Abstract
BackgroundSpontaneous 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.MethodsThe 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.ResultsThe 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.ConclusionThis 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.
Highlights
Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis
Preterm delivery (PTD) is defined as delivery occurring before 37 weeks of gestation [1]
Spontaneous PTD is a common complex condition with no single environmental or genetic factor being completely responsible for its pathogenesis
Summary
Spontaneous preterm delivery (PTD) has a multifactorial etiology with evidence of a genetic contribution to its pathogenesis. Four different pathophysiological pathways have been proposed leading to spontaneous PTD through a common terminal pathway resulting in release of uterotonins and proteases that causes cervical ripening, uterus contractions and membrane rupture [6] These four pathways are: 1) activation of maternal or fetal hypothalamic pituitary-adrenal (HPA) axis, 2) local or systemic inflammation and infection, 3) decidual hemorrhage and 4) pathological distention of the uterus [6]. Immunological factors, such as abnormal allograft reaction and allergy, have been hypothesized as possible mechanisms for spontaneous PTD [7]. How each of these putative causal pathways function has been difficult to elucidate
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