Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
BMC Med Genet. 2011 Dec 30;12:174. doi: 10.1186/1471-2350-12-174.
Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. A number of candidate gene case-control studies have been performed on spontaneous PTD, but the results have been inconsistent, and do not fully assess the role of how two genotypes can impact outcome. To elucidate this latter point we re-analyzed data from a previously published case-control candidate gene study, using a case-parent triad design and a hybrid design combining case-parent triads and control-mother dyads. These methods offer a robust approach to genetic association studies for PTD compared to traditional case-control designs.
The study participants were obtained from the Norwegian Mother and Child Cohort Study (MoBa). A total of 196 case triads and 211 control dyads were selected for the analysis. A case-parent triad design as well as a hybrid design was used to analyze 1,326 SNPs from 159 candidate genes. We compared our results to those from a previous case-control study on the same samples. Haplotypes were analyzed using a sliding window of three SNPs and a pathway analysis was performed to gain biological insight into the pathophysiology of preterm delivery.
The most consistent significant fetal gene across all analyses was COL5A2. The functionally similar COL5A1 was significant when combining fetal and maternal genotypes. PON1 was significant with analytical approaches for single locus association of fetal genes alone, but was possibly confounded by maternal effects. Focal adhesion (hsa04510), Cell Communication (hsa01430) and ECM receptor interaction (hsa04512) were the most constant significant pathways.
This study suggests a fetal association of COL5A2 and a combined fetal-maternal association of COL5A1 with spontaneous PTD. In addition, the pathway analysis implied interactions of genes affecting cell communication and extracellular matrix.
自发性早产（PTD）具有多因素病因，其发病机制有遗传因素的证据。已经对自发性 PTD 进行了许多候选基因病例对照研究，但结果不一致，并且不能充分评估两种基因型如何影响结果。为了阐明后一点，我们使用病例-父母三胞胎设计和结合病例-父母三胞胎和对照-母亲二联体的混合设计，重新分析了先前发表的候选基因病例对照研究的数据。与传统病例对照设计相比，这些方法为 PTD 的遗传关联研究提供了一种强大的方法。
研究参与者来自挪威母亲和儿童队列研究（MoBa）。总共选择了 196 个病例三胞胎和 211 个对照二联体进行分析。使用病例-父母三胞胎设计和混合设计分析了来自 159 个候选基因的 1326 个 SNP。我们将我们的结果与同一样本的先前病例对照研究的结果进行了比较。使用三个 SNP 的滑动窗口分析单体型，并进行途径分析，以获得对早产发病机制的生物学见解。
在所有分析中，最一致的显著胎儿基因是 COL5A2。当组合胎儿和母体基因型时，功能相似的 COL5A1 是显著的。PON1 是在单独分析胎儿基因的单基因关联时具有统计学意义，但可能受到母体效应的混淆。焦点粘附（hsa04510）、细胞通讯（hsa01430）和 ECM 受体相互作用（hsa04512）是最恒定的显著途径。
这项研究表明 COL5A2 与自发性 PTD 具有胎儿关联，COL5A1 与胎儿-母体联合具有相关性。此外，途径分析暗示了影响细胞通讯和细胞外基质的基因相互作用。
