Preterm birth, small-for-gestational age (SGA) and pregnancy induced hypertension (PIH) are major pregnancy complications that impact the health of the mother and the child, often resulting in admission to the neonatal intensive care unit following delivery. We propose a highly efficient, intensive pathway-based analysis of genetic variation and preterm delivery, SGA, and PIH that addresses the following specific aims: (1) To investigate the relationship between polymorphisms in the cell-cycle and apoptosis pathways with risk of preterm delivery, SGA, term SGA and pregnancy induced hypertension (PIH);(2) To investigate the relationship between polymorphisms in the angiogenesis pathway with risk of SGA and PIH;(3) To investigate the relationship between polymorphisms in the inflammation pathway with risk of preterm delivery, total and term SGA, and PIH. To address these aims we will be drawing on a well- characterized prospective cohort study of preterm delivery, the Pregnancy, Infection and Nutrition study (PIN), which enrolled over five thousand women over the course of approximately 10 years. In a nested case-control subset of preterm (n=379), term SGA (n=281, an additional 90 are preterm), and PIH cases (n=468) and a random group of controls (n = 936), DNA has already be extracted and is available for genetic analyses. We propose to analyze these DNA specimens using a haplotype-based approach for approximately 93 genes of interest on the Illumina 1536 chip. The priority pathways we have identified bear relevance to the period of placentation, which is a period of development at which these outcomes may be etiologically linked. With additional investment, this cohort could provide the most comprehensive evidence to date linking variants in these pathways of interest with these adverse birth outcomes.

Public Health Relevance

This study promises to generate a markedly enhanced understanding of the genetic epidemiology of preterm, SGA and PIH. This information will provide a foundation for studying other adverse pregnancy outcomes with shared biological mechanisms.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Ilekis, John V
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Icahn School of Medicine at Mount Sinai
Public Health & Prev Medicine
Schools of Medicine
New York
United States
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He, Qianchuan; Cai, Tianxi; Liu, Yang et al. (2016) Prioritizing individual genetic variants after kernel machine testing using variable selection. Genet Epidemiol 40:722-731
Harmon, Quaker E; Engel, Stephanie M; Wu, Michael C et al. (2014) Polymorphisms in inflammatory genes are associated with term small for gestational age and preeclampsia. Am J Reprod Immunol 71:472-84
Harmon, Quaker E; Engel, Stephanie M; Olshan, Andrew F et al. (2013) Association of polymorphisms in natural killer cell-related genes with preterm birth. Am J Epidemiol 178:1208-18
Wu, Michael C; Maity, Arnab; Lee, Seunggeun et al. (2013) Kernel machine SNP-set testing under multiple candidate kernels. Genet Epidemiol 37:267-75