Evaluation of genetic variants in the reduced folate carrier and in glutamate carboxypeptidase II for spina bifida risk
Introduction
Adequate folic acid intake in early pregnancy reduces the risk of neural tube defects (NTD) in the offspring. Although the mechanism by which this risk reduction occurs is unknown, research in recent years has focused on the identification of genetic variants in enzymes of folate metabolism that might modify risk for NTD. The first such polymorphism is the 677C → T substitution in 5,10-methylenetetrahydrofolate reductase (MTHFR) ([1], reviewed in [2]). In more recent studies, Devlin et al. [3] identified the 1561C → T (H475Y) variant in glutamate carboxypeptidase II (GCPII), which hydrolyzes the glutamate residue of folates at the intestinal brush border membrane; the presence of the mutant allele was associated with lower folate and higher homocysteine in an older English population. However, this variant was not preferentially transmitted to probands in an NTD study using TDT analysis [4].
A polymorphism in the gene for the reduced folate carrier (RFC-1), which transports 5-methyltetrahydrofolate across the plasma membrane, has been reported, but this variant (80A → G; H27R) was not associated with folate or homocysteine levels in a healthy French population [5]. Shaw et al. [6] found an increased risk for spina bifida in California newborns with the G80/G80 genotype whose mothers had not used vitamins. Although the spina bifida risk was not statistically significant, this study did reveal a modest gene-nutrient interaction between infant homozygosity for the RFC-1 G80/G80 genotype and maternal periconceptional intake of vitamins containing folic acid on the risk of spina bifida.
In this study, we assessed the potential impact of the RFC-1 and GCPII genotypes on nutrient and homocysteine levels, and on the risk for having an offspring with spina bifida.
Section snippets
Study population
We examined an extensively studied population reported in two other publications [7], [8]. Mothers of children with spina bifida were recruited from the Spina Bifida Clinic of The Montreal Children’s Hospital after approval of the protocol by the Institutional Review Board. The controls were mothers of other outpatients who were having a venipuncture at the Pediatric Test Center of The Montreal Children’s Hospital. A total of 19 mothers were excluded from the study population because of
Results
The distribution of RFC-1 genotypes is shown in Table 1. In the control population, 22% had the HH RFC1 genotype, while 54 and 24% had the HR and RR genotypes, respectively. For the GCPII genotype, 89% of control mothers had the HH genotype and 11% were heterozygous (HY). There were no homozygous YY mothers in our population. This distribution for GCPII was identical to that in the case mothers (data not shown).
There was no statistical association between spina bifida risk and RFC-1 or GCPII
Discussion
This is the first study to examine women for the H27R variant of the RFC-1 gene, to evaluate the risk of having an offspring with NTD. Women who were homozygous for the RR genotype had an increased risk for having a child with NTD, when compared with the HH genotype (OR=1.39), but this increase was not statistically significant. However, the RR genotype was associated with a significant 4.6-fold increase in risk when combined with low RBC levels. Our results are consistent with Shaw et al. [6]
Acknowledgements
This study was supported by a grant from the Canadian Institutes of Health Research to RR, who is also a Senior Scientist of the CIHR.
References (10)
- et al.
Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida
Lancet
(1995) - et al.
A Polymorphism (80G → A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia
Molec. Genet. Metab.
(2000) - et al.
5,10-methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGe review
Am. J. Epidemiol.
(2000) - et al.
Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia
Hum. Mol. Genet.
(2000) - et al.
Studies with His475Tyr glutamate carboxypeptidase II polymorphism and neural tube defects
Am. J. Med. Gen.
(2002)
Cited by (66)
Trophic Factor, Nutritional, and Hormonal Regulation of Brain Development
2017, Fetal and Neonatal Physiology, 2-Volume SetMolecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy
2014, Drug Metabolism and PharmacokineticsAssociation of glutamate carboxypeptidase II (GCPII) haplotypes with breast and prostate cancer risk
2013, GeneCitation Excerpt :The positive association between folate and prostate cancer risk observed in the current study is consistent with earlier studies (Collin et al., 2010a, 2010b). Out of the 52 SNPs reported in GCPII, only one SNP i.e. H475Y has been investigated extensively for possible association with different diseases (Afman et al., 2003; Chen et al., 2004; Födinger et al., 2003; Lopreato et al., 2008; Morin et al., 2003; Roffman et al., 2011; Winkelmayer et al., 2003). Study by Chen et al. showed a null association of this variant in colorectal cancer (Chen et al., 2004).
A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis
2013, Drug Metabolism and PharmacokineticsReduced folate carrier A80G polymorphism and susceptibility to neural tube defects: A meta-analysis
2012, GeneCitation Excerpt :Fig. 1 presents a flowchart for the process of articles inclusion/exclusion. Among these articles, 6 studies investigated the influence of RFC1 A80G polymorphism in mothers of NTDs offspring on NTDs risk (De Marco et al., 2001; Morin et al., 2003; O'leary et al., 2006; Pei et al., 2009; Relton et al., 2004b; Shang et al., 2008), 5 studies investigated the association of RFC1 A80G polymorphism in infants with NTDs (De Marco et al., 2001; O'leary et al., 2006; Pei et al., 2009; Relton et al., 2004b; Shaw et al., 2002). Table 1 summarizes the general characteristics of the studies included in the meta-analysis.
Paradoxical role of C1561T glutamate carboxypeptidase II (GCPII) genetic polymorphism in altering disease susceptibility
2012, GeneCitation Excerpt :This was consistent with Relton et al., study showing the increased risk of anencephalic pregnancy in GCPII H475Y variants (Relton et al., 2003). However, Morin et al., have observed that the GCPII variant (in the heterozygous state) did not influence NTD risk or metabolite levels with no homozygous mutant women observed in their study group (Morin et al., 2003). The association of GCPII H475Y variant with CAD risk was probably mediated through homocysteine.