Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms.

Abstract:

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 χ(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.

journal_name

Am J Obstet Gynecol

authors

Esplin MS,Manuck TA,Varner MW,Christensen B,Biggio J,Bukowski R,Parry S,Zhang H,Huang H,Andrews W,Saade G,Sadovsky Y,Reddy UM,Ilekis J

doi

10.1016/j.ajog.2015.06.011

subject

Has Abstract

pub_date

2015-09-01 00:00:00

pages

429.e1-9

issue

3

eissn

0002-9378

issn

1097-6868

pii

S0002-9378(15)00594-3

journal_volume

213

pub_type

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