G6PD活性、UGT1A1、SLCO1B1、ABCC2基因多态性和新生儿高胆红素血症的关系研究

The relationship between G6PD activity,UGT1A1,SLCO1B1,ABCC2 gene polymorphisms and neonatal hyperbilirubinemia

目的探讨体内胆红素转运与排泄相关基因(UGT1A1,SLCO1B1和ABCC2)的功能性单核苷酸多态性(single nucleotide polymorphism,SNPs)位点,葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase,G6PD)活性与新生儿血清胆红素峰值浓度的关系。方法 457例新生儿同时采用经皮测和血清胆红素测定,采用G6PD/6PGD比值法和荧光斑点法测定G6PD活性,采用测序法分析所有标本的8个SNPs位点的基因型,统计学分析G6PD活性、各个SNPs位点与总胆红素峰值的关系。结果G6PD缺乏组血清总胆红素浓度峰值为(276.55±94.92)μmol/L,G6PD正常组血清总胆红素浓度峰值为(220.12±89.39)μmol/L,两者之间差异有统计学意义(P<0.001);8个SNPs位点与血清总胆红素浓度相关性分析中,UGT1A1 211 G>A在显性遗传模型、隐性遗传模型和加性遗传模型下均显著影响新生儿外周血胆红素浓度(P<0.01),SLCO1B1-11187G>A在显性遗传模型下显著影响新生儿外周血胆红素浓度(P=0.039)。携带G6PD活性缺乏、UGT1A1 211 G>A和SLCO1B1-11187G>A这3个风险因素组发生新生儿高胆红素血症的风险是不携带上述3个风险因素组的8.78倍(95%置信区间:2.72~28.39)。结论 G6PD活性缺乏、UGT1A1 211 G>A和SLCO1B1-11187G>A为新生儿高胆红素血症发生的3个重要风险因素,三者之间具有积累效应,携带风险因素的数量越多,新生儿外周血胆红素峰值浓度就越高,发生新生儿高胆红素血症并发症的风险就越大。

Objective To investigate the relationship between the candidate functional single nucleotide polymorphism（SNPs）of the genes（UGT1A1,SLCO1B1 and ABCC2）involved with bilirubin transportation and excretion,G6PD activity and the serum bilirubin concentration in neonates. Methods The bilirubin concentrations of 457 neonates were measured by transcutaneous or serum. G6PD activity was measured by G6PD/6PGD activity ratio method and G6PD fluorescent spot test. The genotypes of all 8 SNPs loci in all specimens were analyzed by sequencing. The relationship of G6PD activity,each SNPs site and the peak of total bilirubin were statistically analyzed. Results The peak value of serum total bilirubin concentration in G6PD deficiency group was（276.55±94.92）μmol/L,and the peak of serum total bilirubin concentration in normal G6PD group was（220.12 ± 89.39） μmol/L,and the difference was statistically significant（P 〈0.001）. In the analysis of the correlation between the 8 SNPs sites and the serum total bilirubin concentration,UGT1A1 211 G〉A significantly affected the neonatal peripheral blood bilirubin concentration（P〈0.01）in the dominant genetic model,the recessive genetic model and the additive genetic model,and the SLCO1 B1-11187 G〉A significantly affected the peripheral blood bilirubin concentration in the newborn under the dominant genetic model（P=0.039）. The risk of neonatal hyperbilirubinemia in the 3 risk factors group with G6PD activity deficiency,UGT1A1 211 G〉A,and SLCO1B1-11187G〉A was 8.78 times as high as that of the 3 risk factors group（95% confidence interval：2.72-28.39）. Conclusions The G6PD deficiency,UGT1A1 211 G〉A and SLCO1B1-11187G〉A are 3 crucial risk factors for neonatal hyperbilirubinemia. There is a cumulative effect among the three risk factors. The more the number of risk factors,the higher the peak concentration of the peripheral blood bilirubin in the newborn,the risk of complications of neonatal hyperbilirubinemia.