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    • In this study we examined a possible

    2019-09-09

    In this study, we examined a possible association between the 19-bp Conoidin A and the 9-bp repeat in the DHFR gene and the risk of spina bifida in 121 mothers of a spina bifida affected child, 292 control women, 109 spina bifida patients and 234 pediatric controls using a case-control design. Furthermore, we investigated the effect of the DHFR 19-bp deletion and the DHFR 9-bp repeat on DHFR expression levels in cultured lymphoblasts of 66 spina bifida patients using real-time quantitative PCR.
    Material and methods
    Results
    Discussion In our study population the DHFR del/del genotype was not associated with spina bifida risk in mothers and in children and had no effect on DHFR expression. Johnson et al. demonstrated a twofold increased risk of having a spina bifida affected child for the DHFR del/del genotype relative to the DHFR WT/del and WT/WT genotypes (OR: 2.0; 95%CI: 0.9–4.3) and suggested that the deletion of a possible Sp1 transcription factor binding site, and hence decreased DHFR expression levels, could explain the observed effect of the DHFR 19-bp deletion on maternal spina bifida risk [8]. Although we did not observe an effect of the DHFR del/del genotype on spina bifida risk, we wanted to test this hypothesis of Johnson et al. and examined DHFR expression in 66 spina bifida patients. No changes in DHFR expression levels were observed among the different DHFR 19-bp deletion genotypes. The finding of Noé et al. that removing all introns does not affect DHFR mRNA expression levels in hamster cellines further supports our finding that the deletion of 19-bp in intron-1 of the DHFR gene does not affect DHFR expression levels [18]. A possible explanation for the difference in the observed effect of the DHFR 19-bp deletion on spina bifida risk between our study and the study of Johnson et al. could be the difference in study population. The study population of Johnson et al. consists of families with two or more individuals affected with spina bifida, whereas our study population consists of unrelated spina bifida cases. As they mention, families with two or more spina bifida patients may differ from single case families in ways we do not understand yet [8]. In a previous study of our group, we examined the effect of the DHFR 19-bp deletion on plasma homocysteine concentration [7]. In that study, we demonstrated a significant 14.4% decrease in plasma homocysteine concentration for the DHFR del/del genotype relative to the WT/WT genotype (95%CI: −23.4% to −4.5%). In the current study we used a subset of the study population from our previous study [7], namely only the control women. This could explain the finding that in the present study the DHFR 19-bp deletion does not affect plasma homocysteine concentration. The fact that the DHFR del/del genotype also decreased plasma homocysteine concentration in the pediatric control group supports the data of our previous study [7]. In the case mothers there was a trend towards lower RBC folate concentration for the DHFR WT/del and del/del genotypes relative to the DHFR WT/WT genotype. However, this effect of the DHFR 19-bp deletion was confined to the case mothers, indicating that this may be a chance finding and not an effect of the genetic variant itself. A 9-bp repeat in exon 1 of the MSH3 gene identified by Nakajima et al. [9] was recently described to be also located in the 5′UTR of the DHFR gene by our group [7]. To our knowledge, this is the first time that the DHFR 9-bp repeat is examined in relation to spina bifida risk. Because of the large variety in genotypes, statistical analyses for the DHFR 9-bp repeat were complicated. Therefore we decided to analyze only those genotypes that were relatively frequent in our population (>5%). In mothers, the DHFR 9-bp repeat was not associated with spina bifida risk, except for the 3/6 genotype that might increase the risk of having spina bifida affected offspring 2 times compared to the 3/3 genotype (OR: 2.1; 95%CI: 0.8–5.3). Based on the possible effect of the heterozygous DHFR 3/6 genotype on spina bifida risk, we expected an increased risk of having a spina bifida affected child when having the homozygous DHFR 6/6 genotype. This was not the case and therefore the observation that the DHFR 3/6 genotype increases maternal spina bifida risk is likely a chance finding possibly due to the small study population.