Preterm Birth in Caucasians Is Associated with Coagulation and Inflammation Pathway Gene Variants

Spontaneous preterm birth (<37 weeks gestation—PTB) occurs in ∼12% of pregnancies in the United States, and is the largest contributor to neonatal morbidity and mortality. PTB is a complex disease, potentially induced by several etiologic factors from multiple pathophysiologic pathways. To dissect the genetic risk factors of PTB a large-scale high-throughput candidate gene association study was performed examining 1536 SNP in 130 candidate genes from hypothesized PTB pathways. Maternal and fetal DNA from 370 US Caucasian birth-events (172 cases and 198 controls) was examined. Single locus, haplotype, and multi-locus association analyses were performed separately on maternal and fetal data. For maternal data the strongest associations were found in genes in the complement-coagulation pathway related to decidual hemorrhage in PTB. In this pathway 3 of 6 genes examined had SNPs significantly associated with PTB. These include factor V (FV) that was previously associated with PTB, factor VII (FVII), and tissue plasminogen activator (tPA). The single strongest effect was observed in tPA marker rs879293 with a significant allelic (p = 2.30×10−3) and genotypic association (p = 2.0×10−6) with PTB. The odds ratio (OR) for this SNP was 2.80 [CI 1.77–4.44] for a recessive model. Given that 6 of 8 markers in tPA were statistically significant, sliding window haplotype analyses were performed and revealed an associating 4 marker haplotype in tPA (p = 6.00×10−3). The single strongest effect in fetal DNA was observed in the inflammatory pathway at rs17121510 in the interleukin-10 receptor antagonist (IL-10RA) gene for allele (p = 0.01) and genotype (p = 3.34×10−4). The OR for the IL-10RA genotypic additive model was 1.92 [CI 1.15–3.19] (p = 2.00×10−3). Finally, exploratory multi-locus analyses in the complement and coagulation pathway were performed and revealed a potentially significant interaction between a marker in FV (rs2187952) and FVII (rs3211719) (p<0.001). These results support a role for genes in both the coagulation and inflammation pathways, and potentially different maternal and fetal genetic risks for PTB.

自发性早产（Spontaneous preterm birth, PTB，妊娠<37周）在美国约占所有妊娠的12%，是新生儿发病与死亡的首要诱因。早产是一类复杂疾病，可能由多条病理生理通路中的多种致病因素诱发。为解析早产的遗传风险因素，本研究开展了一项大规模高通量候选基因关联研究，针对已被假说关联到早产通路的130个候选基因中的1536个单核苷酸多态性（Single Nucleotide Polymorphism, SNP）进行了检测。研究对370例美国白人分娩样本的母体与胎儿DNA进行了检测，其中病例组172例，对照组198例。研究分别针对母体与胎儿数据开展了单基因座、单倍型以及多基因座关联分析。针对母体数据的分析显示，与早产相关的蜕膜出血有关的补体-凝血通路中的基因呈现最强关联信号。该通路中检测的6个基因里有3个的SNP与早产存在显著关联，其中包括既往已被报道与早产相关的凝血因子V（Factor V, FV）、凝血因子VII（Factor VII, FVII）以及组织型纤溶酶原激活物（tissue plasminogen activator, tPA）。其中关联效应最强的位点为tPA上的rs879293，其等位基因关联（p=2.30×10⁻³）与基因型关联（p=2.0×10⁻⁶）均与早产存在显著相关性；该SNP在隐性遗传模型下的比值比（Odds Ratio, OR）为2.80[95%置信区间（Confidence Interval, CI）1.77–4.44]。鉴于tPA区域内8个标记位点中有6个具有统计学显著性，本研究开展了滑动窗口单倍型分析，结果发现tPA上存在一段由4个标记位点组成的关联单倍型（p=6.00×10⁻³）。胎儿数据中关联效应最强的位点位于炎症通路上的白细胞介素-10受体拮抗剂（Interleukin-10 Receptor Antagonist, IL-10RA）基因的rs17121510，其等位基因关联（p=0.01）与基因型关联（p=3.34×10⁻⁴）均显著；该基因在加性遗传模型下的比值比为1.92[CI 1.15–3.19]（p=2.00×10⁻³）。最后，本研究针对补体与凝血通路开展了探索性多基因座分析，结果发现凝血因子V上的rs2187952与凝血因子VII上的rs3211719之间存在潜在的显著交互作用（p<0.001）。上述研究结果证实，凝血通路与炎症通路中的基因均参与了早产的发病过程，且母体与胎儿可能存在不同的早产遗传风险。