Journal
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
Volume 213, Issue 3, Pages -Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.ajog.2015.06.011
Keywords
cluster analysis; gene-based analysis; phenotype; spontaneous preterm birth
Categories
Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Genomic and Proteomic Network for Preterm Birth Research [U01-HD-050062, U01-HD-050078, U01-HD-050080, U01-HD-050088, U01-HD-050094]
- NICHD grant [5K23HD067224]
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OBJECTIVE: We sought to use an innovative tool that is based on common biologic pathways to identify specific phenotypes among women with spontaneous preterm birth (SPTB) to enhance investigators' ability to identify and to highlight common mechanisms and underlying genetic factors that are responsible for SPTB. STUDY DESIGN: We performed a secondary analysis of a prospective case-control multicenter study of SPTB. All cases delivered a preterm singleton at SPTB <= 34.0 weeks' gestation. Each woman was assessed for the presence of underlying SPTB causes. A hierarchic cluster analysis was used to identify groups of women with homogeneous phenotypic profiles. One of the phenotypic clusters was selected for candidate gene association analysis with the use of VEGAS software. RESULTS: One thousand twenty-eight women with SPTB were assigned phenotypes. Hierarchic clustering of the phenotypes revealed 5 major clusters. Cluster 1 (n = 445) was characterized by maternal stress; cluster 2 (n = 294) was characterized by premature membrane rupture; cluster 3 (n = 120) was characterized by familial factors, and cluster 4 (n = 63) was characterized by maternal comorbidities. Cluster 5 (n = 106) was multifactorial and characterized by infection (INF), decidual hemorrhage (DH), and placental dysfunction (PD). These 3 phenotypes were correlated highly by chi(2) analysis (PD and DH, P < 2.2e-6; PD and INF, P = 6.2e-10; INF and DH, (P = .0036). Gene-based testing identified the INS (insulin) gene as significantly associated with cluster 3 of SPTB. CONCLUSION: We identified 5 major clusters of SPTB based on a phenotype tool and hierarch clustering. There was significant correlation between several of the phenotypes. The INS gene was associated with familial factors that were underlying SPTB.
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