubinemia.
关键词
高未结合胆红素血症 /
尿苷二磷酸葡萄糖醛酸转移酶1A1 /
葡萄糖-6-磷酸脱氢酶 /
基因突变 /
新生儿
Key words
Unconjugated hyperbilirubinemia /
Uridine-diphosphate-glucuronosyltransferase1A1 /
Glucose-6-phosphate dehydrogenase /
Gene mutation /
Neonate
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参考文献
［1］Akaba K, Kimura T, Sasaki A, Tanabe S, Ikegami T, Hashimoto M, et al. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese［J］. Biochem Mol Biol Int, 1998, 46(1): 21-26.
［2］Huang CS, Hung KL, Huang MJ, Li YC, Liu TH, Tang TK. Neonatal jaundice and molecular mutations in glucose-6-phosphate dehydrogenase deficient newborn infants［J］. Am J Hematol, 1996, 51(1): 19-25.
［3］Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS. Risk factors for severe hyperbilirubinemia in neonates［J］. Pediatr Res, 2004, 56（5）: 682-689.
［4］傅雯萍, 刘义.遗传因素在广西新生儿高胆红素血症中的作用［J］. 中华儿科杂志, 2005, 43(10):743-747.
［5］傅雯萍, 刘义.UGT1A1 TATA突变对G6PD缺乏新生儿高胆红素血症的影响［J］. 广西医科大学学报, 2008, 25(2): 262-263.
［6］田桂英, 徐放生, 朱凤霞, 蓝常肇, 韩颖. 新生儿迁延性黄疸与尿苷二磷酸葡萄糖醛酸转移酶基因突变的关系［J］ .实用儿科临床杂志, 2008, 23(2): 129-130.
［7］罗凤珍.新生儿黄疸［M］//邵肖梅,叶鸿瑁，丘小汕.实用新生儿学. 第4版.北京:人民卫生出版社, 2011: 273.
［8］Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for the nongeneticist: hereditary defects of neonatal bilirubin conjugation［J］. Pediatrics, 2003, 111(4 Pt 1): 886-893.
［9］Pirulli D, Giordano M, Puzzer D, Crovella S, Rigato I, Tiribelli C, et al. Rapid method for detection of extra(TA) in the promoter of the bilirubin-UDP-glucuronosyl transferase 1 gene associated with Gilbert syndrome［J］. Clin Chem, 2000, 46(1): 129-131.
［10］Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome［J］. N Engl J Med, 1995, 333(18): 1171-1175.
［11］Sampietro M, Iolascon A. Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes［J］. Haematologica, 1999, 84(2): 150-157.
［12］Raijmakers MT, Jansen PL, Steegers EA, Peters WH. Association of human liver bilirubin UDP-glucuronosyltransferase activity with a polymorphism in the promoter region of the UGT1A1 gene［J］. J Hepatol, 2000, 33(3): 348-351.
［13］Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbert's syndrome［J］. Lancet, 1996, 347(9001): 578-581.
［14］Iyanagi T, Emi Y, Ikushiro S. Biochemical and molecular aspects of genetic disorders of bilirubin metabolism［J］. Biochim Biophys Acta, 1998, 1407(3): 173-184.
［15］Yamamoto A, Nishio H, Waku S, Yokoyama N, Yonetani M, Uetani Y, et al. Gly71Arg mutation of the bilirubin UDP-glucuronosyltransferase 1A1 gene is associated with neonatal hyperbilirubinemia in the Japanese population［J］. Kobe J Med Sci, 2002, 48(3-4): 73-77.
［16］Ferraris A, D'Amato G, Nobili V, Torres B, Marcellini M, Dallapiccola B. Combined test for UGT1A1-3279T->G and A(TA)nTAA polymorphisms best predicts Gilbert's syndrome in Italian pediatric patients［J］. Genet Test, 2006, 10(2): 121-125.
［17］Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism?［J］. Proc Natl Acad Sci U S A, 1998, 95(14): 8170-8174.
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