Susceptibility to spina bifida; an association study of five candidate genes

Morrison, Katie; Papapetrou, Charalambos; Hol, F.A.; Mariman, E.C.M.; Lynch, Sean; Burn, John; Edwards, Yvonne H.

doi:10.1046/j.1469-1809.1998.6250379.x

Cited by 102 publications

(82 citation statements)

References 43 publications

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“…51 Other gene-environment 52 and genegene interactions 52,53 might also occur. If feasible, interactions between maternal and fetal genotype should also be investigated.…”

Section: Discussionmentioning

confidence: 99%

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

Franchis¹,

Botto

Sebastio³

et al. 2002

Genetics in Medicine

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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...

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“…51 Other gene-environment 52 and genegene interactions 52,53 might also occur. If feasible, interactions between maternal and fetal genotype should also be investigated.…”

Section: Discussionmentioning

confidence: 99%

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

Franchis¹,

Botto

Sebastio³

et al. 2002

Genetics in Medicine

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“…Folate metabolism and homocysteine levels are connected with several clinical disorders, including coronary artery disease, deep venous thrombosis, neural tube defects, and cancer (see Gailey and Gregory 15 for review); the thermolabile variant has been associated in different studies with increased risk of each of these diseases. 13,14,16 -20 However, despite the biologic plausibility of these associations, none have been reproducibly observed across many studies (for example, Ma et al [21][22][23] ).…”

Section: Review Of the Association Study Literaturementioning

confidence: 99%

A comprehensive review of genetic association studies

Hirschhorn

Lohmueller

Byrne

et al. 2002

Genetics in Medicine

1,471

995

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Most common diseases are complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. It has been proposed that common genetic variants, including single nucleotide polymorphisms (SNPs), influence susceptibility to common disease. This proposal has begun to be tested in numerous studies of association between genetic variation at these common DNA polymorphisms and variation in disease susceptibility. We have performed an extensive review of such association studies. We find that over 600 positive associations between common gene variants and disease have been reported; these associations, if correct, would have tremendous importance for the prevention, prediction, and treatment of most common diseases.However, most reported associations are not robust: of the 166 putative associations which have been studied three or more times, only 6 have been consistently replicated. Interestingly, of the remaining 160 associations, well over half were observed again one or more times. We discuss the possible reasons for this irreproducibility and suggest guidelines for performing and interpreting genetic association studies. In particular, we emphasize the need for caution in drawing conclusions from a single report of an association between a genetic variant and disease susceptibility. Genet Med 2002:4(2):45-61.

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“…The 68-bp insertion in the exon 8 of the gene appeared to be associated with an increased risk in several studies. [46,[52][53]. Multiplicative interaction of the CBS 68-bp insertion with the homozygosity for the MTHFR 677CT variant was showed to confer a five-fold increased risk for NTDs children, The MTHFR mutation alone had a two-fold increased risk, whereas there was no risk for CBS mutant genotype alone.…”

Section: Variantmentioning

confidence: 99%

“…[45] The methionine synthase (MTR), a vitamin B 12 -dependent enzyme, utilizes 5-methyltetrahydrofolate, generated by MTHFR, for homocysteine remethylation to methionine. A polymorphism of the MTR gene, the 2756AG (D919G) that lead to the substitution of an aspartic acid with a glycine residue, has been studied in several studies, but the majority have not reported a significant association [36,40,[46][47][48].…”

Section: Variantmentioning

confidence: 99%

Advances in Genetics of Non Syndromic Neural Tube Defects

Marco¹

2012

Neural Tube Defects - Role of Folate, Prevention Strategies and Genetics

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Susceptibility to spina bifida; an association study of five candidate genes

Cited by 102 publications

References 43 publications

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

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

A comprehensive review of genetic association studies

Advances in Genetics of Non Syndromic Neural Tube Defects

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