Genetic polymorphisms in Thai neonates with hyperbilirubinemia

Aim:  Polymorphisms of the UGT1A1 gene, SLCO1B1 gene and GST gene have been associated with significant hyperbilirubinemia. We would like to determine whether the variation of UGT1A1 gene, SLCO1B1 gene and GST gene may play a significant role in neonatal hyperbilirubinemia in Thai infants.
Methods:  Ninety-one study subjects (hyperbilirubinemic group) and 86 control subjects were studied.
Results:  The cause of neonatal hyperbilirubinemia could not be identified in 64 infants (70.3%), ABO blood group incompatibility in 14.3% and Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in 8.8%. In the hyperbilirubinemic group, 23 of 91 (25.3%) infants demonstrated variant of UGT1A1 at nucleotides (nt) 211 as compared to 6 of 86 (7%) in the control group (p = 0.001). There were no significant differences between groups in the variants UGT1A1 at nt 686, SLCO1B1 gene at nt 388, 463 and the GST gene. Male infants with G-6-PD deficiency were associated with hyperbilirubinemia (21.2% vs. 4.8% in the control group) with an odds ratio (OR) of 5.37 (p =0.02). The relationship between G-6-PD and variant in UGT1A1 gene at nt 211 could not be determined.
Conclusion:  Thai infants with variant in the UGT1A1 at nt 211 or with G-6-PD deficiency are at higher risk for developing neonatal hyperbilirubinemia.     

遗传因素在广西新生儿高胆红素血症中的作用

目的探讨UGT1A1 G71R突变、OATP2A388G突变和G-6-PD缺乏对在广西新生儿高胆红素血症发病的作用。方法用四氮唑蓝定量法（NBT法）测定G-6-PD酶活性。聚合酶链反应-等位基因特异性寡核苷酸探针点杂交（PCR-ASO）法确定G71R基因型。限制性片段长度多态性分析（RFLP）检测A388G基因型。测定109例新生儿脐血的G-6-PD活性及G71R基因型,其中101例同时检测了A388G基因型。据G-6-PD活性及G71R或A388G基因型分组,分析UGT1A1G71R突变、OATP2A388G突变和G-6-PD缺乏与足月新生儿高胆红素血症之间关系。结果G71R等位基因频率在G-6-PD缺乏组为22．03％,在G-6-PD正常组为28．00％。G-6-PD缺乏共存有G71R突变纯合子或杂合子的新生儿高胆红素血症发生率（95．50％）高于G-6-PD正常且G71R为野生型的新生儿（53．90％）,x^2=10．45,P=0．0012,前者发生高胆红素血症的机会比（95％可信区间）[OR（95％CI）]为18．00（2．12,152．9）。A388G等位基因频率在G-6-PD缺乏组为20．O％,在G-6-PD正常组为18．5％。G-6-PD缺乏共存有A388G突变新生儿的高胆红素血症发生率（90．0％）高于G-6-PD正常且A388G为野生型的新生）L（44．80％）,X2=10．39,P=0．0013,前者发生高胆红素血症的伽（95％CT）为11．08（2．15,56．48）。结论G71R突变与G-6-PD缺乏共存或A388G突变与G-6-PD缺乏共存对广西足月新生儿高胆红素血症的发生有协同作用。     

Homozygous variant of UGT1A1 gene mutation and severe neonatal hyperbilirubinemia

Background: The aim of the present study was to compare, in a case–control study, the prevalence of nucleotide 211 guanine to adenine (G→A) mutation of uridine diphosphoglucuronosyl transferase (UGT1A1) gene in Malaysian Chinese newborns with and without severe hyperbilirubinemia (total serum bilirubin >250 µmol/L during first 48 h of life or ≥300 µmol/L thereafter), and to determine whether this mutation was a significant risk factor associated with severe hyperbilirubinemia. Methods: Seventy‐four term infants of Chinese descent admitted with severe hyperbilirubinemia were recruited. Infants without severe hyperbilirubinemia (n = 125) were randomly selected from among healthy Chinese term infants. UGT1A1 nucleotide 211 polymorphism was assayed using the Taqman single nucleotide polymorphism genotyping method. Using gestational age, types of feeds, G6PD mutation, G6PD enzyme levels, and UGT1A1 gene mutation status as independent variables, logistic regression analysis was carried out to determine the significant risk factors associated with severe hyperbilirubinemia. Results: UGT1A1 gene mutation was significantly more common among hyperbilirubinemic infants (39.2%) than controls (25.6%; P = 0.04). Gestational age (adjusted odds ratio [OR], 0.7; 95% confidence intervals [CI]: 0.5–0.9; P = 0.01), G6PD mutation (adjusted OR, 7.2; 95%CI: 2.7–19.0; P < 0.0001), exclusive breast‐feeding (adjusted OR, 11.7; 95%CI: 2.7–49.9; P = 0.001), and homozygous variant of UGT1A1 gene mutation (adjusted OR, 32.2; 95%CI: 3.8–273.2; P = 0.001) were significant risk factors. Heterozygous variant of UGT1A1 gene mutation, actual levels of G6PD enzyme, and mixed feeding were not. Conclusion: Homozygous variant of nucleotide 211 G→A mutation of UGT1A1 gene is a significant risk factor associated with severe hyperbilirubinemia among Malaysian Chinese newborns.     

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.     

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.     

Neonatal hyperbilirubinemia and the bilirubin uridine diphosphate-glucuronosyltransferase gene: The common −3263T > G mutation of phenobarbital response enhancer module is not associated with the neonatal hyperbilirubinemia in Japanese

BACKGROUND: Neonatal hyperbilirubinemia is frequent and severe in Japanese newborns. Previously, it has been reported that half of the Japanese neonates with severe hyperbilirubinemia carried the 211G > A (p.G71R) mutation of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene causing Gilbert syndrome. Recently, it was reported that the -3263T > G mutation in the phenobarbital response enhancer module in UGT1A1 was associated with the majority of cases of Gilbert syndrome. The gene frequency of the -3263T > G mutation was determined and the relation with neonatal hyperbilirubinemia in Japanese was studied. METHODS: UGT1A1 in 119 neonates born at Yamagata University Hospital, Yamagata, Japan, and 26 subjects who had undergone phototherapy due to severe hyperbilirubinemia at four other hospitals were studied. The gene frequency of -3263T > G mutation in Japanese, Korean, Chinese and German healthy adult controls was also determined. Hyperbilirubinemia was assessed with a Jaundice Meter and UGT1A1 was analyzed by sequence determination or restriction enzyme method. RESULTS: The gene frequency of the -3263T > G mutation was 0.26 in Japanese subjects and was similar to the prevalence in Korean, Chinese and German populations. However, there was no significant increase in the gene frequency of the mutation in the neonates who required phototherapy for hyperbilirubinemia compared to that in the neonates without severe hyperbilirubinemia. In addition, neonates with or without the mutation did not show a significant change in the level of bilirubin and the mutation also did not show a synergic effect with the 211G > A mutation on the level of bilirubin. CONCLUSION: The -3263T > G mutation is not likely to be associated with the neonatal hyperbilirubinemia in Japanese.     

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.     

Heme oxygenase-1 gene variants and hyperbilirubinemia risk in North Indian newborns

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in bilirubin metabolism, and its genetic variant may modulate hyperbilirubinemia risk in neonates. The aim of the present study was to assess the association between heme oxygenase-1 gene variants and hyperbilirubinemia risk in Indian newborns. In a prospective case–control study, we analyzed (GT)_n repeats and g.-413A>T variant of HO-1 gene and UGT1A1 gene variants in 100 case newborns with total serum bilirubin (TSB) levels exceeding 95th percentile and 100 control newborns with TSB levels below 75th percentile on the hour-specific bilirubin nomogram of the American Academy of Pediatrics. Study population consisted of term (37–41 weeks) and late preterm (34–36 weeks) newborns during the first 2 weeks of age. In our analysis, the (GT)_n allele was highly polymorphic, ranging in number from 15 to 40. The incidence of short (GT)_n allele (≤20) was significantly higher in neonates with hyperbilirubinemia than in controls. Although g.-413A>T variant was widely prevalent in the study population, no difference was noted in its prevalence between cases and controls. Short (GT)_n repeats of HO-1 gene, c.211G>A variant of UGT1A1 gene, and excessive weight loss were independent risk factors for neonatal hyperbilirubinemia. In the presence of two or more risk factors, the odds of developing neonatal hyperbilirubinemia were high. Shorter (GT)_n genotype in the promoter region of HO-1 gene is significantly associated with hyperbilirubinemia risk in Indian newborns. This genotype may interact with other genetic and clinical risk factors to further potentiate hyperbilirubinemia risk in newborns.     

UGT1A1基因多态性与新生儿黄疸遗传关联性的Meta分析

目的 评价不同人群UGT1A1基因GLY71ARG多态性、TATA重复多态性与新生儿黄疸的遗传关联性。方法 制定原始文献的纳入标准、排除标准及检索策略,检索PubMed、EMBASE、Web of sciences、Cochrance图书馆、中国期刊全文数据库、万方数据库、维普中文科技期刊数据库及中国生物医学文献数据库,检索时间均为建库至2010年2月。获得UGT1A1基因GLY71ARG多态性、TATA重复多态性与新生儿黄疸遗传关联性的相关文献。以新生儿黄疸为病例组。依据NHI-NHGRI研究工作组2007年制定的遗传关联性研究报告规范为基础,并依据相关文献选取其中的14条标准用于文献质量评价。以基因型和等位基因频率为指标,采用RevMan 5.0软件进行Meta分析,计算合并的OR值及其95%CI。 结果 共检索到相关文献284篇,22篇文献进入Meta分析（英文文献18篇,中文文献4篇）;病例组1 444例,对照组1 835例。按人群构成分为4个亚组：中国,日本,马来西亚和泰国及高加索人群（印度、土耳其和美国）。①GLY71ARG基因型A/A+G/A频率：中国（OR=2.84,95%CI：2.14~3.76）,日本（OR=3.22,95%CI：2.03~5.11）,马来西亚和泰国人群（OR=2.41,95%CI：1.56~3.72）病例组均显著高于对照组;高加索人群（OR=1.98,95%CI：0.49~8.03）病例组与对照组差异无统计学意义。基因型A/A频率：中国（OR=6.47,95%CI：3.24~12.94）,马来西亚和泰国人群（OR=21.01,95%CI：5.21~84.79）病例组均显著高于对照组;日本（OR=3.08,95%CI：1.00~9.49）和高加索人群（OR=5.89,95%CI：0.24~145.49）病例组与对照组差异均无统计学意义。A等位基因频率：中国（OR=2.82,95%CI：2.22~3.58）,日本（OR=2.50,95%CI：1.72~3.62）,马来西亚和泰国人群（OR=3.01,95%CI：2.07~4.37）病例组均显著高于对照组;高加索人群（OR=2.47,95%CI：0.66~9.25）病例组与对照组差异无统计学意义。②TATA基因型7/7+6/7频率：中国（OR=0.59,95%CI：0.36~0.96）和日本人群（OR=0.15,95%CI：0.04~0.51）对照组均显著高于病例组;马来西亚（OR=1.31,95%CI：0.59~2.92）和高加索人群（OR=1.18,95%CI：0.68~2.02）病例组与对照组差异无统计学意义。基因型7/7频率：中国（OR=1.78,95%CI：0.11~28.69）,日本（OR=0.38,95%CI：0.04~3.56）,马来西亚（OR=2.46,95%CI：0.46~13.06）和高加索人群（OR=1.45,95%CI：0.91~2.33）病例组与对照组差异均无统计学意义。等位基因7频率：中国（OR=0.65,95%CI：0.35~1.21）,马来西亚（OR=1.40,95%CI：0.59~3.29）和高加索人群（OR=1.17,95%CI：0.80~1.69）病例组与对照组差异均无统计学意义;日本人群（OR=0.15,95%CI：0.04~0.50）对照组显著高于病例组。结论 现有证据表明UGT1A1基因GLY71ARG多态性与中国、日本、马来西亚及泰国人群新生儿黄疸有关联性;启动子TATA重复多态性与新生儿黄疸无关联性。     

UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因G71R突变与新生儿严重高胆红素血症的相关性。方法采用病例对照研究的方法,病例组为复旦大学附属儿科医院(我院)收治的不明原因严重高胆红素血症(血清总胆红素水平≥342μmol·L-1)新生儿,采用PCR对外周血UGT1A1基因进行检测。对照组为我院新生儿出生缺陷生物样本数据库中血清总胆红素水平221μmol·L-1病例。病例组及对照组新生儿均要求胎龄≥35周,出生体重≥2 500 g。结果病例组和对照组各65例。UGT1A1 G71R是病例组中最常见的突变类型(73.8%,48/65)。对照组UGT1A1 G71R突变位点与既往Meta分析中提取的中国健康新生儿对比,在基因型分布及等位基因频率上差异均无统计学意义(P0.05)。病例组和对照组UGT1A1基因G71R突变中A等位基因频率分别为0.5和0.15,差异有统计学意义(P0.001),把握度为0.993。与携带G/G基因型新生儿相比,UGT1A1 G71R突变(A/A+G/A基因)可增加新生儿严重高胆红素血症的发病风险(OR=7.373,95%CI:3.395~16.008),把握度为1.0。结论 UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关。     

新生儿高胆红素血症与有机阴离子转运体1B1 T521C/A388G多态性的相关性研究

目的 有机阴离子转运体1B1(OATP 1B1)跨膜转运体内非结合胆红素(UCB),其基因变异能显著影响体内胆红素水平.此课题即为研究OATP 1B1基因多态性与新生儿高胆红素血症的相关性.方法 用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法分析220例高胆红素血症新生儿及200名对照者OATP 1B1 T521/A388G基因型,观察基因突变频率及基因型分布、基因多态性与疾病的相关性及对患儿血清总胆红素、结合胆红素、非结合胆红素水平的影响.结果 在高胆红素血症新生儿中,OATP 1B1 T521C等位基因突变频率显著下降,仅为8.2%.野生型的患者比例要显著高于对照组中野生型个体比例,达到84.1%.携带C等位基因的个体患病风险下降(OR=0.530,95%CI=0.328～0.857).血清总胆红素、结合胆红素、非结合胆红素水平在OATP 1B1A388G野生型患者中最高,杂合子次之,突变纯合子最低.结论 OATP 1B1 T521C多态性在新生儿高胆红素血症患儿中存在明显差异,OATP 1B1 A388G多态性显著影响新生儿高胆红素血症患儿血清胆红素水平.OATP 1B1 T521C/A388G是和新生儿高胆红素血症相关的重要基因多态位点.     

211 G to a variation of UDP-glucuronosyl transferase 1A1 gene and neonatal breastfeeding jaundice

Breastfeeding jaundice is a common problem in neonates who were exclusively breastfed, but its pathogenesis is still unclear. The uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) gene polymorphism was shown to contribute to the development of neonatal hyperbilirubinemia. We hypothesize that the variation of UGT1A1 gene may contribute to neonatal breastfeeding jaundice. We prospectively enrolled 688 near-term and term infants who were exclusively breastfed (BF group) or were supplemented by infant formula partially (SF group) before onset of hyperbilirubinemia. Genotyping of the promoter and exon1 of UGT1A1 was performed in all neonates. Neonates in BF group had a significantly higher maximal body weight loss ratio, peak bilirubin level, and a greater incidence of hyperbilirubinemia than those in SF group. Neonates with nucleotide 211 GA or AA variation in UGT1A1 genotypes had higher peak serum bilirubin levels and higher incidence of hyperbilirubinemia than WTs (GG). This phenomenon was only seen in BF group but not in SF group when subset analysis was performed. This suggests that neonates who carry the nucleotide 211 GA or AA variation within coding region in UGT1A1 gene are more susceptible to develop early-onset neonatal breastfeeding jaundice.     

The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: a systematic review with meta-analysis

ObjectiveTo determine whether three variants (388 G>A, 521 T>C, and 463 C>A) of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) are associated with neonatal hyperbilirubinemia.Data sourceThe China National Knowledge Infrastructure and MEDLINE databases were searched. The systematic review with meta-analysis included genetic studies which assessed the association between neonatal hyperbilirubinemia and 388 G>A, 521 T>C, and 463 C>A variants of SLCO1B1 between January of 1980 and December of 2012. Data selection and extraction were performed independently by two reviewers.Summary of the findingsTen articles were included in the study. The results revealed that SLCO1B1 388 G>A is associated with an increased risk of neonatal hyperbilirubinemia (OR, 1.39; 95% CI, 1.07–1.82) in Chinese neonates, but not in white, Thai, Latin American, or Malaysian neonates. The SLCO1B1 521 T>C mutation showed a low risk of neonatal hyperbilirubinemia in Chinese neonates, while no significant associations were found in Brazilian, white, Asian, Thai, and Malaysian neonates. There were no significant differences in SLCO1B1 463 C>A between the hyperbilirubinemia and the control group.ConclusionThis study demonstrated that the 388 G>A mutation of the SLCO1B1 gene is a risk factor for developing neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations; the SLCO1B1 521 T>C mutation provides protection for neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations.     

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。     

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.     

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.     

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。     

新生儿高未结合胆红素血症遗传因素的研究

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。     

新生儿高胆红素血症与基因多态性研究进展

高胆红素血症是一种新生儿普遍存在的疾病,也是新生儿生后第1周住院的主要原因,该病主要由胆红素产生与消除的不平衡所致。尿苷二磷酸葡萄糖醛酸转移酶1、有机阴离子转运载体2、血红素氧合酶1及胆绿素还原酶A在胆红素代谢过程中扮演至关重要的角色。这些酶的编码基因突变与高胆红素血症的关系越来越多地被认识。该文就常见胆红素代谢酶的基因多态性与高胆红素血症的相关研究进展进行总结。     

(TA)n UDP-glucuronosyltransferase 1A1 promoter polymorphism in Nigerian neonates

Nigerian neonates have a high incidence of bilirubin encephalopathy. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is prevalent in this population. (TA)7 promoter polymorphism in the gene encoding the bilirubin conjugating enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) potentiates hyperbilirubinemia in G-6-PD deficient neonates. We studied (TA)n allele frequency to determine, at least in part, its contribution to the frequency and severity of hyperbilirubinemia. DNA was extracted from umbilical cord blood of sequentially born Nigerian neonates and the (TA)n UGT1A1 promoter sequence determined. The (TA)n allele distribution was compared with reported adults of varying African ancestry and Sephardic Jewish neonates. Among 88 Nigerian neonates, (TA)6 and (TA)7 alleles were almost equally distributed (0.46 and 0.43, respectively). Some individuals with (TA)5 and (TA)8 sequences were encountered. Allele distribution was similar to that of the African ancestry population but differed from the Sephardic Jewish newborns, in whom the (TA)6/(TA)7 distribution was 0.65/0.35. Whereas 45% of Nigerian alleles and 50% of African ancestry alleles, respectively, included a (TA)7 or (TA)8 sequence, only 35% of Jewish alleles were (TA)7 (p < 0.001), and no (TA)8 alleles were encountered. The high frequency of (TA)n promoter polymorphism, coupled with G-6-PD deficiency, may contribute to the pathogenesis of extreme neonatal hyperbilirubinemia in Nigeria.