胎龄≤34周的汉族早产儿脐带血内皮型一氧化氮合成酶基因多态性及其与早产儿主要并发症的关系研究
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摘要
目的探讨新乡市汉族早产儿脐带血内皮型一氧化氮合成酶(eNOS)基因的多态性,并研究这种多态性与早产儿主要并发症的关系。方法选择2014年2月—2016年12月于新乡市中心医院出生的≤34周的早产儿231例为研究对象,母亲分娩时取脐带血,测定eNOS基因3个位点rs2070744、rs1799983和rs61722009的基因型和等位基因。记录早产儿的临床资料,分析eNOS基因多态性与早产儿主要并发症的关系。结果 rs2070744 C、rs1799983 T和rs61722009 a的等位基因频率分别是0.145、0.188和0.159。与Ensembl数据库中已知研究比较,差异无统计学意义(χ~2=0.875,P=0.646;χ~2=3.541,P=0.173)。单因素分析结果示rs2070744 TC+CC基因型和rs1799983GT+TT基因型与支气管肺发育不良有关(crude OR=0.370、0.484,P=0.003、0.030)。多因素Logistic回归分析结果示rs2070744 TC+CC基因型是支气管肺发育不良的独立危险因素(OR=1.875,P=0.020);rs61722009 aa+ab基因型和rs1799983 GT+TT基因型同时存在是早产儿视网膜病变Ⅲ~Ⅴ期的独立危险因素(OR=2.961,P=0.041)。结论 eNOS基因多态性与早产儿主要并发症的发生有关,脐带血测定早产儿eNOS基因多态性有助于评估患儿预后。
Objective To examine the association of gene polymorphisms of nitric oxide synthase(NOS) in endothelial cells of umbilical cord vessels and major complications among Han premature infants of ≤ 34 weeks' gestational age in Xinxiang.Methods This study was conducted in a cohort of preterm infants(n=231) with a gestational age of ≤ 34 weeks delivered in Xinxiang Central Hospital from February 2014 to December 2016.Allele and genotype frequencies at 3 single nucleotide polymorphisms(rs2070744,rs1799983 and rs61722009) of eNOS in endothelial cells of umbilical cord vessels(extracted at the delivery).We collected the clinical data of the preterm infants.The association of gene polymorphisms of eNOS with the development of bronchopulmonary dysplasia(BPD),necrotizing enterocolitis(NEC),stage Ⅲ-Ⅴ retinopathy(ROP),stage Ⅲ-Ⅳ periventricular-intraventricular hemorrhage(PIVH),neonatal respiratory distress syndrome(RDS) requiring mechanical ventilation(MV) and death.Results The frequency of C allele of rs2070744 polymorphism,and T allele of rs1799983 polymorphism was 0.145,0.188,respectively,which was similar to that proposed in the studies collected in Ensembl genome database(χ~2=0.875,P=0.646;χ~2=3.541,P=0.173).The a allele of rs61722009 polymorphism was identified to be 0.159.Univariate analysis found that rs2070744 TC+CC genotypes(crude OR=0.370,P=0.003) and rs1799983 GT+TT genotypes(crude OR=0.484,P=0.030) were associated with the development of BPD.Multivariate Logistic regression analysis revealed that rs2070744 TC+CC genotypes were independent risk factors for BPD(OR=1.875,P=0.020),and synchronized appearance of rs61722009 aa+ab and rs1799983 GT+TT genotypes were independent risk factors for stage Ⅲ-Ⅴ ROP(OR =2.961,P=0.041).Conclusion The eNOS gene polymorphisms are associated with the major complications of Han preterm infants in Xinxiang.Genotyping may be helpful to identify patients with higher risk of BPD and stage Ⅲ-Ⅴ ROP.
Objective To examine the association of gene polymorphisms of nitric oxide synthase(NOS) in endothelial cells of umbilical cord vessels and major complications among Han premature infants of ≤ 34 weeks' gestational age in Xinxiang.Methods This study was conducted in a cohort of preterm infants(n=231) with a gestational age of ≤ 34 weeks delivered in Xinxiang Central Hospital from February 2014 to December 2016.Allele and genotype frequencies at 3 single nucleotide polymorphisms(rs2070744,rs1799983 and rs61722009) of eNOS in endothelial cells of umbilical cord vessels(extracted at the delivery).We collected the clinical data of the preterm infants.The association of gene polymorphisms of eNOS with the development of bronchopulmonary dysplasia(BPD),necrotizing enterocolitis(NEC),stage Ⅲ-Ⅴ retinopathy(ROP),stage Ⅲ-Ⅳ periventricular-intraventricular hemorrhage(PIVH),neonatal respiratory distress syndrome(RDS) requiring mechanical ventilation(MV) and death.Results The frequency of C allele of rs2070744 polymorphism,and T allele of rs1799983 polymorphism was 0.145,0.188,respectively,which was similar to that proposed in the studies collected in Ensembl genome database(χ~2=0.875,P=0.646;χ~2=3.541,P=0.173).The a allele of rs61722009 polymorphism was identified to be 0.159.Univariate analysis found that rs2070744 TC+CC genotypes(crude OR=0.370,P=0.003) and rs1799983 GT+TT genotypes(crude OR=0.484,P=0.030) were associated with the development of BPD.Multivariate Logistic regression analysis revealed that rs2070744 TC+CC genotypes were independent risk factors for BPD(OR=1.875,P=0.020),and synchronized appearance of rs61722009 aa+ab and rs1799983 GT+TT genotypes were independent risk factors for stage Ⅲ-Ⅴ ROP(OR =2.961,P=0.041).Conclusion The eNOS gene polymorphisms are associated with the major complications of Han preterm infants in Xinxiang.Genotyping may be helpful to identify patients with higher risk of BPD and stage Ⅲ-Ⅴ ROP.
引文
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[2]马琼,杨文亮,郭华棋,等.内皮型一氧化氮基因(T786C)多态性与妊娠期高血压疾病关系的meta分析[J].中华围产医学杂志,2017,20(4):299-303.DOI:10.3760/cma.j.issn.1007-9408.2017.04.012.MA Q,YANG W L,GUO H Q,et al.Association between endothelial nitric oxide synthase gene(T786C)Polymorphism and hypertensive disorder of pregnancy:a meta-analysis[J].Chinese Journal of Perinatal Medicine,2017,20(4):299-303.DOI:10.3760/cma.j.issn.1007-9408.2017.04.012.
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[5]邵肖梅,叶鸿瑁,丘小汕.实用新生儿学[M].北京:人民卫生出版社,2011:416-422,706-715,477-483.SHAO X M,YE H M,QIU X S.Practice of eonatology[M].Beijing:People's Medical Publishing House,2011:416-422,706-715,477-483.
[6]中华医学会眼科学分会眼底病学组.中国早产儿视网膜病变筛查指南(2014年)[J].中华眼科杂志,2014,50(12):933-935.DOI:10.3760/cma.j.issn.0412-4081.2014.12.017.
[7]茹喜芳,冯琪.新生儿呼吸窘迫综合征的管理——欧洲共识指南2013版[J].中国新生儿科杂志,2013,28(5):356-358.DOI:10.3969/j.issn.1673-6710.2013.05.021.RU X F,FENG Q.The management of neonatal respiratory distress syndrome——European consensus guidelines 2013[J].Chinese Journal of Neonatology,2013,28(5):356-358.DOI:10.3969/j.issn.1673-6710.2013.05.021.
[8]FATINI C,SOFI F,GORI A M,et al.Endothelial nitric oxide synthase-786T>C,but not 894G>T and 4a4b polymorphism influences plasma homocysteine concentrations in persons with normal vitamin status[J].Clin Chem,2005,51(7):1159-1164.DOI:10.1373/clinchem.2005.048850.
[9]Variant:rs2070744.The 1000 Genomes Project Phase 3[EB/OL].(2015-10-01)[2017-05-02].http://www.Ensembl.org./Homo_sapiens/Variation/Population?db=core;r=7:150992491-150993491;V=rs2070744;vdb=variation;vf=1492708.
[10]Variant:rs1799983.The 1000 Genomes Project Phase 3[EB/OL].(2015-10-01)[2017-05-02].http://www.Ensembl.org./Homo_sapiens/Variation/Population?db=core;r=7:150998523-150999523;v=rs1799983;vdb=variation;vf=1244106.
[11]CAICEDO A,DE SMET D,VANDERHAEGEN J,et al.Impaired cerebral autoregulation using near-infrared spectroscopy and its relation to clinical outcomes in premature infants[J].Adv Exp Med Biol,2011,701:233-239.DOI:10.1007/978-1-4419-7756-4_31.
[12]BATTON B,LI L,NEWMAN N S,et al.Early blood pressure,anti-hypotensive therapy and outcomes at 18 to 22 month corrected age in extremely preterm infants[J].Arch Dis Child Fetal Neonatal Ed,2016,101(3):F201-206.DOI:10.1136/arch dischild-2015-308899.
[13]ALICIGUZEL Y,OZEN I,ASLAN M,et al.Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats[J].J Lab Clin Med,2003,142(3):172-177.DOI:10.1016/S0022-2143(03)00110-0.
[14]STEPANOVA E L,SKVARSKAIA E A.Role of polymorphism NOsynthase gene in the pathogenesis of multifactorial disease[J].Lik Sprava,2014(5/6):47-55.
[15]GIBSON C S,MACLENNAN A H,DEKKER G A,et al.Candidate genes and cerebral palsy:a population-based study[J].Pediatrics,2008,122(5):1079-1085.DOI:10.1542/peds.2007-3758.
[16]RUSAI K,VANNAY A,SZEBENI B,et al.Endothelial nitric oxide synthase gene T-786C and 27-bp repeat gene polymorphisms in retinopathy of prematurity[J].Mol Vis,2008,14:286-290.
[17]YANAMANDRA K,NAPPER D,PRAMANIK A,et al.Endothelial nitric oxide synthase genotypes in the etiology of retinopathy of prematurity in premature infants[J].Opthalmic Genet,2010,31(4):173-177.DOI:10.3109/13816810.2010.497528.
[18]SZPECHT D,GADZINOWSKI J,SEREMAK-MROZIKIEWICZ A,et al.Role of endothelial nitric oxide synthase and endothelin-1polymorphism genes with the pathogenesis of intraventricular hemorrhage in preterm infants[J].Sci Rep,2017,7:42541.DOI:10.1038/srep42541.
[19]DEMIRCUBUK A G,COSKUN M Y,DEMIRYUREK S,et al.Endothelial NOS gene Glu298Asp polymorphism in preterm neonates with respiratory distress syndrome[J].Pediatr Pulmonol,2013,48(10):976-980.DOI:10.1002/ppul.22759.
[2]马琼,杨文亮,郭华棋,等.内皮型一氧化氮基因(T786C)多态性与妊娠期高血压疾病关系的meta分析[J].中华围产医学杂志,2017,20(4):299-303.DOI:10.3760/cma.j.issn.1007-9408.2017.04.012.MA Q,YANG W L,GUO H Q,et al.Association between endothelial nitric oxide synthase gene(T786C)Polymorphism and hypertensive disorder of pregnancy:a meta-analysis[J].Chinese Journal of Perinatal Medicine,2017,20(4):299-303.DOI:10.3760/cma.j.issn.1007-9408.2017.04.012.
[3]VANNEMREDDY P,NOTARIANNI C,YANAMANDRA K,et al.Is an endothelial nitric oxide synthase gene mutation a risk factor in the origin of intraventricular hemorrhage?[J].Neurosurg Focus,2010,28(1):E11.DOI:10.3171/2009.10.FOCUS09143.
[4]POGGI C,GIUSTI B,GOZZINI E,et al.Genetic contributions to the development of complications in preterm newborns[J].PLoS One,2015,10(7):e0131741.DOI:10.1371/journal.pone.0131741.
[5]邵肖梅,叶鸿瑁,丘小汕.实用新生儿学[M].北京:人民卫生出版社,2011:416-422,706-715,477-483.SHAO X M,YE H M,QIU X S.Practice of eonatology[M].Beijing:People's Medical Publishing House,2011:416-422,706-715,477-483.
[6]中华医学会眼科学分会眼底病学组.中国早产儿视网膜病变筛查指南(2014年)[J].中华眼科杂志,2014,50(12):933-935.DOI:10.3760/cma.j.issn.0412-4081.2014.12.017.
[7]茹喜芳,冯琪.新生儿呼吸窘迫综合征的管理——欧洲共识指南2013版[J].中国新生儿科杂志,2013,28(5):356-358.DOI:10.3969/j.issn.1673-6710.2013.05.021.RU X F,FENG Q.The management of neonatal respiratory distress syndrome——European consensus guidelines 2013[J].Chinese Journal of Neonatology,2013,28(5):356-358.DOI:10.3969/j.issn.1673-6710.2013.05.021.
[8]FATINI C,SOFI F,GORI A M,et al.Endothelial nitric oxide synthase-786T>C,but not 894G>T and 4a4b polymorphism influences plasma homocysteine concentrations in persons with normal vitamin status[J].Clin Chem,2005,51(7):1159-1164.DOI:10.1373/clinchem.2005.048850.
[9]Variant:rs2070744.The 1000 Genomes Project Phase 3[EB/OL].(2015-10-01)[2017-05-02].http://www.Ensembl.org./Homo_sapiens/Variation/Population?db=core;r=7:150992491-150993491;V=rs2070744;vdb=variation;vf=1492708.
[10]Variant:rs1799983.The 1000 Genomes Project Phase 3[EB/OL].(2015-10-01)[2017-05-02].http://www.Ensembl.org./Homo_sapiens/Variation/Population?db=core;r=7:150998523-150999523;v=rs1799983;vdb=variation;vf=1244106.
[11]CAICEDO A,DE SMET D,VANDERHAEGEN J,et al.Impaired cerebral autoregulation using near-infrared spectroscopy and its relation to clinical outcomes in premature infants[J].Adv Exp Med Biol,2011,701:233-239.DOI:10.1007/978-1-4419-7756-4_31.
[12]BATTON B,LI L,NEWMAN N S,et al.Early blood pressure,anti-hypotensive therapy and outcomes at 18 to 22 month corrected age in extremely preterm infants[J].Arch Dis Child Fetal Neonatal Ed,2016,101(3):F201-206.DOI:10.1136/arch dischild-2015-308899.
[13]ALICIGUZEL Y,OZEN I,ASLAN M,et al.Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats[J].J Lab Clin Med,2003,142(3):172-177.DOI:10.1016/S0022-2143(03)00110-0.
[14]STEPANOVA E L,SKVARSKAIA E A.Role of polymorphism NOsynthase gene in the pathogenesis of multifactorial disease[J].Lik Sprava,2014(5/6):47-55.
[15]GIBSON C S,MACLENNAN A H,DEKKER G A,et al.Candidate genes and cerebral palsy:a population-based study[J].Pediatrics,2008,122(5):1079-1085.DOI:10.1542/peds.2007-3758.
[16]RUSAI K,VANNAY A,SZEBENI B,et al.Endothelial nitric oxide synthase gene T-786C and 27-bp repeat gene polymorphisms in retinopathy of prematurity[J].Mol Vis,2008,14:286-290.
[17]YANAMANDRA K,NAPPER D,PRAMANIK A,et al.Endothelial nitric oxide synthase genotypes in the etiology of retinopathy of prematurity in premature infants[J].Opthalmic Genet,2010,31(4):173-177.DOI:10.3109/13816810.2010.497528.
[18]SZPECHT D,GADZINOWSKI J,SEREMAK-MROZIKIEWICZ A,et al.Role of endothelial nitric oxide synthase and endothelin-1polymorphism genes with the pathogenesis of intraventricular hemorrhage in preterm infants[J].Sci Rep,2017,7:42541.DOI:10.1038/srep42541.
[19]DEMIRCUBUK A G,COSKUN M Y,DEMIRYUREK S,et al.Endothelial NOS gene Glu298Asp polymorphism in preterm neonates with respiratory distress syndrome[J].Pediatr Pulmonol,2013,48(10):976-980.DOI:10.1002/ppul.22759.