Frey Heather A, Stout Molly J, Pearson Laurel N, Tuuli Methodius G, Cahill Alison G, Strauss Jerome F, Gomez Luis M, Parry Samuel, Allsworth Jenifer E, Macones George A
Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH.
Department of Obstetrics and Gynecology, Washington University in St Louis, St Louis, MO.
Am J Obstet Gynecol. 2016 Aug;215(2):235.e1-8. doi: 10.1016/j.ajog.2016.03.008. Epub 2016 Mar 12.
Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery.
The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women.
This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks' gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self-identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single-nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks' gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term.
Of the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-α (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single-nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single-nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term.
We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African-American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity.
早产被认为是一种多因素导致的情况；然而，新出现的证据表明个体间的基因变异可能起重要作用。先前的研究表明，与免疫系统相关基因，尤其是母体炎症反应相关的单核苷酸多态性，可能与早产风险增加有关。
本研究的目的是在一组非裔美国女性队列中识别与<37周自然早产相关的单核苷酸多态性。
这是一项对评估牙周疾病与早产的随机试验的二次分析。2004年至2007年期间，在3家产前保健诊所招募妊娠6至20周的女性。收集母体DNA样本，并使用定制的1536单核苷酸多态性基因分型芯片进行分析，该芯片旨在评估参与炎症的基因。如果女性自我认定为非裔美国人，则纳入本研究。我们排除了多胎妊娠或医源性早产的女性。我们进行了基于等位基因和基因型的分析，以评估自然早产与标签单核苷酸多态性之间的关联。在基于基因型的分析中，我们使用逻辑回归来调整先前的早产情况。在亚组分析中，我们将妊娠<34周分娩的女性与足月分娩的女性进行了比较。在芯片内，我们识别了祖先信息标记，并比较了早产女性与足月分娩女性之间的全基因组祖先估计。
在该研究中有基因型数据的833名非裔美国女性中，77名女性（9.2%）自然早产，而756名女性足月分娩。在基于等位基因的分析中，4个与蛋白激酶C-α（PRKCA）基因相关的单核苷酸多态性与<37周自然早产风险增加有关，而1个与fms相关酪氨酸激酶1（FLT1）相关的单核苷酸多态性与<34周自然早产有关。基于基因型的分析揭示了与PRKCA基因相关的单核苷酸多态性与自然早产之间的类似关联。此外，在基于基因型的分析中，与基质金属蛋白酶-2（MMP2）、基质金属蛋白酶组织抑制剂-2（TIMP2）和白细胞介素16（IL16）基因相关的单核苷酸多态性与<3周自然早产有关。与MMP2、基质金属蛋白酶-1（MMP1）和白血病抑制因子受体反义RNA 1（LIFR-AS1）基因相关的基因变异与<34周较高的早产率有关。自然早产女性与足月分娩女性之间的祖先估计相似。
我们识别了与7个对炎症、细胞外重塑和细胞信号传导至关重要的基因相关的标签单核苷酸多态性，这些基因与非裔美国女性的自然早产有关。具体而言，我们发现与PRKCA基因有很强的关联。基因组这些区域的基因变异可能在早产的发病机制中起重要作用。在未来早产的基因组研究设计中应考虑我们的结果。
