Spina bifida and folate-related genes: A study of gene-gene interactions

Abstract

Purpose: To assess whether interactions of common alleles of two folate genes contribute to spina bifida risk.Methods: Case-control study, comparing 203 children with spina bifida to 583 controls. Results: Homozygosity for the 677C-T allele of 5,10-methylenetetrahydrofolate reductase (MTHFR) alone was associated with an odds ratio for spina bifida of 1.57 (95% confidence interval [CI], 1.02-2.38). For the 844ins68 allele of cystathionine-␤-synthase alone, the odds ratio was 0.83 (95% CI, 0.39 -1.64). For the joint genotype, the odds ratio was 3.69 (95% Spina bifida is a common and severe congenital anomaly that yearly affects approximately 1 in 1,000 newborns in Italy 1 and 200,000 newborns or more worldwide. 2,3 Clinical and epidemiologic evidence, such as the variability of occurrence rates by geography, time, socioeconomic status, and ethnicity, and the relatively low recurrence risk within families, suggests that the etiology of spina bifida involves interactions between multiple genetic and environmental factors. 4,5 However, defining these factors and interactions has proven difficult. The protective effect of folic acid on the occurrence of spina bifida 6 -8 suggests that the study of folate metabolism might identify some of the genetic determinants of spina bifida. Several candidate genes have been studied, including 5,10-methylenetetrahydrofolate reductase (MTHFR), cystathionine-␤-synthase (CBS), methionine synthase, and methionine synthase reductase. A pooled analysis suggests that homozygosity for the 677C-T allele of MTHFR in infants is associated with approximately a 70% increased risk for spina bifida. 9 Common mutations of other genes, such as the 844ins68 allele of CBS, 10 have also been described, although their association with spina bifida is still unclear. Limited data are available on potential interactions among alleles of different folate-related genes. In 1997, Ramsbottom and associates 11 from Ireland reported data on the 677C-T allele of MTHFR and the 844ins68 allele of CBS and suggested that they indicated no interaction effects for spina bifida. We suggested that these data were consistent with the presence of interaction, 12 although the original authors thought otherwise. 13 Subsequent studies yielded discordant findings, with one study from Germany reporting no interaction effects 14 and another study from the United States reporting possible evidence for interaction. 15 In this report, which expands findings reported in abstract, 16 we assess the independent and joint effects of these two common alleles (677C-T and 844ins84) on the risk for spina bifida, using data from a large case-control study from Italy. MATERIALS AND METHODS Study populationThe study population comprised 203 children with open spina bifida without other unrelated major malformations (case-subjects) and 583 healthy young adults and newborns (control-subjects). The subjects with spina bifida had been included in another study of MTHFR allelic variants. 17 Of the 203 children with spina bifida, 173 (85%) had my...

Cystathionine beta-synthase c.844ins68 gene variant and non-syndromic cleft lip and palate

“…A similar gene-gene interaction has been reported in NTD-affected cases [de Franchis et al, 2002], suggesting that interactions between variant alleles of CBS and MTHFR genes can be an etiologic factor shared by these two common midline defects.…”

“…However, the co-occurrence of this allele with the c.677T allele of the MTHFR c.677C > T polymorphism has been associated with a significant increase in the risk for arterial and venous occlusive disease [de Franchis et al, 2000], and, in some studies, for spina bifida [de Franchis et al, 2002]. Specifically, although data from individual studies vary, the combined evidence [Ramsbottom et al, 1997;Speer et al, 1999;de Franchis et al, 2002] suggests an increased frequency of c.677TT homozygosity combined with c.844ins68 heterozygosity among neural tube defects (NTDs) patients compared to controls (data summarized in de Franchis et al, 2002].…”

Genetic association study of putative functional single nucleotide polymorphisms of genes in folate metabolism and spina bifida

“…CBS rs5742905 has not been examined previously in relation to SB. The most common CBS mutation studied is the 844ins68 allele, 11 bp downstream of rs5745905, which has shown varied association with NTDs or SB in different ethnic populations 28, 33, 34. Supporting this finding the CBS 844ins68 allele has been associated with lower serum homocysteine in a recent population study of over 10,000 subjects in Norway 35…”

“…Further experiments are needed to determine if the rs3737965 variant directly affects MTHFR transcription or is linked with a disease causing allele in our SB patients. Other studies have noted gene-gene interactions in various SNP alleles of MTHFR 28, 34, 41. All of these studies identified risk related to C677T.…”

Genetic studies of the cystathionine beta‐synthase gene and myelomeningocele

“…Mutations of the CBS gene, such as the 844ins68 allele, have been described (Sebastio et al, 1995). There have been conflicting studies regarding the potential interaction among alleles of different folate-related genes, such as the 677C-T allele of the methylene tetrahydrofolate reductase ( MTHFR ) gene and the 844ins68 allele of CBS , and their combined contribution to risk of SB (Ramsbottom et al, 1997; Speer et al, 1999; de Franchis et al, 2002; Houcher et al, 2009). …”