The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk for spina bifida in the Irish population.

Abstract

Periconceptional maternal folic acid supplementation can prevent up to 70% of pregnancies affected with neural tube defects (NTDs), including spina bifida. This has focused attention on folate-related genes such as dihydrofolate reductase (DHFR) in a bid to identify the genetic factors that influence NTD risk through either the fetal or maternal genotype. We considered a novel intronic 19-bp deletion polymorphism and two polymorphisms within the 3' untranslated region (721A>T and 829C>T) of the DHFR gene as candidates for NTD risk. We studied NTD cases (n=283), mothers of cases (n=280), fathers of cases (n=279), and controls (n=256). We did not find the DHFR 829C>T polymorphism to be variable within the Irish population. The 19-bp intron deletion and the 721A>T polymorphisms were found to be in linkage disequilibrium. In contrast to a previous study, the 19-bp intron deletion allele did show a significant protective effect in mothers of NTD cases when present in one (relative risk 0.59 [95%CI: 0.39-0.89], P=0.01) or two copies (relative risk 0.52 [95%CI: 0.32-0.86], P=0.01). Analysis of mRNA levels revealed a small increase in expression ( approximately 1.5-fold) associated with the 19-bp intron deletion polymorphism, but this was not significant. In conclusion, the DHFR intron 19-bp deletion allele may be a protective NTD genetic factor by increasing DHFR mRNA levels in pregnant women.

• Authors: Anne Parle-McDermott, Faith Pangilinan, James L Mills, Peadar N Kirke, Eileen R Gibney, James Troendle, Valerie B O'Leary, Anne M Molloy, Mary Conley, John M Scott, Lawrence C Brody
• Journal: American journal of medical genetics. Part A (Am J Med Genet A) Vol. 143A Issue 11 Pg. 1174-80 (Jun 01 2007) ISSN: 1552-4825 [Print] United States
• PMID: 17486595 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2007 Wiley-Liss, Inc.

Chemical References

• RNA, Messenger
• Tetrahydrofolate Dehydrogenase

Topics

• Base Pairing
• Case-Control Studies
• Exons (genetics)
• Female
• Gene Expression Regulation, Enzymologic
• Haplotypes
• Humans
• Introns (genetics)
• Ireland
• Male
• Odds Ratio
• Polymorphism, Genetic
• Pregnancy
• RNA, Messenger (genetics, metabolism)
• Risk Factors
• Sequence Deletion (genetics)
• Spinal Dysraphism (enzymology, genetics)
• Tetrahydrofolate Dehydrogenase (genetics)
• White People (genetics)