白细胞介素-15基因rs10833位点多态性与自发性早产遗传易感性的病例对照研究

A case-control study on the interleukin-15 rs10833 polymorphisms and susceptibility to spontaneous preterm birth

目的探讨白细胞介素-15(interleukin-15,IL-15)基因rs10833位点多态性与自发性早产遗传易感性的关联性,以获得中国人群的易感基因和单核苷酸多态性(single nucleotide polymorphisms,SNPs)。方法2009年1月至2014年9月,在解放军总医院第七医学中心八一儿童医院早产儿监护病房住院的新生儿中,选择遗传学上无关联的北京及周边地区的汉族人纳入研究。病例组为胎龄<37周、单胎妊娠、自发性早产的新生儿;对照组为胎龄≥37周的单胎妊娠,孕妇无自发性早产或早产胎膜早破(preterm rupture of membranes,PPROM)。采集新生儿EDTA抗凝血样本,采用最新Sequenom MassARRAY®SNP检测技术对IL-15基因rs10833位点多态性位点进行SNP分型。每个SNP位点的基因型频率和等位基因用频数(百分率)表示,并在共显性、显性、超显性、加性和隐性5种遗传模式中进行分析。采用χ2检验、Logistic回归进行统计学分析。结果病例组718例,进一步分为3个亚组(超早产组59例、极早产组186例、轻度早产组473例),对照组641例。病例组及3个亚组分别与对照组比较,等位基因G、A的分布频率、以及GG、GA、AA基因型的构成比,差异均无统计学意义(P>0.05);Logistic回归分析显示,IL-15基因rs10833位点与自发性早产的遗传易感性不相关,与超早产、极早产和轻度早产的遗传易感性也均不相关(P>0.05)。病例组进一步分为PPROM组197例、无PPROM组521例。PPROM组与对照组比较,A等位基因分布频率低于对照组(χ^2=5.660,P=0.020);两组间GG、GA、AA基因型构成比的差异无统计学意义(χ^2=5.510,P=0.060);Logistic回归分析显示,IL-15基因rs10833位点的A等位基因是PPROM的保护性等位基因且具有剂量效应,GA基因型是PPROM的保护性基因型。无PPROM组与对照组比较,A等位基因分布频率高于对照组(χ^2=4.310,P=0.038);两组间GG、GA、AA基因型构成比的差异无统计学意义(χ^2=5.340,P=0.070);Logistic回归分析显示,IL-15基因rs10833位点A等位基因是不合并PPROM的危险等位基因且具有剂量效应,A等位型(GA+AA基因型)是不合并PPROM的自发性早产的风险基因型。结论IL-15基因rs10833多态性位点的A等位基因和GA基因型可降低PPROM的患病风险。

Objective To analyze the association between the genetic polymorphisms of rs10833 locus of interleukin(IL)-15 gene and genetic susceptibility to spontaneous preterm birth(SPTB)and to obtain susceptibility genes and single nucleotide polymorphisms(SNPs)in Chinese population.Methods From January 2009 to September 2014,among the newborns hospitalized in the premature intensive care unit of Bayi Children's Hospital,the Seventh Medical Center of PLA General Hospital,Han nationality newborns from Beijing and surrounding areas who were not genetically related were selected for the study.In the case group,the newborns with gestational age less than 37 weeks,singleton pregnancy and SPTB were included.In the control group,the newborns with gestational age greater than 37 weeks and singleton pregnancy were included,and the pregnant women had no history of SPTB or preterm rupture of membranes(PPROM).Neonatal blood samples were collected and SNP typing of rs10833 polymorphism of IL-15 gene was carried out by using Sequenom MassARRAY®SNP technology.The genotype frequency and allele of each SNP locus were expressed by frequency(percentage),and were analyzed in five genetic models of codominance,dominance,superdominance,additiveness and recessiveness.The statistical analysis were performed byχ2 test and Logistic regression.Results 718 cases in the case group were further divided into three subgroups(59 cases in the super preterm group,186 cases in the extremely preterm group and 473 cases in the mild preterm group).The control group was 641 cases.There was no significant difference between the case group and the three subgroups compared with the control group in the distribution frequency of alleles G,A and the proportion of GG,GA,AA genotypes(P>0.05).Logistic regression analysis showed that rs10833 locus of IL-15 gene was not related to the genetic susceptibility of SPTB,and was not related to the genetic susceptibility of super preterm birth,extremely preterm birth and mild preterm birth(P>0.05).The patients of case group were further divided into two groups:PPROM group(197 cases)and without PPROM group(521 cases).The distribution frequency of A allele in PPROM group was lower than that in the control group(χ^2=5.660,P=0.020),but there was no significant difference in the proportion of GG,GA and AA genotypes in two groups(χ^2=5.510,P=0.060).Logistic regression analysis showed that the A allele of IL-15 rs10833 was the protective allele of PPROM and had dose effect,and GA genotype was the protective genotype of PPROM.The distribution frequency of A allele in the group without PPROM was higher than that in the control group(χ^2=4.310,P=0.038),but there was no significant statistical difference in the proportion of GG,GA,AA genotypes in two groups(χ^2=5.340,P=0.070).Logistic regression analysis showed that the A allele of IL-15 rs10833 was a risk allele without PPROM and had dose effect.The A allele(GA+AA genotype)was a risk genotype of SPTB without PPROM.Conclusion The A allele and GA genotype of rs10833 polymorphism of IL-15 gene can reduce the risk of PPROM.