Open Access Research article

Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study

Wei Lu1, Adrian R Guzman1, Wei Yang2, Claudia J Chapa5, Gary M Shaw2, Robert M Greene3, M Michele Pisano3, Edward J Lammer4, Richard H Finnell5 and Huiping Zhu5*

Author Affiliations

1 Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX, USA

2 Stanford University, Stanford, CA, USA

3 University of Louisville Birth Defects Center, Louisville, KY, USA

4 Children's Hospital Oakland Research Institute, Oakland, CA, USA

5 Dell Pediatric Research Institute, UT Austin, Austin, TX, USA

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BMC Medical Genetics 2010, 11:141  doi:10.1186/1471-2350-11-141

Published: 8 October 2010



Spina bifida is a malformation of the neural tube and is the most common of neural tube defects (NTDs). The etiology of spina bifida is largely unknown, although it is thought to be multi-factorial, involving multiple interacting genes and environmental factors. Mutations in transcriptional co-activator genes-Cited2, p300, Cbp, Tfap2α, Carm1 and Cart1 result in NTDs in murine models, thus prompt us to investigate whether homologues of these genes are associated with NTDs in humans.


Data and biological samples from 297 spina bifida cases and 300 controls were derived from a population-based case-control study conducted in California. 37 SNPs within CITED2, EP300, CREBBP, TFAP2A, CARM1 and ALX1 were genotyped using an ABI SNPlex assay. Odds ratios and 95% confidence intervals were calculated for alleles, genotypes and haplotypes to evaluate the risk for spina bifida.


Several SNPs showed increased or decreased risk, including CITED2 rs1131431 (OR = 5.32, 1.04~27.30), EP300 rs4820428 (OR = 1.30, 1.01~1.67), EP300 rs4820429 (OR = 0.50, 0.26~0.50, in whites, OR = 0.7, 0.49~0.99 in all subjects), EP300 rs17002284 (OR = 0.43, 0.22~0.84), TFAP2A rs3798691 (OR = 1.78, 1.13~2.87 in Hispanics), CREBBP rs129986 (OR = 0.27, 0.11~0.69), CARM1 rs17616105 (OR = 0.41, 0.22~0.72 in whites). In addition, one haplotype block in EP300 and one in TFAP2A appeared to be associated with increased risk.


Modest associations were observed in CITED2, EP300, CREBBP, TFAP2A and CARM1 but not ALX1. However, these modest associations were not statistically significant after correction for multiple comparisons. Searching for potential functional variants and rare causal mutations is warranted in these genes.