不明原因新生儿高胆红素血症与UGT1A1基因突变的关系

Relationship between unexplained neonatal hyperbilirubinemia and UGT1A1 gene mutation

目的:探讨不明原因新生儿高胆红素血症与胆红素—尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因编码的启动子区TATA盒及第1外显子区基因突变类型的关系。方法:对100例不明原因高胆红素血症新生儿(病例组)和100例健康新生儿(对照组)进行全基因组DNA提纯,对UGT1A1基因启动子区及第1外显子区进行PCR扩增、凝胶电泳、基因测序。分析比较两组的UGT1A1基因突变类型及等位基因频率。结果:两组间在启动子区存在TATA盒(TA)7插入突变,在编码区第1外显子区存在G71R错义突变和P229Q错义突变。两组间G71R错义突变等位基因频率分别为18.5%、5.0%,病例组的G71R基因型分布及等位基因频率均高于对照组(P<0.001)。两组TATA盒(TA)7插入突变和P229Q错义突变基因型分布及等位基因频率比较,差异均无统计学意义(P>0.05)。Logistic回归分析显示UGT1A1 TATA盒(OR:1.362,95%CI:0.573~3.237)、G71R(OR:4.540,95%CI:2.070~9.958)、P229Q(OR:0.614,95%CI:0.119~3.161),UGT1A1 G71R错义突变是不明原因新生儿高胆红素血症的危险因素(P<0.001)。结论:本研究共检测出3种UGT1A1基因突变类型:(TA)7插入突变、G71R错义突变和P229Q错义突变;其中UGT1A1 G71R错义突变是不明原因新生儿高胆红素血症的危险因素。

Objective:To explore the relationship between neonatal hyperbilirubinemia and the type of gene mutation in uridine diphosphate glucuronosyltransferase 1A1(UGT1A1)gene encoding TATA box in promoter region and first exon region.Methods:Genomic DNA was purified from 100 newborns with unexplained hyperbilirubinemia(case group)and 100 healthy newborns(control group).The promoter region and first exon region of UGT1A1 gene were amplified by PCR,gel electrophoresis and gene sequencing.The mutation types and allele frequencies of UGT1A1 gene were analyzed and compared between the two groups.Results:There was TATA box(TA)7 insertion mutation in the promoter region,G71R missense mutation and P229Q missense mutation in the first exon of the coding region between the two groups.The allele frequencies of G71R missense mutations between the two groups were 18.5%and 5.0%,respectively.The distributions of G71R genotypes and allele frequencies in the case group were significantly higher than those in the control group(P<0.001).There was no significant difference in the genotype distribution and allele frequency of TATA box(TA)7 insertion mutation and P229Q missense mutation between the two groups(P>0.05).Logistic regression analysis showed that UGT1A1 TATA box(OR:1.362,95%CI:0.573-3.237),G71R(OR:4.540,95%CI:2.070-9.958),P229Q(OR:0.614,95%CI:0.119~3.161).UGT1A1 G71R missense mutation was risk factors for unexplained neonatal hyperbilirubinemia(P<0.001).Conclusion:In this study,three types of UGT1A1 gene mutations are detected:(TA)7 insertion mutation,G71R missense mutation and P229Q missense mutation,among which UGT1A1 G71R missense mutation is a risk factor for unexplained neonatal hyperbilirubinemia.