中国西南地区新生儿高胆红素血症基因多态性研究

doi:10.12372/jcp.2022.21e1598

Abstract

Abstract:

Objective To investigate the relationship between uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), organic anion transporter family member 1B1 (SLCO1B1) and glucose-6-phosphate dehydrogenase (G6PD) gene polymorphisms and neonatal hyperbilirubinemia in southwest China. Methods A total of 190 neonates with neonatal hyperbilirubinemia from September 2016 to December 2019 in Yunnan, Guizhou and Sichuan provinces were selected as the study group, and 200 neonates without jaundice who were hospitalized during the same period were randomly selected as the control group. Genomic DNA was extracted from venous blood and 17 SNPs sites were genotyped by Sequenom-specific SNP detection. Genotype and allele frequency were compared between the study and control groups. Results There were 190 patients (98 boys and 92 girls) in the study group, and the average gestational age was (38.7±1.2) weeks. In the control group, there were 200 neonates (116 boys and 84 girls), and the average gestational age was (38.9±1.3) weeks. The allele frequencies of UGT1A1 rs873478, rs34946978 and rs4148323 were higher in the study group than those in the control group, while the allele frequency of SLCO1B1 rs72559748 was lower in the study group than that in the control group, and the differences were statistically significant (P<0.05). The G6PD rs72554664 variant was detected in two boys with hyperbilirubinemia, and the detection rate was 1.05%. There was significant difference in the distribution of risk alleles between the study group and the control group (P<0.05), and the proportion of risk alleles ≥2 was higher in the study group. Conclusions The UGT1A1 rs873478, rs34946978 and rs4148323 polymorphisms were associated with higher risk of neonatal hyperbilirubinemia in southwest China. The SLCO1B1 polymorphism was not significantly associated with the incidence of neonatal hyperbilirubinemia and lack of G6PD enzyme activity may not be a major risk factor for neonatal hyperbilirubinemia in this region.

Key words: uridine diphosphate-glucuronosyl transferase 1A1, organic anion transporter family member 1B1, glucose-6-phosphate dehydrogenase, hyperbilirubinemia, neonate

LIU Ling, JIANG Yuhui, NIE Panrong, ZENG Limei, DUAN Gaiyuan, LI Yuchen. Investigation of the relationship between gene polymorphisms and neonatal hyperbilirubinemia in southwest China[J].Journal of Clinical Pediatrics, 2022, 40(9): 672-678.

Figures/Tables 8

References 27

[1]	Maisels MJ. Neonatal jaundice[J]. Pediatr Rev, 2006, 27(12): 443-454. doi: 10.1542/pir.27.12.443
[2]	林佳媛. 胆红素代谢及其调节的研究进展[J]. 复旦学报(医学版), 2014, 41(3): 405-411.
[3]	卜爱林, 李贵南. UGT1A1基因多态性与新生儿不明原因高胆红素血症的相关性[J]. 中国医师杂志, 2020, 22(11): 1736-1738.
[4]	American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation[J]. Pediatrics, 2004, 114(1): 297-316. doi: 10.1542/peds.114.1.297
[5]	Mehrad-Majd H, Haerian MS, Akhtari J, et al. Effects of Gly71Arg mutation in UGT1A1 gene on neonatal hyperbilirubinemia: a systematic review and meta-analysis[J]. J Matern Fetal Neonatal Med, 2019, 32(10): 1575-1585. doi: 10.1080/14767058.2017.1410789 pmid: 29179591
[6]	Yueh MF, Chen S, Nguyen N, et al. Developmental, genetic, dietary, and xenobiotic influences on neonatal hyperbilirubinemia[J]. Mol Pharmacol, 2017, 91(5): 545-553. doi: 10.1124/mol.116.107524
[7]	Li H, Zhang P. UGT1A1*28 gene polymorphism was not associated with the risk of neonatal hyperbilirubinemia: a meta-analysis[J]. J Matern Fetal Neonatal Med, 2021, 34(24): 4064-4071. doi: 10.1080/14767058.2019.1702962
[8]	Amandito R, Rohsiswatmo R, Carolina E, et al. Profiling of UGT1A16, UGT1A1*60, UGT1A1*93, and UGT1A1**28 polymorphisms in Indonesian neonates with hyperbilirubinemia using multiplex PCR sequencing[J]. Front Pediatr, 2019, 7: 328. doi: 10.3389/fped.2019.00328 pmid: 31440488
[9]	尹迪, 魏珊珊, 许无恨, 等. UGT1A1基因多态性与新生儿不明原因重度高胆红素血症的关系[J]. 中华新生儿科杂志, 2021, 36(6): 55-58.
[10]	陈虹, 钟丹妮. 尿苷二磷酸葡萄糖醛酸转移酶1A1基因多态性的表达研究进展[J]. 中华实用儿科临床杂志, 2019, 5: 388-391.
[11]	肖奇志, 郭洪创, 李恋湘, 等. 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[J]. 分子诊断与治疗杂志, 2018, 10(3): 163-168.
[12]	Sticova E, Lodererova A, van de Steeg E, et al. Down-regulation of OATP1B proteins correlates with hyper-bilirubinemia in advanced cholestasis[J]. Int J Clin Exp Pathol, 2015, 8(5): 5252-5262.
[13]	Hoekstra LT, de Graaf W, Nibourg GA, et al. Physiological and biochemical basis of clinical liver function tests: a review[J]. Ann Surg, 2013, 257(1): 27-36. doi: 10.1097/SLA.0b013e31825d5d47 pmid: 22836216
[14]	van de Steeg E, Stránecký V, Hartmannová H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver[J]. J Clin Invest, 2012, 122(2): 519-528. doi: 10.1172/JCI59526
[15]	D’Silva S, Colah RB, Ghosh K, et al. Combined effects of the UGT1A1 and OATP2 gene polymorphisms as major risk factor for unconjugated hyperbilirubinemia in Indian neonates[J]. Gene, 2014, 547: 18-22. doi: 10.1016/j.gene.2014.05.047
[16]	王朝, 赵玉平. 葡萄糖-6-磷酸脱氢酶缺乏症的发病机制及诊疗现状[J]. 国际输血及血液学杂志, 2017, 40(2): 178-181.
[17]	Olusanya BO, Emokpae AA, Zamora TG, et al. Addressing the burden of neonatal hyperbilirubinaemia in countries with significant glucose-6-phosphate dehydrogenase deficiency[J]. Acta Paediatr, 2014, 103: 1102-1109. doi: 10.1111/apa.12735
[18]	Hu R, Lin M, Ye J, et al. Molecular epidemiological investigation of G6PD deficiency by a gene chip among Chinese Hakka of southern Jiangxi province[J]. Int J Clin Exp Pathol, 2015, 8(11): 15013-15018.
[19]	奎莉越, 王明英, 周百灵, 等. 云南省婴儿期不同民族高非结合性胆红素血症UGT1A1基因多态性研究[J]. 分子诊断与治疗杂志, 2020, 12(3): 386-390.
[20]	钟勇, 蒋晓梅, 冯于玲, 等. UGT1A1基因多态性与不同民族间新生儿高胆红素血症的关系[J]. 临床儿科杂志, 2013, 31(4): 324-327.
[21]	何翠红, 屈艺. 新生儿高胆红素血症与基因多态性研究进展[J]. 中国当代儿科杂志, 2020, 22(3): 280-284.
[22]	Huang MJ, Chen YC, Huang YY, et al. Effect of UDP-glucuronosyltransferase 1A1 activity on risk for developing Gilbert's syndrome[J]. Kaohsiung J Med Sci, 2019, 35(7): 432-439.
[23]	MiXX, Yan J, Ma XJ, et al. Analysis of the UGT1A1 genotype in hyperbilirubinemia patients: differences in allele frequency and distribution[J]. Biomed Res Int, 2019, 2019:6272174.
[24]	蒋榆辉, 刘玲, 奚敏, 等. SLCO1B1基因多态性与新生儿高胆红素血症的相关性[J]. 临床儿科杂志, 2018, 36(9): 7-10.
[25]	Riskin A, Gery N, Kugelman A, et al. Glucose-6-phosphate dehydrogenase deficiency and borderline deficiency: association with neonatal hyperbilirubinemia[J]. J Pediatr, 2012, 161(2): 191-196. doi: 10.1016/j.jpeds.2012.02.018
[26]	Liu Z, Yu C, Li Q, et al. Chinese newborn screening for the incidence of G6PD deficiency and variant of G6PD gene from 2013 to 2017[J]. Hum Mutat, 2020, 41(1): 212-221. doi: 10.1002/humu.23911
[27]	许冰莹, 黄尤光, 程振江, 等. 云南籍葡萄糖-6-磷酸脱氢酶缺乏症基因突变研究[J]. 昆明医学院学报, 2007, 28(4): 6-12.

项目	病例组(n=190)	对照组(n=200)	统计量	P
男性[n(%)]	98(51.6)	116(58.0)	χ²=1.62	0.203
胎龄(x±s)/d	38.7±1.2	38.9±1.3	t=0.57	0.448
出生体重(x±s)/kg	3.2±0.4	3.2±0.4	t=0.33	0.744
日龄[M(P₂₅~P₇₅)]/d	7.9(4.0~11.0)	8.3(4.0~11.5)	Z=0.56	0.573
开奶时间[M(P₂₅~P₇₅)]/h	1.4(0.5~2.0)	1.6(0.5~2.0)	Z=0.49	0.961
剖宫产[n(%)]	33(17.4)	38(19.0)	χ²=0.17	0.676
红细胞压积(x±s)/%	58.5±5.4	56.4±5.8	t=1.50	0.870
总胆红素(x±s)/μmol·L^-1	342.0±62.7	62.4±9.7	t=24.16	<0.001
结合胆红素(x±s)/μmol·L^-1	27.9±6.7	6.6±1.3	t=18.02	<0.001

基因型	病例组(n=190)	对照组(n=200)	χ²值	P
rs873478			5.86	0.055
GG	153(80.5)	177(88.5)
CG	30(15.8)	21(10.5)
CC	7(3.7)	2(1.0)
等位基因			6.86	0.009
G	336(88.4)	375(93.8)
C	44(11.6)	25(6.3)
rs34946978¹⁾			4.38	0.112
CC	167(89.3)	190(95.0)
TC	18(9.6)	9(4.5)
TT	2(1.1)	1(0.5)
等位基因			4.65	0.031
C	352(94.1)	389(97.3)
T	22(5.9)	11(2.8)
rs4148323²⁾			10.61	0.005
GG	95(50.3)	127(63.5)
GA	65(34.4)	60(30.0)
AA	29(15.3)	13(6.5)
等位基因			12.06	0.001
G	255(67.5)	314(78.5)
A	123(32.5)	86(21.5)
rs34993780			2.92	0.087
TT	185(97.4)	199(99.5)
GT	5(2.6)	1(0.5)
等位基因			2.90	0.089
T	375(98.7)	399(99.8)
G	5(1.3)	1(0.3)
rs35350960			0.17	0.678
CC	185(97.4)	196(98.0)
CA	5(2.6)	4(2.0)
等位基因			0.17	0.680
C	375(98.7)	396(99.0)
A	5(1.3)	4(1.0)

基因型	病例组(n=190)	对照组(n=200)	χ²值	P
rs72559748			5.42	0.020
AA	175(92.1)	169(84.5)
AG	15(7.9)	31(15.5)
等位基因			4.71	0.030
A	365(96.0)	369(92.3)
G	15(4.0)	31(7.8)
rs4149056			1.24	0.549
TT	154(81.1)	164(82.0)
CT	25(13.2)	29(14.5)
CC	11(5.8)	7(3.5)
等位基因			0.50	0.503
T	333(87.6)	357(89.3)
C	47(12.4)	43(10.8)

基因型	病例组(n=190)	对照组(n=200)	P¹⁾
rs72554664			0.237
CC	188(98.9)	200(100.0)
CT	2(1.1)	0(0.0)
等位基因			0.237
C	378(99.5)	400(100.0)
T	2(0.5)	0(0.0)

风险等位基因个数	病例组(n=190)	对照组(n=200)
0	70(36.8)	111(55.5)
1	65(34.2)	60(30.0)
2	43(22.6)	26(13.0)
≥3	12(6.3)	3(1.5)

Investigation of the relationship between gene polymorphisms and neonatal hyperbilirubinemia in southwest China

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