广西黑衣壮族高胆红素血症新生儿UGT1A1基因突变分析

目的 探讨广西黑衣壮族高胆红素血症新生儿尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）基因的突变分布特点及其与高胆红素血症的关系。方法 提取黑衣壮族高胆红素血症新生儿（病例组）及对照组新生儿血液基因组DNA各100例,对UGT1A1 启动子TATA盒及所有外显子进行PCR扩增及直接测序。结果 检测到UGT1A1 启动子TATA盒（TA）7插入突变、第1外显子G71R错义突变及第5外显子中4个SNP位点（rs199539868、rs114982090、rs1042640、rs8330）。病例组的G71R等位基因频率显著高于对照组（PP>0.05）。Logistic回归分析显示UGT1A1 TATA盒、G71R、rs1042640及rs8330对新生儿高胆红素血症发生的OR值（95%CI）分别为0.846（0.440,1629）、3.932（1.745,8.858）、0.899（0.364,2.222）。结论 UGT1A1基因（TA）7插入突变与G71R错义突变是广西黑衣壮族高胆红素血症新生儿的常见突变类型,4个SNP 位点（rs199539868、rs114982090、rs1042640、rs8330）为国内首次报道。UGT1A1 G71R错义突变是广西黑衣壮族新生儿高胆红素血症的危险因素。     

新生儿重症高胆红素血症与UGTlA1基因多态性的相关性研究

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因G1y71Arg多态性对新生儿重症高胆红素血症的影响。方法选取2014年7月至2015年7月我院收治的重症高胆红素血症新生儿为高胆组,生理性黄疸新生儿为对照组。采用聚合酶链反应扩增UGT1A1基因第一外显子,并对其产物进行DNA测序。结果高胆组和对照组各纳入60例,两组性别、出生体重、日龄、血型、入院时肝功能比较,差异均无统计学意义(P>0.05),入院时总胆红素值比较,差异有统计学意义(P<0.05)。两组UGT1A1基因第一外显子G1y71Arg基因型Arg/Arg、Arg/Gly、Gly/Gly频率分别为43.3%、50.0%、6.7%和3.3%、65.0%、31.7%,基因型分布差异有统计学意义(x~2=31.528,P<0.001);高胆组Gly71Arg中Arg等位基因频率为68.3%,显著高于对照组35.8%,差异有统计学意义(x~2=25.394,P<0.001)。UGT1A1基因Gly71Arg多态性是新生儿高胆红素血症的影响因素(OR=3.864,95%CI2.261~6.604)。结论 UGT1A1基因Gly71Arg多态性可能与新生儿重症高胆红素血症相关。     

UGT1A1基因多态性分析与新生儿高胆红素血症的关系

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因Gly71Arg突变与新生儿高胆红素血症的关系。方法选择2009年6月至2011年4月深圳市第五人民医院出生的新生儿,分为高胆红素血症组(观察组)和对照组。采用突变特异性扩增系统法检测UGT1A1基因Gly71Arg突变。结果观察组168例,对照组157例,UGT1A1基因Gly71Arg突变中A等位基因频率分别为0.27和0.12,差异有统计学意义(χ2=22.58,P<0.05)。与携带G/G基因型新生儿相比,Gly71Arg突变(A/A+G/A)可增加新生儿高胆红素血症的发病风险(OR=2.71,95%CI1.68～4.38)。结论 UGT1A1基因Gly71Arg突变与新生儿高胆红素血症发生相关。     

维吾尔族新生儿高未结合胆红素血症UGT1A1基因突变分析

目的研究维吾尔族高未结合胆红素血症新生儿的尿苷二磷酸葡萄糖醛酸转移酶1A1(uridine diphosphate glucuronosyltransterase 1A1,UGT1A1)基因突变情况。方法选取2013—2016年新疆维吾尔自治区人民医院住院治疗的34例高未结合胆红素血症患儿为试验组,选取同期11例生理性黄疸患儿为对照组。提取外周血基因组DNA,扩增UGT1A1基因的编码序列及启动子区,对扩增产物进行测序确定基因突变。结果病例资料中发生UGT1A1基因突变共7种,分别为第1外显子Gly71Arg(G71R),Val674Gly(V225G),第3外显子Pro1091Leu(P364L),Asp1195Asn(D399N),第5外显子Pro1352Leu(P451L),Tyr486Asp(Y486D),TATAA盒TA插入转录突变。其中G71R及TATAA盒TA插入转录突变发生频率最高,但试验组及对照组突变频率差异无统计学意义(χ~2=1.681,P=0.195;χ~2=0.214,P=0.643);在维吾尔族与汉族对照组中G71R突变频率差异无统计学意义(χ~2=0.253,P=0.615),TATAA盒TA插入转录突变频率差异有统计学意义(χ~2=4.675,P=0.031)。结论新疆维吾尔族新生儿中UGT1A1基因突变存在多种类型;TATAA盒TA插入转录突变频率均明显高于当地汉族新生儿。     

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

目的 探讨胆红素-尿苷二磷酸葡萄糖醛酸转移酶(UGT1A1)基因Gly71Arg变异与北京地区汉族新生儿黄疸发病的关系.方法 应用聚合酶链反应-限制性长度多态性方法测定无亲缘关系的北京地区汉族新生儿黄疸[病例组,n=96,总胆红素(307.6±38.5)μmoL/L,未结合胆红素(292.9±35.9)μmoL/L]与健康对照组[n=101,总胆红素(131.2±42.1)μmoL/L,未结合胆红素(126.3±39.7)μmoL/L]UGT1A1 Gly71Arg基因多态性的基因型,并检验二组基因型分布、等位基因频率差异和UGT1A1基因Gly71Arg变异对病例组总胆红素的效应.采用SPSS 10.0软件进行统计学分析,组间差异采用t检验及协方差分析,基因型频率采用χ2检验.结果 病例组新生儿UGT1A1 Gly71Arg基因多态性频率与健康对照组存在明显差异(χ2=9.47 P<0.01),Arg等位基因频率明显高于健康对照组(χ2=10.34 P<0.01).病例组新生儿UGT1A1 Gly71Arg基因多态性Arg等位基因纯合子携带者总胆红素水平明显高于杂合子携带者和非携带Arg等位基因者(Pa<0.001),采用协方差分析校正胎龄和出生体质量影响后,Arg等位基因纯合子携带者总胆红素水平仍明显高于杂合子携带者和非携带Arg等位基因者(Pa<0.001).结论 UGT1A1基因Gly71Arg变异可能是北京地区汉族新生儿黄疸的发病原因之一,该基因多态性Arg等位基因纯合子携带者黄疸更严重.     

新生儿黄疸与胆红素-尿苷二磷酸葡萄糖醛酸转移酶和有机阴离子转运因子2基因突变的关系

目的 探讨胆红素-尿苷二磷酸葡萄糖醛酸转移酶（UGT1A1）基因Gly71Arg突变和有机阴离子转运因子2（OATP2）基因Asn130Asp突变与新生儿黄疸发病的关系。方法应用聚合酶链反应-限制性长度多态性方法测定无亲缘关系的汉族新生儿黄疸组与健康对照组的UGT1A1Gly71Arg和OATP2Asn130Asp基因多态性的基因型,并检验两组基因型分布、等位基因频率差异,应用Logistic多元回归分析两种基因突变对新生儿黄疸的OR值和95%CI。结果 新生儿黄疸组UGT1A1Gly71Arg和OATP2Asn130Asp基因多态性的基因型分布与对照组差异有统计学意义（χ^2=9.47和6.16,P=0.002和0.046）,Arg和Asp等位基因频率明显高于对照组（χ^2=10.34和6.85,P=0.001和0.009）;logistic多元回归分析UGT1A1基因Gly71Arg和OATP2基因Asn130Asp突变对新生儿黄疸的OR值和95%CI分别为2.66（1.38～4.51）和2.32（1.23～3.95）（P=0.011和0.024）。结论 UGT1A1基因Gly71Arg和OATP2基因Asn130Asp突变可能参与新生儿黄疸的发病。     

北方地区新生儿高胆红素血症患儿UGT1A1和OATP2基因突变的研究

目的了解我国北方地区新生儿高胆红素血症的形成与尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)和有机阴离子转运载体2(OATP2)基因突变的关系。方法应用聚合酶链反应-限制性片段长度多态性方法测定新生儿重症高胆红素血症、高胆红素血症及非高胆红素血症患儿的UGT1A1基因211位点(Gly71Arg)突变及OATP2基因388位点(Asn130Asp)突变,并检验各组基因型分布及等位基因频率差异。应用Logistic回归模型,分析两种基因突变对高胆红素血症的影响。结果重症高胆红素血症组68例,高胆红素血症组95例,对照组63例。重症高胆红素血症组和高胆红素血症组UGT1A1基因211位点突变率和OATP2基因388位点突变率均高于对照组(36.8%、26.8%比14.3%,25.7%、25.8%比9.5%,P均<0.05);重症高胆红素血症组和高胆红素血症组差异无统计学意义(P>0.05)。Logistic回归分析显示,UGT1A1基因211位点突变和OATP2基因388位点突变是新生儿重症高胆红素血症的危险因素,OR值(95%CI)分别为5.052(2.383～10.713)和2.692(1.236～5.862)(P=0.001和0.013)。结论携带UGT1A1基因211位点突变及OATP2基因388位点突变与新生儿高胆红素血症的形成有一定关系。     

广西新生儿胆红素-尿苷二磷酸葡萄糖醛酸转移酶基因Gly71Arg突变的研究

目的　探讨广西新生儿迁延性黄疸与胆红素 尿苷二磷酸葡萄糖醛酸转移酶 (UGT1A1,B UGT)基因Gly71Arg突变的关系。方法　采用常规方法提取广西 2 5例病因不明的迁延性黄疸新生儿及 6 0例正常健康儿DNA ,用聚合酶链反应 (PCR)方法扩增UGT1A1第 1外显子 ,琼脂糖凝胶电泳鉴定产物 ,用等位特异性寡核苷酸探针杂交法 (ASO)检测基因Gly71Arg突变。选部分经ASO检测正常和突变的PCR产物进行DNA测序。结果　 2 5例迁延性黄疸新生儿中 15例UGT1A1基因存在Gly71Arg错义突变 ,即第 2 11位核苷酸有G→A点突变 (G2 11A) ,使第 71位密码子GGA变成AGA ,相应编码的甘氨酸变成精氨酸。 13例为杂合子 ,2例为纯合子 ,等位基因频率 0 34。 6 0例正常健康儿Gly71Arg等位基因频率 0 0 8。迁延性黄疸新生儿等位基因频率较正常健康儿显著增高 (P <0 0 0 0 1)。送检样品测序结果与ASO结果一致。结论　广西存在UGT1A1基因Gly71Arg突变。广西迁延性黄疸患儿与UGT1A1基因Gly71Arg突变密切相关 ,提示这可能是广西新生儿迁延性黄疸的原因之一     

G-6-PD缺乏新生儿高胆红素血症发病机制的研究进展

在我国南方 ,葡萄糖 6 磷酸脱氢酶 (G 6 PD)缺乏是新生儿高胆红素血症的主要病因。新生儿G 6 PD缺乏的最大危害为可引起高胆红素血症与核黄疸。G 6 PD缺乏所致新生儿高胆红素血症的发病机制是多因素共同作用的结果 ,既往强调溶血是其发病的主因 ,目前认为胆红素结合能力不足也参与发病。UGT1A1基因突变导致胆红素结合障碍是 2 1世纪的研究热点。不少学者提出UGT1A1基因突变与G 6 PD缺乏二者对高胆红素血症起协同作用。     

广西三江县侗族新生儿UGT1A1基因变异分析北大核心CSCD

目的探讨广西柳州三江县侗族新生儿UGT1A1基因变异特点及其与侗族新生儿高胆红素血症发生的关系。方法前瞻性选取2021年1月至2022年1月于三江县人民医院新生儿科诊断不明原因高胆红素血症的新生儿84例为研究对象;另选取同期健康新生儿60例纳入健康对照组。提取两组新生儿外周血基因组DNA,对UGT1A1启动子区TATA盒和外显子1进行PCR扩增并进行基因测序。结果病例组检测出33例G71R错义突变,突变率为39%,A等位基因频率(21%)显著高于健康对照组(10%)(P<0.05)。携带G71R错义突变基因型的侗族新生儿发生高胆红素血症的风险是携带野生型的健康新生儿的2.588倍(P<0.05)。Hardy-Weinberg遗传平衡检验结果提示两组新生儿UGT1A1 G71R位点基因型符合遗传平衡(P>0.05)。结论UGT1A1 G71R突变是三江县侗族新生儿高频基因变异类型,且G71R错义突变与侗族新生儿发生高胆红素血症相关。     

Relationship between bilirubin UDP-glucuronosyl transferase 1A1 gene and neonatal hyperbilirubinemia

The variation rate within the coding region of UDP-glucuronosyl transferase 1A1 (UGT1A1) gene in Taiwan Chinese was found to be 29.3%. This study sought to determine whether that high variation rate of UGT1A1 gene is a risk factor for neonatal hyperbilirubinemia. The study subjects consisted of 123 newborn infants suffering from unconjugated hyperbilirubinemia who had no known risk factors for hyperbilirubinemia and 218 healthy control neonates. The promoter area, exons 1 to 4, coding region of exon 5, and the flanking intronic regions in UGT1A1 gene were determined by the PCR in all subjects. Wild UGT1A1 gene, variation in the promoter, variation at nucleotide 211, variation at nucleotide 1091, and compound heterozygous variation of UGT1A1 gene were found. The percentage of neonates with wild UGT1A1 gene and the percentage of neonates with variation at nucleotide 211 were significantly different between the study subjects and controls. The percentages with bilirubin >or=342 micro M (20.0 mg/dL) and with persistent hyperbilirubinemia in the subjects carrying homozygous variation at nucleotide 211 (Gly71Arg) were significantly higher than the neonates carrying wild type or other genotypes. In conclusion, this study has demonstrated that variation at nucleotide 211 of the UGT1A1 gene is a risk factor for the development of neonatal hyperbilirubinemia. Pediatricians should closely follow hyperbilirubinemic newborn infants who carry homozygous 211 G to A variation in UGT1A1 gene.     

Association of neonatal hyperbilirubinemia with uridine diphosphate‐glucuronosyltransferase 1A1 gene polymorphisms: Meta‐analysis

Background: Recent reports have suggested that genetic factors, including mutations in the coding region or promoter of uridine diphosphate‐glucuronosyltransferase 1A1 (UGT1A1) may increase the risk of development of neonatal hyperbilirubinemia, but the relationship has not been evaluated on systematic review or meta‐analysis. Methods: A meta‐analysis of observational studies reporting effect estimates and 95% confidence intervals (95%CI) was conducted on the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. Results: A total of 27 eligible studies were identified. In total, 17 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, which indicated that these polymorphisms were associated with an increased risk of neonatal hyperbilirubinemia (A/A+G/A vs G/G: odds ratio [OR], 2.70; P= 0.00; 95%CI: 2.22–3.29; I²= 0.0%; P_{heterogeneity}= 0.55). Subgroup analyses by ethnicity validated this correlation in Asian, but not in Caucasian, populations (OR, 1.74; P= 0.10; 95%CI: 0.90–3.35; I²= 0.00%; P_{heterogeneity}= 0.67). Furthermore, 18 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphisms. These studies concluded that TATA promoter variants were not associated with an increased risk of neonatal hyperbilirubinemia (7/7 + 6/7 vs 6/6: OR, 1.13; P= 0.23; 95%CI: 0.93–1.37; I²= 80.0%; P_{heterogeneity}= 0.00). Conclusion: UGT1A1 Gly71Arg polymorphisms are a risk factor for developing neonatal hyperbilirubinemia in Asian, but not Caucasian, subjects. UGT1A1 TATA promoter polymorphisms were not associated with an increased risk of neonatal hyperbilirubinemia in Asian subjects, but results from the Caucasian population were conflicting and require further epidemiological investigation.     

Chemotherapy-induced unconjugated hyperbilirubinemia caused by a mutation of the bilirubin uridine-5'-diphosphate-glucuronosyltransferase gene

Chemotherapy for malignant neoplasms sometimes causes unconjugated hyperbilirubinemia in the absence of liver dysfunction. We analyzed the association of chemotherapy-induced hyperbilirubinemia with mutations of the bilirubin uridine-5'-diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1) from two leukemic patients in whom chemotherapy resulted in a hyperbilirubinemic response. We isolated genomic DNA from peripheral blood samples and amplified UGT1A1 by polymerase chain reaction. The amplified DNA fragments were analyzed by direct sequencing. The genes of the two patients revealed an identical heterozygous missense mutation in exon 1 (211G-->A: G71R). This UGT1A1 mutation may be the basis of chemotherapy-induced unconjugated hyperbilirubinemia.     

胆红素-尿苷二磷酸葡萄糖醛酸基转移酶G71R基因型对广西地区新生儿黄疸程度的影响

目的 探讨胆红素-尿苷二磷酸葡萄糖醛酸基转移酶1A1(UGT 1A1)基因突变对广西新生儿黄疸的影响.方法 收集73例高胆红素血症新生儿及31例健康新生儿外周血,应用突变特异性扩增系统(amplification refractory mutation system,ARMS)法及直接测序法对所有新生儿行UGT1A1基因G71R突变检测,分析胆红素脑病发生率,胆红素峰值及总胆红素(total serum bilirubin,TSB)>20 mg/dl的机会比.结果 (1)本研究人群G71R等位基因频率为0.1915,病例组为0.2329,健康对照组为0.097,病例组的G71R等位基因频率显著高于健康对照组(P<0.05).(2)G71R纯合子的胆红素脑病发病率及72 h的TSB浓度(28.57%,23.12±4.58 mg/dl)均高于野生型组(0%,17.68±2.69 mg/dl),差异有统计学意义(P<0.001).(3)G71R纯合子组中5例的TSB>20 mg/dl,G71R纯合子TSB>20 mg/dl的机会比(odds ratio,OR)为7.955,总体机会比95%可信区间(confidence interval,CI)为(1.349,46.899).结论 G71R突变与本地新生儿黄疸的发病存在相关性.G71R纯合子的胆红素脑病发病率及生后72 h的TSB较对照组及野生型增高.G71R纯合子发生TSB>20 mg/dl的危险性是野生型的7.955倍.     

Neonatal hyperbilirubinemia and Gly71Arg mutation of UGT1A1 gene: a Chinese case-control study followed by systematic review of existing evidence

Aim: To determine whether the UDP‐glucuronosyltransferase 1A1 gene (UGT1A1) Gly71Arg (211G>A) mutation is associated with neonatal hyperbilirubinemia. Methods: The study consisted of two parts. The case–control study included 112 hyperbilirubinemic infants and 105 control subjects from the Fifth People’s Hospital of Shenzhen. Polymerase chain reaction, restriction fragment length polymorphisms and agarose gel electrophoresis techniques were used to detect the UGT1A1 211G>A mutation. Meta‐analyses was performed to assess the association between neonatal hyperbilirubinemia and UGT1A1 211G>A. Results: Our case–control study revealed that the likelihood of developing neonatal hyperbilirubinemia was 2.65 times higher in the infants with the A allele in the UGT1A1 211G>A than in the infants with the G allele (95% CI, 1.60–4.39). Meta‐analyses (including data from our study) revealed that UGT1A1 211G>A is associated with an increased risk of neonatal hyperbilirubinemia [ odds ratio (OR), 2.37; 95% CI, 2.05–2.74]. In the subgroup analyses based on ethnicity, significantly elevated risks were found in Asian populations (OR, 2.45; 95% CI, 2.10–2.84), but no significant associations were present in Caucasian populations (OR, 1.54; 95% CI, 0.87–2.75). Conclusion: The UGT1A1 211G>A mutation is associated with neonatal hyperbilirubinemia in Asians, but not in Caucasians.     

Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population

BACKGROUND: Gilbert syndrome is caused by defects in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. These mutations differ among different populations and many of them have been found to be genetic risk factors for the development of neonatal jaundice. OBJECTIVES: The objective was to determine the frequencies of the following mutations in the UGT1A1 gene: A(TA)7TAA (the most common cause of Gilbert syndrome in Caucasians), G71R (more common in the Japanese and Taiwanese population), and G493R (described in a homozygous Malay woman with Crigler-Najjar syndrome type 2) in a group of Malaysian babies with hyperbilirubinemia and a group of normal controls. METHODS: The GeneScan fragment analysis was used to detect the A(TA)7TAA variant. Mutation screening of both G71R and G493R was performed using denaturing high performance liquid chromatography. RESULTS: Fourteen out of fifty-five neonates with hyperbilirubinemia (25%) carried the A(TA)7TAA mutation (10 heterozygous, 4 homozygous). Seven out of fifty controls (14%) carried this mutation (6 heterozygous, 1 homozygous). The allelic frequencies for hyperbilirubinemia and control patients were 16 and 8%, respectively (p=0.20). Heterozygosity for the G71R mutation was almost equal among both groups (5.5% for hyperbilirubinemia patients and 6.0% for controls; p=0.61). One subject (1.8%) in the hyperbilirubinemia group and none of the controls were heterozygous for the G493R mutation (p=0.476). CONCLUSIONS: The A(TA)7TAA seems more common than the G71R and G493R mutations in the Malaysian population.     

Cord blood bilirubin level in relation to bilirubin UDP-glucuronosyltransferase gene missense allele in Chinese neonates

AIM: To investigate bilirubin UDP-glucuronosyltransferase (UGT1A1) gene allele in healthy Chinese neonates, their cord bilirubin level and the subsequent hyperbilirubinemia to determine relationships among them. METHODS: Cord blood of 48 neonates was obtained to determine the exon 1 of UGT1A1 gene, total serum bilirubin, albumin, glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT) and haemoglobin (Hb) concentration. Neonatal jaundice was assessed by measurement of transcutaneous bilirubin (TCB) and serum bilirubin. Neonates were divided into two groups according to mutant or normal allele to compare the variables. RESULTS: Nineteen infants had the nucleotide 211 G-->A allele, 3 had the heterozygous variation (686C-->A, 845 A-->T, 231G-->A). In the 211 A allele group, cord bilirubin was significantly higher than in the 211 G allele group (p = 0.034), but there were no differences in albumin (p = 0.678), GPT (p = 0.460), GOT (p = 0.440) and Hb (p = 0.886). The TCB (at 48, 96 h), the frequency of the hyperbilirubinemia and prolonged jaundice were also significantly higher in the 211 A allele group. CONCLUSIONS: The UGT1A1 gene codon G71R allele is a risk factor for neonatal hyperbilirubinemia in the Chinese population. Its effect on bilirubin metabolism may present early on, as well as late in foetal life.