摘要
目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因检测对临床病因不明新生儿高胆红素血症的诊断价值。方法选取2015年1月—2016年12月入住上海交通大学医学院附属上海儿童医学中心新生儿科胎龄≥37周、出生体重≥2 500g、血清总胆红素水平≥221μmol/L(以间接胆红素为主)且病因不明的高胆红素血症患儿,均行UGT1A1基因检测,采用PCR扩增UGT1A1基因第1~5外显子及其侧翼序列,对其产物进行DNA测序。根据最常见基因突变位点Gly71Arg(211G→A)(以下简称G71R位点)突变情况将患儿分组,比较各组间患儿的一般情况(性别构成、产式、喂养方式、胎龄、出生体重、胎次、产次、入院日龄)和血清总胆红素峰值。比较不同入院日龄、不同喂养方式患儿UGT1A1基因突变频率和血清总胆红素峰值,以及母乳喂养不同G71R位点突变患儿的血清总胆红素峰值。结果共纳入180例患儿,共检出UGT1A1基因突变位点12个,UGT1A1基因总基因突变频率为73.33%(132/180)。最常见的基因突变位点是G71R,其基因突变频率为63.89%(115/180)。Gly54Glu(161G→A)、Alab1Gly(182C→G)、Pro82Ser(244C→T)、Leu179Gln(536T→A)、Asn400His(1198A→C)是新发现的UGT1A1基因突变位点。根据最常见G71R位点突变情况分为无基因突变组(48例)、G71R单位点纯合突变组(38例)、G71R单位点杂合突变组(59例)、G71R复合杂合突变组(18例)。无基因突变组患儿入院日龄显著小于G71R复合杂合突变组(P<0.05),血清总胆红素峰值显著低于G71R单位点纯合突变组(P<0.05)。入院日龄<7d(98例)患儿的UGT1A1基因突变频率、血清总胆红素峰值均显著低于入院日龄≥7d患儿(82例,P值均<0.05);母乳喂养(110例)患儿的血清总胆红素峰值显著高于混合喂养(56例)和人工喂养患儿(14例,P值均<0.05)。母乳喂养无基因突变组的血清总胆红素峰值显著低于G71R单位点纯合突变组(P<0.05)。多元线性回归分析结果显示,喂养方式(回归系数为0.303)、G71R位点突变(回归系数为0.178)、入院日龄(回归系数为0.163)是影响血清总胆红素峰值的危险因素(P值均<0.05)。结论 UGT1A1基因检测对病因不明的新生儿高胆红素血症有一定的诊断价值,其中G71R位点突变最常见,且该位点突变、母乳喂养和入院日龄≥7d对高胆红素血症新生儿的血清总胆红素峰值存在影响。
Objective To explore the role of the uridinediphosphate glucuronosyl transferase 1A1 （UGT1A 1） gene detection in the diagnosis of etiology-unknown neonatal hyperbilirubinemia. Methods Neonates with unknown-cause hyperbilirubinemia and gestational age≥ 37 weeks, birth weight≥ 2 500 g, total serum bilirubin （TSB）≥221 μmol/L （mainly elevated indirect bilirubin） were admitted to our department from January 20T5 to December 2016 and retrospectively reviewed in this study. All of them performed UGT1A 1 gene test. Exon 1 --5 of UGT1A 1 gene and their flanking sequences were amplified by polymerase chain reaction （PCR）, and the mutation of UGT1A 1 gene was screened by direct DNA sequence measurement. The patients were groupedaccording to the most common Gly71Arg（211G→A）, here after called G71R gene mutation. The general condition such as neonatal gender, delivery mode, feeding pattern, gestational age, birth weight, gravida, parity, age of admission and peak TSB were compared among different groups. The UGT1A1 gene mutation and peak TSB between patients with different ages of admission and different feeding patterns were also compared. Meanwhile, the peak TSB was assessed in breastfeeding neonates with different G71R mutation. Results A total of 180 neonates were enrolled in this study, and 12 mutation sites of UGT1A 1 gene were found. The mutation rate was 73.33% （132/180）. G71R was the most common gene mutation site, and its mutation rate was 63.89% （115/ 180）. The novel UGT1A1 gene mutation sites Gly54Glu（ 161G→A）, Ala61Gly （1820→G）, Pro82Ser（244C→T）, Leu179GIn（536T→A）, Asn400His（ 1198A→C）. The patients were assigned to non-mutation group （ n = 48）, G71R single site homozygous mutation group （n = 38）, G71R single site heterozygous mutation group （n = 59）, and G71R compound homozygous mutation group （n = 18）. Compared with those in the non-mutation group, the age of admission in the G71R compound homozygous mutation group and peak TSB in the G71R single site homozygous mutation group significantly increased （P〈0. 05）. UGT1A1 gene mutation frequency and peak TSB in the neonates with age of admission〈7 days （n = 98） were significantly lower than those in the neonates with age of admissionS7 days （n = 82, P 〈 0.05）. The peak TSB in breast feeding neonates （n = 110） was significantly higher than that in artificial feeding neonates （n = 14） and mixed feeding neonates （n = 56, P〈0.05）. The peak TSB in breastfreeding neonates without gene mutation is significantly lower than with G71R single site homozygous gene mutation （P〈0.05）. Multiple linear regression analysis showed that feeding pattern （β = 0. 303）, G71R mutation （β = 0. 178） and admission age （β= 0. 163） were risk factors for serum TSB （ P^0.05）. Conclusion It has certain diagnostic value to perform the UGT1A1 gene test for clinical etiology-unknown neonatal hyperbilirubinemia. （371R is the most common site of UGT1A 1 gene mutation. G71R mutation, breastfeeding and admission age≥7 days are the impact factors for the peak TSB of neonatal hyperbilirubinemia.
出处
《上海医学》
北大核心
2017年第10期608-613,共6页
Shanghai Medical Journal
