Literature search results.

<p>Literature search results.</p

Pathway Analysis of Genetic Factors Associated with Spontaneous Preterm Birth and Pre-Labor Preterm Rupture of Membranes

<div><p>Background</p><p>Pre-term birth (PTB) remains the leading cause of infant mortality and morbidity. Its etiology is multifactorial, with a strong genetic component. Genetic predisposition for the two subtypes, spontaneous PTB with intact membranes (sPTB) and preterm prelabor rapture of membranes (PPROM), and differences between them, have not yet been systematically summarised.</p><p>Methods and findings</p><p>Our literature search identified 15 association studies conducted in 3,600 women on 2175 SNPs in 274 genes. We used Ingenuity software to impute gene pathways and networks related to sPTB and PPROM. Detailed insight in the defined functional ontologies clearly separated integrated datasets for sPTB and PPROM. Our analysis of upstream regulators of genes suggests that glucocorticoid receptor (NR3C1), peroxisome proliferator activated receptor γ (PPARG) and interferon regulating factor 3 (IRF3) may be sPTB specific. PPROM-specific genes may be regulated by estrogen receptor2 (ESR2) and signal transducer and activator of transcription (STAT1). The inflammatory transcription factor NFκB is linked to both sPTB and PPROM, however, their inflammatory response is distinctly different.</p><p>Conclusions</p><p>Based on our analyses, we propose an autoimmune/hormonal regulation axis for sPTB, whilst pathways implicated in the etiology of PPROM include hematologic/coagulation function disorder, collagen metabolism, matrix degradation and local inflammation. Our hypothesis generating study has identified new candidate genes in the pathogenesis of PPROM and sPTB, which should be validated in large cohorts.</p></div

Focus genes used in Ingenuity Pathway Analysis.

<p>Focus genes are defined in the Ingenuity Pathway Analysis as the important (associated or above a cutoff) genes which interact with molecules in the Global Molecular Network.</p><p>*The only gene from the list of 17 genes unique to PPROM that was not investigated in sPTB was TNFRSF6 (Highlighted in bold). All other genes were investigated in both, sPTB and PPROM, but were positive for PPROM only.</p><p>** From this list of 86 associated genes, 44 were investigated in sPTB only, but not in PPROM. Genes (N = 42) not validated for PPROM, are highlighted in bold.</p><p>Focus genes used in Ingenuity Pathway Analysis.</p

Top ranked gene network reconstructed from genes associated with sPTB (blue and orange blocks).

<p>Genes unique for the African American dataset, not studied in relation to pPROM condition are shown in orange. Links projected from ‘Functions and diseases’ (Fx) categories of IPA’s knowledge database are shown in oval shapes at the top of the figure. Lines correspond to functional (arrows) or physical interactions (lines) between proteins. An arrow indicates a regulatory vector. Solid lines imply direct relationships between proteins, dotted lines imply indirect interactions. Relationships include post-translational modifications, transcription regulation, proteolysis or co-expression. Different node shapes represent the following: complexes or unknown (NfkB), cytokines and growth factors (IL8), enzymes (DHFR), peptidases (MMP1), transcription regulators (NFKB1), nuclear receptors (NR3C1), channels (SCNN1A).</p

Top ranked upstream regulators (inner circle) suggested by IPA for preterm birth-associated genes (outer circle).

<p>Orange blocks-genes unique for sPTB, turquoise blocks- genes unique for pPROM and green blocks correspond to genes associated with both sPTB and pPROM. Functions of the main transcription regulators are presented with different colour lines. Blue lines represent both sPTB and pPROM regulators (NFkB1, NFkB complex), while turquoise and orange lines represent mainly pPROM (PPARG, IRF3 and NR3C1) and sPTB (STAT1 and ESR2), respectively. Genes with SNPs studied only in relation to sPTB in African American population are presented in red. Regulation by NFkB is shown in blue lines, IRF3 or NR3C1 in orange, ESR2 or STAT1 in turquoise. Arrows correspond to transcription regulation and lines to physical interactions between proteins. Solid lines imply direct and dotted lines imply indirect transcription regulation. Different node shapes and their functions are presented in the legend.</p

Top ranked gene network reconstructed from genes associated with PPROM (green and blue blocks).

<p>Green color represents pPROM specific functions, blue- genes associated with both sPTB and pPROM and yellow-functions specific for sPTB. Ovals- links projected from ‘Functions and diseases’ (Fx) and ‘Biomarkers’ (Bm) categories of IPA’s knowledge database. Lines correspond to functional (arrows) or physical interactions (lines) between proteins. An arrow indicates a regulatory vector. Solid lines imply direct relationships between proteins, dotted lines imply indirect interactions. Relationships include post-translational modifications, transcription regulation, proteolysis or co-expression. The blue lines indicate the NfkB area of influence. Different node shapes represent the following: complexes or unknown (an example is NfkB), cytokines and growth factors (as for CSF1), enzymes (NOS3), peptidases (MMP1), transcription regulators (TP53).</p

Demographic and clinical characteristics of women who were monitored at home (n = 70).

a<p>Mean (standard deviation).</p>b<p>Median (range).</p>c<p>Cord pHs - normal for these 3 cases.</p

Outcome of home monitoring.

a<p>Median (range).</p>b<p>Overall monitoring success rate - mean (SD).</p

Monitoring display.

<p>Continuous monitoring display from the MONICA AN24 device of fetal and maternal heart rate, uterine contractions and maternal movements. (Fetal heart rate – black line (top); maternal heart rate – green line (middle); Uterine contractions – black line (bottom); maternal movements – orange bars).</p

Risk factors for uterine rupture in women with prior delivery by caesarean section.

a<p>Percentage of individuals with complete data.</p>b<p>Adjusted for woman's age as a continuous linear term, ethnicity, body mass index as a continuous linear term, parity as a continuous linear term, number of previous caesarean deliveries as a continuous linear term, previous uterine surgery, interval between last caesarean section and last menstrual period as a categorical term, placenta praevia, and macrosomia.</p>c<p>Labour either not induced or induced without prostaglandin.</p