TY - JOUR
T1 - Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida
AU - van der Linden, Ivon J.M.
AU - Nguyen, Uyen
AU - Heil, Sandra G.
AU - Franke, Barbara
AU - Vloet, Suzanne
AU - Gellekink, Henkjan
AU - Heijer, Martin den
AU - Blom, Henk J.
N1 - Funding Information: We would like to thank S.H.H.M. Vermeulen for her support with the statistical analyses. This study was supported by Grant No. MAR04-0121 from the Prinses Beatrix Fonds, The Netherlands, and Grant No. C042083 from The Dutch Kidney Foundation. Martin den Heijer is supported by The Netherlands Organization for Scientific Research (VENI grant NWO).
PY - 2007/5
Y1 - 2007/5
N2 - The dihydrofolate reductase (DHFR) enzyme is important for folate availability, folate turnover and DNA synthesis. The 19-bp deletion in intron-1 of DHFR has been associated with the risk of having spina bifida affected offspring, supposedly by changing DHFR gene expression. A 9-bp repeat in exon 1 of the mutS homolog 3 (MSH3) gene was recently demonstrated to be also located in the 5′UTR of DHFR and may possibly affect DHFR gene expression as well. We examined the association between these DHFR variants and spina bifida risk and investigated their effect on DHFR expression. Our study population, consisting of 121 mothers of a spina bifida affected child, 109 spina bifida patients, 292 control women and 234 pediatric controls was screened for the DHFR 19-bp deletion and the DHFR 9-bp repeat. DHFR gene expression was measured in 66 spina bifida patients, using real-time PCR analysis. In this study population, the DHFR 19-bp del/del genotype was not associated with spina bifida risk in mothers and children (OR: 0.8; 95%CI: 0.4-1.5 and OR: 1.2; 95%CI: 0.6-2.2, respectively) and both the WT/del and the del/del genotype did not affect DHFR expression relative to the WT/WT genotype (relative expression = 0.89, p = 0.46 and relative expression = 1.26, p = 0.24, respectively). The DHFR 9-bp repeat was not associated with spina bifida risk in mothers and children. DHFR expression of the 6/6 allele was 73% increased compared to the 3/3 allele, although not significantly (relative expression = 1.73, p = 0.09). We did not find evidence for an effect of the DHFR 19-bp deletion or 9-bp repeat on spina bifida risk in mothers and children. An effect of the 6/6 repeat genotype on DHFR expression cannot be ruled out.
AB - The dihydrofolate reductase (DHFR) enzyme is important for folate availability, folate turnover and DNA synthesis. The 19-bp deletion in intron-1 of DHFR has been associated with the risk of having spina bifida affected offspring, supposedly by changing DHFR gene expression. A 9-bp repeat in exon 1 of the mutS homolog 3 (MSH3) gene was recently demonstrated to be also located in the 5′UTR of DHFR and may possibly affect DHFR gene expression as well. We examined the association between these DHFR variants and spina bifida risk and investigated their effect on DHFR expression. Our study population, consisting of 121 mothers of a spina bifida affected child, 109 spina bifida patients, 292 control women and 234 pediatric controls was screened for the DHFR 19-bp deletion and the DHFR 9-bp repeat. DHFR gene expression was measured in 66 spina bifida patients, using real-time PCR analysis. In this study population, the DHFR 19-bp del/del genotype was not associated with spina bifida risk in mothers and children (OR: 0.8; 95%CI: 0.4-1.5 and OR: 1.2; 95%CI: 0.6-2.2, respectively) and both the WT/del and the del/del genotype did not affect DHFR expression relative to the WT/WT genotype (relative expression = 0.89, p = 0.46 and relative expression = 1.26, p = 0.24, respectively). The DHFR 9-bp repeat was not associated with spina bifida risk in mothers and children. DHFR expression of the 6/6 allele was 73% increased compared to the 3/3 allele, although not significantly (relative expression = 1.73, p = 0.09). We did not find evidence for an effect of the DHFR 19-bp deletion or 9-bp repeat on spina bifida risk in mothers and children. An effect of the 6/6 repeat genotype on DHFR expression cannot be ruled out.
KW - DHFR
KW - Real-time quantitative PCR
KW - Spina bifida
UR - http://www.scopus.com/inward/record.url?scp=34047248403&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ymgme.2007.01.009
DO - https://doi.org/10.1016/j.ymgme.2007.01.009
M3 - Article
C2 - 17336564
SN - 1096-7192
VL - 91
SP - 98
EP - 103
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1
ER -