早产和胎膜早破中免疫调节基因的祖先信息标记及选定的单核苷酸多态性：一项病例对照研究。
Ancestry informative markers and selected single nucleotide polymorphisms in immunoregulatory genes on preterm labor and preterm premature rupture of membranes: a case control study.
作者信息
Ramos Bruna Ribeiro de Andrade, Mendes Niele Dias, Tanikawa Aline Aki, Amador Marcos Antônio Trindade, dos Santos Ney Pereira Carneiro, dos Santos Sidney Emanuel Batista, Castelli Erick C, Witkin Steven S, da Silva Márcia Guimarães
机构信息
Department of Pathology, Botucatu Medical School, São Paulo State University - UNESP, Distrito de Rubião Júnior, 18618-970, Botucatu, São Paulo, Brazil.
Blood Transfusion Center, Botucatu Medical School, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil.
出版信息
BMC Pregnancy Childbirth. 2016 Feb 5;16:30. doi: 10.1186/s12884-016-0823-1.
BACKGROUND
A genetic predisposition to Preterm Labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) has been suggested; however the relevance of polymorphisms and ancestry to susceptibility to PTL and PPROM in different populations remains unclear. The aim of this study was to evaluate the contribution of maternal and fetal SNPs in the IL1B, IL6, IL6R, TNFA, TNFR, IL10, TLR2, TLR4, MMP9, TIMP1 and TIMP2 genes and the influence of ancestry background in the susceptibility to PTL or PPROM in Brazilian women.
METHODS
Case-control study conducted at a tertiary hospital in São Paulo State, Brazil. We included women with PTL or PPROM and their babies (PTL: 136 women and 88 babies; PPROM: 65 women and 44 babies). Control group included 402 mother-babies pairs of term deliveries. Oral swabs were collected for identification of AIMs by fragment analysis and SNPs by Taqman® SNP Genotyping Assays and PCR. Linkage Disequilibrium and Hardy-Weinberg proportions were evaluated using Genepop 3.4. Haplotypes were inferred using the PHASE algorithm. Allele, genotype and haplotype frequencies were compared by Fisher's exact test or χ (2) and Odds Ratio. Logistic regression was performed. Clinical and sociodemographic data were analyzed by Fisher's exact test and Mann-Whitney.
RESULTS
PTL was associated with European ancestry and smoking while African ancestry was protective. The fetal alleles IL10-592C (rs800872) and IL10-819C (rs1800871) were also associated with PTL and the maternal haplotype TNFA-308G-238A was protective. Maternal presence of IL10-1082G (rs1800896) and TLR2A (rs4696480) alleles increased the risk for PPROM while TNFA-238A (rs361525) was protective. Family history of PTL/PPROM was higher in cases, and time to delivery was influenced by IL1B-31T (rs1143627) and TLR4-299G (rs4986790).
CONCLUSION
There is an association between European ancestry and smoking and PTL in our Brazilian population sample. The presence of maternal or fetal alleles that modify the inflammatory response increase the susceptibility to PTL and PPROM. The family history of PTL/PPROM reinforces a role for genetic polymorphisms in susceptibility to these outcomes.
背景
已有研究表明早产（PTL）和胎膜早破（PPROM）存在遗传易感性；然而，不同人群中多态性和血统与PTL和PPROM易感性的相关性仍不明确。本研究旨在评估巴西女性中白细胞介素1β（IL1B）、白细胞介素6（IL6）、白细胞介素6受体（IL6R）、肿瘤坏死因子α（TNFA）、肿瘤坏死因子受体（TNFR）、白细胞介素10（IL10）、Toll样受体2（TLR2）、Toll样受体4（TLR4）、基质金属蛋白酶9（MMP9）、金属蛋白酶组织抑制因子1（TIMP1）和金属蛋白酶组织抑制因子2（TIMP2）基因中母体和胎儿单核苷酸多态性（SNP）的贡献以及血统背景对PTL或PPROM易感性的影响。
方法
在巴西圣保罗州的一家三级医院进行病例对照研究。我们纳入了患有PTL或PPROM的女性及其婴儿（PTL组：136名女性和88名婴儿；PPROM组：65名女性和44名婴儿）。对照组包括402对足月分娩的母婴。通过片段分析收集口腔拭子以鉴定祖先信息标记（AIM），并通过Taqman® SNP基因分型检测和聚合酶链反应（PCR）检测SNP。使用Genepop 3.4评估连锁不平衡和哈迪-温伯格平衡比例。使用PHASE算法推断单倍型。通过Fisher精确检验或χ²检验以及优势比比较等位基因、基因型和单倍型频率。进行逻辑回归分析。通过Fisher精确检验和曼-惠特尼检验分析临床和社会人口统计学数据。
结果
PTL与欧洲血统和吸烟有关，而非洲血统具有保护作用。胎儿等位基因IL10 - 592C（rs800872）和IL10 - 819C（rs1800871）也与PTL有关，母体单倍型TNFA - 308G - 238A具有保护作用。母体存在IL10 - 1082G（rs1800896）和TLR2A（rs4696480）等位基因会增加PPROM的风险，而TNFA - 238A（rs361525）具有保护作用。PTL/PPROM的家族史在病例组中更高，分娩时间受IL1B - 31T（rs1143627）和TLR4 - 299G（rs4986790）影响。
结论
在我们的巴西人群样本中，欧洲血统和吸烟与PTL之间存在关联。改变炎症反应的母体或胎儿等位基因的存在会增加对PTL和PPROM的易感性。PTL/PPROM的家族史强化了基因多态性在这些结局易感性中的作用。
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