(TA)n UGT 1A1 promoter polymorphism: a crucial factor in the pathophysiology of jaundice in G-6-PD deficient neonates

Increased heme catabolism has been reported in glucose-6-phosphate dehydrogenase (G-6-PD)-normal neonates who were also homozygous for (TA)7/(TA)7 (UGT1A1*28) uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT) promoter polymorphism (Gilbert syndrome). As G-6-PD deficiency is associated with increased hemolysis, we hypothesized that in G-6-PD-deficient neonates who also have the (TA)7/(TA)7 UGT promoter genotype, steady-state hemolysis would be even further increased. Male G-6-PD-deficient neonates were sampled for plasma total bilirubin (PTB), blood carboxyhemoglobin corrected for inhaled carbon monoxide in ambient air (COHbc) (an index of heme catabolism), and UGT (TA)n promoter genotype determination and compared with previously published G-6-PD-normal neonates. Although COHbc values were higher in the G-6-PD-deficient than in the G-6-PD-normal cohorts (0.97 +/- 0.32% of total Hb (tHb) versus 0.76 +/- 0.19% of tHb, p < 0.001), PTB values were similar (9.2 +/- 3.4 mg/dL versus 8.9 +/- 3.0 mg/dL, respectively, p = 0.3). Within the G-6-PD-deficient group, although COHbc values were alike between the three UGT promoter genotypes, PTB was higher in the (TA)7/(TA)7 homozygotes (11.1 +/- 4.0 mg/dL) compared with (TA)6/(TA)7 heterozygotes (9.1 +/- 3.2 mg/dL, p = 0.03) and wild-type (TA)6/(TA)6 homozygotes (8.8 +/- 3.4 mg/dL, p = 0.02). In the steady state, similar rates of hemolysis, but increased PTB in the G-6-PD- deficient, (TA)7/(TA)7 homozygotes, imply that (TA)7/(TA)7, homozygosity is central to increased PTB.     

The frequency of UDP-glucuronosyltransferase 1A1 promoter region (TA)7 polymorphism in newborns and it's relation with jaundice

Increased bilirubin formation and decreased bilirubin conjugation play an important role in the pathogenesis of the newborn jaundice. Although physiologic jaundice is seen in most of the newborns, there are many risk factors that affect the severity and duration of hyperbilirubinemia. The latest studies showed that the frequency and severity of neonatal jaundice have been increased when mutations of the gene coding UDP-glucuronosyltransferase(UGT)1A1 coexist with other risk factors. Healthy term newborns weighing over 2500 g. were included in this study. The patient group consisted of 107 newborns either with total bilirubin level over 15 mg dl(-1) within 7 days or 5 mg dl(-1) after 15 days of age. The control group consisted of 55 newborns with bilirubin levels in physiological ranges. We investigated the frequency of promoter region [thymine-adenine(TA)]7 polymorphism in UGT1A1 gene. Factors which might cause pathologic and prolonged jaundice with coexisting polymorphism were also investigated. UGT1A1 6/7 genotype was found to be 11% in patient group and 13% in the control group. The difference between patient and control groups was not statistically significant. (TA)7 allele frequency was 0.069 and it is concluded that UGT1A1 promoter region polymorphism was not a risk factor for neonatal jaundice.     

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。     

Analyses of polymorphism for UGT1*1 exon 1 promoter in neonates with pathologic and prolonged jaundice

In this study, we investigated whether a TATA box polymorphism in the promoter of the UGT1*1 exon I, the most common detected DNA polymorphism in Gilbert's syndrome, is a contributory factor in unexplained pathologic or prolonged jaundice. 38 neonates who had unexplained pathologic jaundice, 37 neonates who had unexplained prolonged jaundice, and 35 healthy, nonjaundiced neonates were enrolled in the study. Genotypes were assigned as follows: 6/6 (homozygous for a normal allele bearing the sequence [TA](6)TAA), 7/7 (homozygous for an abnormal allele with the sequence [TA](7)TAA), and 6/7 (heterozygous with one of each allele). Of the 110 infants, 10 (9%) had 7/7, 51 (46%) had 6/7, and 49 (45%) had 6/6 genotype; the differences between the three groups were not statistically significant. Also no differences were observed among different genotypes and mean serum total bilirubin concentrations. In conclusion, we showed that TA 7/7 and TA 6/7 genotypes are not rare in our population and that the presence of these polymorphisms alone does not play a significant role in the etiology of unexplained pathologic or prolonged neonatal hyperbilirubinemia.     

A new case of (TA)8 allele in the UGT1A1 gene promoter in a Caucasian girl with Gilbert syndrome

The authors describe a 5-year-old Caucasian girl, referred to their hospital for evaluation of an unconjugated hyperbilirubinemia (57.9 μmol/L) detected from blood analysis during an episode of fever. The molecular analysis of the TATA-box region of the UGT1A1 gene revealed that the patient was a compound heterozygote for two insertions, one TA and the other TATA [(TA)₇/(TA)₈]. This is the first case of (TA)8 allele found in a Portuguese Caucasian patient and the third found in the literature.     

Fasting hyperglycaemia and polymorphism in glucokinase promoter (rs1799884)

Glucokinase is one of the most important regulators of fasting glucose levels. There are several mutations in the glucokinase gene (GCK) which are linked with monogenic diabetes. Recently, a polymorphism in its promoter has been described, which is associated with impaired fasting glucose levels. We present a 7 years and 7 months old boy with overweight and a familial background of diabetes in two previous generations. In the oral glucose tolerance test, he had impaired fasting glucose levels and after two hours, with a high insulin response. Laboratory abnormalities improved after weight loss, but he maintains a slight fasting hyperglycaemia. The molecular study of the most common monogenic diabetes forms, MODY subtypes 1, 2, and 3, was negative. The allelic variant G/A was however detected at the GCK promoter polymorphism rs1799884.     

Kernicterus associated with hereditary spherocytosis and UGT1A1 promoter polymorphism

InTRODUCTION: An apparent re-emergence of kernicterus has been recently reported, with some cases occurring in otherwise healthy breastfed newborn. METHODS: We describe a case of kernicterus in a term Caucasian newborn. RESULTS: An exceptional polymorphism of UGT1A1 gene promoter co-existed with asymptomatic inherited spherocytosis, due to erythroid anion exchange (band-3) deficiency. Both concurred to the development of severe neonatal hyperbilirubinaemia. CONCLUSION: As some cases of kernikterus remain unresolved, haemolytic diseases and bilirubin metabolism disorders should be carefully investigated in unexplained severe neonatal hyperbilirubinaemia.     

尿苷二磷酸葡萄糖醛酸转移酶1A1基因与新生儿黄疸

尿苷二磷酸葡萄糖醛酸转移酶（UGT）是胆红素结合的关键酶,此酶的缺陷使胆红素不能与葡萄糖醛酸结合形成结合胆红素,使非结合胆红素在体内堆积,导致Crigler—Najjiar综合征（包括Ⅰ型、Ⅱ型）和Gilbert综合征。CN—Ⅰ型患儿由于高度缺乏UGT,生后1～2d即出现严重黄疸,血清间接胆红素可达256．5～595．0μnaol／L,苯巴比妥治疗无效,需换血与光疗结合,常见短期内出现胆红素脑病,多在新生儿期和婴儿期死亡,属常染色体隐性遗传。CN—Ⅱ型为UGT活性缺陷,但并非完全缺乏,可表现为新生儿期较轻的黄疸,但也可发生严重的高胆红素血症和核黄疸。血清间接胆红素浓度一般在85—340μmol／L,苯巴比妥治疗有效,属常染色体显性遗传。Gilbert综合征为一种轻度的慢性高间接胆红素血症,系由肝脏摄取胆红素缺陷和UGT活性降低所致,通常于青春期才症状明显,给苯巴比妥能降低总胆红素值,是一种常染色体显性遗传病。     

Mini-erythrocyte sedimentation rates in healthy and infected Nigerian neonates

Normal values for mini-erythrocyte sedimentation rates (mini-ESR) in healthy Nigerian neonates are reported and compared with values obtained for infected neonates. The mean and 95th percentile values, measured in mm/h in healthy neonates in the first week of life, range from 1.8 to 7.7, and in the 4th week of life from 9.1 to 16. The mini-ESR values of the infected neonates were significantly higher than the 95th percentile values of healthy neonates. Because the sensitivity and specificity of the mini-ESR in the diagnosis of neonatal infection are high, its application as an appropriate technology for evaluating suspected cases of infection in the developing countries should be encouraged.     

放射测定胎鼠肝脏尿苷二磷酸葡萄糖醛酸转移酶1A1活性

目的探讨大鼠肝脏发育不成熟期葡萄糖醛酸转移酶1A1活性的发育规律，为研究新生儿期葡萄糖醛酸结合反应提供实验依据。方法用Heridrun Matem方法放射测定不同孕龄（孕17～19d各5只）及出生后不同日龄（生后1～5d各10只，生后2周的5只）大鼠的肝脏葡萄糖醛酸转移酶1A1活性。结果大鼠肝脏在孕17～19d UGT1A1活性较低，而且增长幅度小，孕19d酶的活性占成熟鼠活性的6．7％。生后1～2d时增长幅度很大，生后5d基本达成熟鼠水平，占成熟鼠活性的88．1％。将孕17d、孕19d、生后1d、成熟鼠这4组UGT1A1活性进行统计学检验，具有统计学意义。结论不成熟大鼠肝脏葡萄糖醛酸转移酶1A1活性很低，导致此期的胆红素葡萄糖醛酸结合反应水平低下。     

放射测定胎鼠肝脏尿苷二磷酸葡萄糖醛酸转移酶1A1活性

目的探讨大鼠肝脏发育不成熟期葡萄糖醛酸转移酶1A1活性的发育规律,为研究新生儿期葡萄糖醛酸结合反应提供实验依据。方法用HeridrunMatern方法放射测定不同孕龄(孕17～19d各5只)及出生后不同日龄(生后1～5d各10只,生后2周的5只)大鼠的肝脏葡萄糖醛酸转移酶1A1活性。结果大鼠肝脏在孕17～19dUGT1A1活性较低,而且增长幅度小,孕19d酶的活性占成熟鼠活性的6.7%。生后1～2d时增长幅度很大,生后5d基本达成熟鼠水平,占成熟鼠活性的88.1%。将孕17d、孕19d、生后1d、成熟鼠这4组UGT1A1活性进行统计学检验,具有统计学意义。结论不成熟大鼠肝脏葡萄糖醛酸转移酶1A1活性很低,导致此期的胆红素葡萄糖醛酸结合反应水平低下。     

云南苯丙氨酸羟化酶基因内(TCTA)n多态性及其在苯丙酮尿症诊断中的应用

目的应用苯丙氨酸羟化酶（ＰＡＨ）基因内（ＴＣＴＡ）ｎ多态性连锁分析进行经典型苯丙酮尿症（ＰＫＵ）的基因诊断和产前诊断。方法应用聚合酶链反应扩增片段长度多态性（ＰＣＲＡｍｐＦＬＰ）方法,分析云南省１３个家系苯丙氨酸羟化酶（ＰＡＨ）基因内（ＴＣＴＡ）ｎ多态性。结果在１３个家系中检测到２２４～２５２ｂｐ的８种等位片段,其ＰＩＣ为０．６９８,杂合频率是５１％。可诊断率为１００％和５０％的家系各６个,１个家系因双亲带型为纯合型而未能诊断,可诊断率为６９％。完成１例产前基因诊断和２例回顾性的基因诊断。结论（ＴＣＴＡ）ｎ的ＰＣＲＡｍｐＦＬＰ分析可作为经典型ＰＫＵ基因诊断和产前诊断的一种简便有效的方法。     

Variations in the promoter region of the apolipoprotein A-1 gene influence plasma lipoprotein(a) levels in Asian Indian neonates from Singapore

We studied the influence of two DNA polymorphisms (-75 bp G/A and +83 bp C/T) in the promoter region of the apolipoprotein A-1 (apoA1) gene on cord plasma level of lipoprotein(a) [Lp(a)] in 1076 newborns of both genders from the three major ethnic groups in Singapore-Chinese, Malays, and Asian Indians. The frequency of the A: allele at -75 bp in the Indians was significantly lower than the Chinese and Malays. There was no linkage disequilibrium between the two sites studied. Both polymorphic sites were not significantly associated with any lipid factors except for Lp(a) levels in the Asian Indians. The AA and CC homozygotes were significantly associated with lower Lp(a) levels. These associations were specific only to the male Indian neonates. The genetic variations at the -75 and +83 bp explained 6.9% and 7.2%, respectively, of the total variability of plasma Lp(a) levels at birth in the Asian Indians. The Lp(a) levels were also significantly different between composite genotypes in the order GG/TT > GA/CT > GG/CT > GA/CC > GG/CC > AA/CC. The effects of the two polymorphisms seem to be additive as the composite genotypes were able to explain 14% of the Lp(a) variance, equivalent to the sum of the two constituent sites. Our results showed that there is significant ethnic- and gender-specific influence of the apoA1 gene on plasma Lp(a) levels at birth that is inherent and independent of known gene-environment interactions.     

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目的探讨肺泡表面活性物质蛋白A1(SPA1)基因多态性与新生儿支气管肺发育不良(BPD)相关性。方法应用聚合酶链反应-限制酶切技术(PCR-RFLP)分析2008年7月至2010年10月同济医院接诊的38例武汉汉族BPD患儿与55例对照组的SPA1基因分布。结果 BPD组和对照组之间AA50基因型分布(P=0.038)和等位基因频率(P=0.012)差异有统计学意义。AA219、AA62、AA19三个位点基因型分布和等位基因频率差异无统计学意义(P>0.05)。AA50病例组CC基因型明显低于对照组(7vs23),差异有统计学意义(P<0.05)。结论 SPA1上AA50位点基因多态性可能与新生儿支气管肺发育不良有关,CC基因型可能对BPD患病有保护作用。     

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.     

A new PTGDR promoter polymorphism in a population of children with asthma

Recently, functional genetic variants of the PTGDR gene have been associated with asthma. The objective of this work was to study polymorphisms of the promoter region of PTGDR and their haplotype and diplotype combinations in a Spanish population of children with asthma. In this study, 200 Caucasian individuals were included. Asthma was specialist–physician diagnosed according to the ATS criteria. The polymorphisms were analyzed by direct sequencing. In the study, the new polymorphism (-613C > T) in the promoter region of PTGDR was analyzed. The CT genotype was more common in controls (17%) than in patients with asthma (1%) (p-value = 0.0003; OR, 0.057; 95% CI, 0.007–0.441). The CCCT CCCC diplotype (promoter positions -613, -549, -441, and -197) was more frequent in the group of patients with asthma [Fisher's p-value = 0.012; OR, 10.24; 95% CI (1.25–83.68)]; this diplotype is unambiguous. To our knowledge, this is the first study of -613C > T PTGDR polymorphism in patients. This analysis provides more complete information on influence of diplotype combinations of PTGDR polymorphisms in asthma.     

胰岛素样生长因子Ⅰ启动子区域基因多态性与新生儿血清IGF-Ⅰ水平的关系

目的 检测新生儿胰岛素样生长因子Ⅰ（IGF-Ⅰ）启动子区域（CA）n重复标记位点的基因多态性,及新生儿血清IGF-Ⅰ浓度,探讨基因多态性与血清IGF-Ⅰ浓度的关系,分析相关的遗传背景.方法 202名健康新生儿根据胎龄分为早产（111名）和足月（91名）两组,记录出生体重、身长;于生后第3～5天取血,酶联免疫法检测血清IGF-Ⅰ、生长激素（GH）浓度;提取DNA,分析IGF-Ⅰ启动子区域基因多态性.结果 在202名新生儿中,发现7种不同的等位基因及20种基因型.7种等位基因频率分别为7.92%、14.60%、43.56%、7.43%、21.78%、3.96%、1.10%,其中携带190等位基因的早产新生儿的血清IGF-Ⅰ水平及出生体重相对较低.未发现基因多态性与出生身长相关.结论 IGF-Ⅰ基因启动子区域190等位基因可能与早产新生儿出生体重及血清IGF-Ⅰ浓度相关.本研究提示基因可能影响出生前生长和血清IGF-Ⅰ水平的关系.     

ACE基因多态性与新生儿SIRS易感性的研究

目的研究血管紧张素转换酶(ACE)基因I/D多态性及其作用产物血管紧张素II(AngII)血清水平与新生儿全身炎症反应综合征(SIRS)易感性的关系。方法采用PCR和放射免疫法分别测定70例妊高征孕妇分娩的高危新生儿和30例正常新生儿的ACE基因型和血清AngII的含量,同时观察了SIRS的发生率。结果高危新生儿合并有SIRS组(I组)基因D/D型和D等位基因分布频率明显高于正常对照组,分别为34.2%vs 10%;60.53%vs 28.33%(P均<0.05)。且I组血清AngII水平[(546.3±363.21)ng/L]明显高于高危新生儿无SIRS组(II组)[(398.93±313.31)ng/L]及正常对照组[(364.52±321.70)ng/L]。II组与对照组无明显差异。各组血清AngII水平以D/D型最高,I/I型最低。携带D/D型的I组新生儿AngII水平明显高于正常对照组(P<0.05),而与II组比较无明显差异。结论ACE基因的D等位基因可能是SIRS易感性的一个危险因素,ACE基因型和AngII水平可作为推测SIRS易感性的参考指标。