Birth defects are among the leading causes of infant mortality worldwide, yet primary prevention is limited. Congenital heart defects, including right- and left-sided obstructive heart defects (OHDs), are among the most serious and lethal of birth defects. Congenital heart defects occur in 8 of every 1,000 live births in the United States, and a quarter of these are OHDs. Most genetic studies of OHDs have focused on specific biological pathways, leaving the vast majority of the genome unexplored. We propose, therefore, a genome-wide scan of OHDs, taking advantage of recently available genetic tools based on the International HapMap and 1000 Genomes projects. We hypothesize that OHDs are associated with maternal and infant genetic variants, copy number variants (CNVs), and gene-specific DNA methylation patterns. Crucial to the proposed study is our access to thousands of previously collected DNA samples from the National Birth Defects Prevention Study (NBDPS). The NBDPS is the largest case-control study of birth defects ever conducted in the United States. Its sample is a well-characterized population-based cohort defined by uniform diagnostic criteria, which has accompanying maternal reports of pregnancy exposures and lifestyle factors. In the discovery phase of our proposed project, we will use the Illumina HumanOmni2.5-8 BeadChip to genotype both common and rare single nucleotide polymorphisms (SNPs) and CNVs in 1,000 case-parental triads and control-maternal dyads (5,000 subjects total) who participated in the Arkansas, California, or Iowa NBDPS sites. In the validation phase, we will use a custom GoldenGate SNP array to validate the role of 1,536 SNPs identified in the discovery phase, in a sample of 1,000 case-parental triads and 1,000 control-maternal dyads (again, 5,000 subjects total) who participated in the five remaining NBDPS sites. In parallel to these efforts, we will compare gene-specific methylation profiles between 250 OHD case-maternal dyads to those of 250 control-maternal dyads (1,000 subjects total) using the Illumina Infinium HumanMethylation450 BeadChip. Our project brings together expert scientists from six birth defects research programs to integrate genomic and epigenomic findings and identify novel pathways involved in the etiology of OHDs. Through our discoveries, we will contribute to a substantially richer understanding of the etiology of OHDs, providing a foundation for public health and clinical prevention and treatment strategies.

Public Health Relevance

Congenital obstructive heart defects are among the most prevalent and serious of birth defects, affecting about 1% of all live births. Most research studie of CHDs focus on selected candidate pathways, leaving most of the genome unexplored. We propose a genetic and epigenetic approach that will take advantage of recently available technological advances based on the 1000 Genomes;thereby, making our findings of the proposed study a significant contribution to evidence-based public health and clinical interventions to prevent and treat congenital obstructive heart defects.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039054-13
Application #
8644812
Study Section
Special Emphasis Panel (ZRG1-PSE-K (03))
Program Officer
Javois, Lorette Claire
Project Start
2000-09-25
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$1,054,555
Indirect Cost
$276,856
Name
Arkansas Children's Hospital Research Institute
Department
Type
DUNS #
002593692
City
Little Rock
State
AR
Country
United States
Zip Code
72202
Hobbs, Charlotte A; Chowdhury, Shimul; Cleves, Mario A et al. (2014) Genetic epidemiology and nonsyndromic structural birth defects: from candidate genes to epigenetics. JAMA Pediatr 168:371-7
Shaw, Gary M; Yang, Wei; Carmichael, Suzan L et al. (2014) One-carbon metabolite levels in mid-pregnancy and risks of conotruncal heart defects. Birth Defects Res A Clin Mol Teratol 100:107-15
Li, Ming; Cleves, Mario A; Mallick, Himel et al. (2014) A genetic association study detects haplotypes associated with obstructive heart defects. Hum Genet 133:1127-38
Li, Ming; Erickson, Stephen W; Hobbs, Charlotte A et al. (2014) Detecting maternal-fetal genotype interactions associated with conotruncal heart defects: a haplotype-based analysis with penalized logistic regression. Genet Epidemiol 38:198-208
Tang, Xinyu; Nick, Todd G; Cleves, Mario A et al. (2014) Maternal obesity and tobacco use modify the impact of genetic variants on the occurrence of conotruncal heart defects. PLoS One 9:e108903
Hobbs, Charlotte A; Cleves, Mario A; Macleod, Stewart L et al. (2014) Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways. Birth Defects Res A Clin Mol Teratol 100:116-26
Cleves, Mario A; Hobbs, Charlotte A; Zhao, Weizhi et al. (2011) Association between selected folate pathway polymorphisms and nonsyndromic limb reduction defects: a case-parental analysis. Paediatr Perinat Epidemiol 25:124-34
Chowdhury, Shimul; Erickson, Stephen W; MacLeod, Stewart L et al. (2011) Maternal genome-wide DNA methylation patterns and congenital heart defects. PLoS One 6:e16506
Chowdhury, Shimul; Cleves, Mario A; MacLeod, Stewart L et al. (2011) Maternal DNA hypomethylation and congenital heart defects. Birth Defects Res A Clin Mol Teratol 91:69-76
Hobbs, Charlotte A; Cleves, Mario A; Karim, Mohammad A et al. (2010) Maternal folate-related gene environment interactions and congenital heart defects. Obstet Gynecol 116:316-22

Showing the most recent 10 out of 21 publications