Anorectal atresia and Variants at Predicted Regulatory Sites in Candidate Genes. (6th November 2012)

• Record Type: Journal Article
• Authors: Carter, Tonia C.; Kay, Denise M.; Browne, Marilyn L.; Liu, Aiyi; Romitti, Paul A.; Kuehn, Devon; Conley, Mary R.; Caggana, Michele; Druschel, Charlotte M.; Brody, Lawrence C.; Mills, James L.
• Is Part Of: Annals of human genetics. Volume 77:Number 1(2013:Jan.)
• Page Start: 31
• Page End: 46
• Publication Date: 2012-11-06
• Subjects: Human genetics -- Periodicals; 599.935
• DOI: 10.1111/j.1469-1809.2012.00734.x
• Languages: English
• ISSNs: 0003-4800

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in <italic>WNT3A</italic>, <italic>PCSK5</italic>, <italic>TCF4</italic>, <italic>MKKS</italic>, <italic>GLI2</italic>, <italic>HOXD12</italic>, and <italic>BMP4</italic> were associated with anorectal atresia based on a nominal <italic>P</italic> value < 0.05. The <italic>GLI2</italic> and <italic>BMP4</italic> variants are reported to be moderately associated with gene expression changes (Spearman's rank correlation coefficients between −0.260 and 0.226). We did not find evidence for interaction between maternal pre‐pregnancy obesity and variants in <italic>MKKS</italic>, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for <italic>MKKS</italic> support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered <italic>GLI2</italic> and <italic>BMP4</italic> expression is important in anorectal atresia in humans.</p> </abstract>