Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study - Maternal Glycemia and Birthweight GEI Study

Low and high birth weight are not only major causes of neonatal morbidity and mortality, but epidemiological data have established an association between birth weight and later life risk of adult metabolic diseases. Fetal growth is determined by complex interactions between fetal genes and the maternal uterine environment. Subtle or overt variation in maternal glucose tolerance, which is, in part, genetically determined, is related to fetal size at birth. Moreover, new emerging data suggest that genetic variation in the fetus can impact maternal metabolism (e.g., blood pressure and glucose tolerance). Given the above, we are addressing the hypothesis that, during pregnancy, gene-environment interactions in the context of the maternal-fetal unit impact fetal size at birth and maternal metabolism. Genes that control fetal growth or maternal metabolism during pregnancy are largely unknown, so the first step to address our hypothesis will be to identify genetic variation that impacts fetal growth and maternal metabolism and to determine the interaction of that variation with the intrauterine and fetal environment.

To accomplish this, we are performing genome wide association (GWA) mapping on a subset of ~37,000 DNA samples that were collected from mothers and their offspring as part of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO is a multicenter, international study in which high quality phenotypic data related to fetal growth and maternal glucose metabolism has been collected from 25,000 pregnant women of varied racial and socio-demographic backgrounds using standardized protocols that were uniform across centers. For these studies, we are genotyping 1,500 infants and their mothers of European descent, 1,250 Afro-Caribbean infants and mothers, 800 Hispanic (Mexican-American) infants and mothers, and 1200 Thai infants and mothers. Genotyping is being performed using the Illumina Human610 Quad (European ancestry participants), Human1M Duo (Afro-Caribbean and Hispanic participants), and Omni1-Quad_v1-0_B (Thai participants).

The specific aims for the project are as follows: (1) To apply analytic approaches for conducting GWA mapping studies on quantitative phenotypes related to offspring size at birth (birth weight, ponderal index, head circumference and adiposity) allowing for other known influences such as gestational age, parity, and maternal weight gain. (2) To apply the above approaches to identify genetic variation that impacts maternal glucose tolerance at ~28 weeks of gestation (fasting glucose, glucose during an oral glucose tolerance test, and insulin sensitivity expressed as quantitative traits) allowing for other known influences such as maternal weight gain, parity and age. (3) To examine the interaction between maternal genes, the intrauterine environment, and fetal genes to identify interactions that modulate genetic regulation of size at birth and fetal genetic variation that impacts on maternal glucose tolerance. GWA mapping will provide initial evidence for association of specific SNPs with the quantitative traits outlined above.

As low and high birth weight are not only major causes of neonatal morbidity and mortality but have also been associated with increased risk of metabolic diseases in adults, identification of genes that regulate fetal growth and maternal metabolism will provide novel information about the pathways that regulate these processes as well as important insight into susceptibility genes for chronic diseases like type 2 diabetes.

The Version 1 (v1) dbGaP release will include data only from the Hispanic study participants. The Version 2 (v2) dbGaP release will include data from the Hispanic and European ancestry study participants. The Version 3 (v3) dbGaP release will include data from the Afro-Caribbean, Hispanic and European ancestry participants. The Version 4 (v4) dbGaP release will include data from all participants (i.e., Afro-Caribbean, Hispanic, European ancestry, and Thai participants).

This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to maternal metabolism and birthweight through large-scale genome-wide association studies of infants and their mothers at multiple international sites. Genotyping was performed at the Broad Institute of MIT and Harvard, and at CIDR of Johns Hopkins University, GENEVA genotyping centers. Data cleaning and harmonization was performed at the GEI-funded GENEVA Coordinating Center at the University of Washington.

• Study Design:
  • Prospective Longitudinal Cohort
• Study Type:
  • Prospective
  • Observational
  • Cohort
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 9987
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH
• PMC

A pregnant woman was ineligible to participate in HAPO if any of the following exclusion criteria applied:

1. Age < 18 years, i.e., has not completed 18th year of life by the first interview.
2. Planning to deliver at another hospital or location.
3. Date of last menstrual period is not certain AND no ultrasound estimation from 6-24 weeks of gestational age is available or will be available.
4. Unable to complete OGTT within 32 weeks gestation, or currently > 31 weeks gestation.
5. Known multiple pregnancy.
6. Became pregnant with assistance of advanced reproductive technology such as in vitro fertilization (IVF) or superovulation with gonadotropins.
7. Any unblinded blood glucose testing AND/OR diagnosis of GDM during this pregnancy prior to enrollment in this protocol.
8. Previous diagnosis of diabetes requiring treatment with medication outside of pregnancy.
9. Currently receiving treatment with oral glucocorticoids, thiazide diuretics, -blockers, ACE inhibitors, oral -mimetics, dilantin, or antiretroviral agents.
10. Participation in another study which may interfere with the HAPO Study.
11. Known to be HIV positive or to have Hepatitis B or C.
12. Participation in the HAPO Study during a previous pregnancy.
13. Inability to converse in language(s) used in field center forms without the aid of an interpreter.

Note: Women with any of the exclusion criteria present (except 11) were excluded since any of these criteria may confound study results. Women with criterion 11 present were excluded for protection of others since blood samples were transported across international borders.

2001-2006: Participant enrollment
2006: Final HAPO baby delivered
2006-2007: Data cleanup
06/2007: Initial results presented

HAPO enrolled over 25,000 pregnant women at 15 field centers in 9 countries. DNA was collected from ~18,000 mothers and 17,000 babies at 14 field centers. As part of this study, DNA from ~4,600 mothers and 4,600 babies (~90% of which were from a mother-baby pair) was included in this GWA study. Study participants are of Hispanic (Bellflower, CA), Afro-Caribbean (Barbados), European ancestry (Toronto, Canada, Belfast, UK, Brisbane and Newcastle, Australia), and Thai (Bangkok) descent.

• Primary Phenotype: Pregnancy Complications
• Pregnancy

• Principal Investigator
  • William L. Lowe, Jr, MD. Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
• Institute
  • National Human Genome Research Institute. National Institutes of Health, Bethesda, MD, USA.
• Funding Source
  • U01 HG004415. National Institutes of Health, Bethesda, MD, USA.
• Co-Investigators
  • Geoff Hayes, PhD. Northwestern University Feinberg School of Medicine, Chicago, IL USA.
  • Boyd E. Metzger, MD. Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Alan R. Dyer, PhD. Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Lynn P. Lowe, PhD. Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Margrit Urbanek, PhD. Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • Nancy Cox, PhD. Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.
  • Dan Nicolae, PhD. Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.