Maternal polymorphisms in folic acid metabolic genes are associated with nonsyndromic cleft lip and/or palate in the Brazilian population

Bufalino, Andréia; Paranaíba, Lívia Máris Ribeiro; Aquino, Sibele Nascimento de; Martelli‐Júnior, Hercílio; Swerts, Mário Sérgio Oliveira; Coletta, Ricardo D.

doi:10.1002/bdra.20732

Cited by 43 publications

(45 citation statements)

References 46 publications

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“…In this regard, it is interesting to note effects of maternal genotype and maternalspecific environmental modifiers such as smoking, drinking and vitamin intake during pregnancy on oral cleft susceptibility have been previously reported in various studies. 2,[10][11][12][13][14][15][16][17][18][19] However, it should be noted that the parental asymmetry tests we applied here do not specifically test for maternal effects which would be expected to occur via alterations of the in utero environment. Calculation of genomic inflation factors for the MAT and PAT tests showed a small increase for the MAT compared with the PAT in all categories, this increased inflation factor in the MAT does not discern the underlying cause, being consistent with either a true excess of biological associations with the maternally inherited alleles, or alternatively differing population structure between the two parental populations.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, evidence in support of this idea has recently been published. 15 As such, some genetic effects on disease risk can operate via a mechanism of maternal/fetal interaction. Previous candidate gene studies have suggested evidence for PofO effects in CL/P providing a strong rationale for performing comprehensive analysis to identify unconventional modes of inheritance.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

et al. 2013

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Parent-of-origin (PofO) effects, such as imprinting are a phenomenon where the effect of variants depends on parental origin. Conventional association studies assume that phenotypic effects are independent of parental origin, and are thus severely underpowered to detect such non-Mendelian effects. Risk of orofacial clefts is influenced by genetic and environmental effects, the latter including maternal-specific factors such as perinatal smoking and folate intake. To identify variants showing PofO effects in orofacial clefts we have used a modification of the family-based transmission disequilibrium test to screen for biased transmission from mothers and fathers to affected offspring, biased ratios of maternal versus paternal transmission, and biased frequencies of reciprocal classes of heterozygotes among offspring. We applied these methods to analyze published genomewide single-nucleotide polymorphism (SNP) data from B2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of B1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (Po5 Â 10 À8 ). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P ¼ 0.013), and identified two loci that showed nominally significant effects in the same direction in both the discovery and replication cohorts, raising the potential for PofO effects. These include a possible maternal-specific transmission bias associated with rs12543318 at 8q21.3, a locus identified in a recent meta-analysis of non-syndromic cleft (maternal-specific P ¼ 1.5 Â 10 À7 , paternal-specific P ¼ 0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

et al. 2013

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“…To understand the developmental mechanisms underlying NSCL/P, it is essential to review a large and varied field of research 14 . The environmental risk factors for NSCL/P include maternal use of medications such as antiepileptic agents or corticosteroids, smoking and alcohol consumption during pregnancy 15 , intrapartum interval 10 , parity 16 , folic acid deficiencies 17 and maternal and paternal age 5 . However, there is no consensus on the association of parental age and NSCL/P 18 .…”

Section: Introductionmentioning

confidence: 99%

Parental age is related to the occurrence of cleft lip and palate in Brazilian populations

et al. 2017

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Aim: To evaluate the association of environmental risk factors, particularly paternal and maternal age, with gender and type of oral cleft in newborn with nonsyndromic cleft lip with or without cleft palate (NSCL/P). Methods: This study included 1,346 children with NSCL/P of two Brazilian Services for treatment of craniofacial deformities. Parental ages were classified into the following groups: maternal age <35, 36-39, and ≥40 years; paternal age <39 and ≥40 years. The data was analyzed with chi-square test and multinomial logistic regression analysis. The odds ratios were estimated with a 95% confidence interval. Results: Of the 1,346 children included in this study, CLP was the type of NSCL/P with highest prevalence, followed by, respectively, CL and CP. There was a greater occurrence of NSCL/P in males compared to females (55.8% versus 44.2%). CLP was more common in men, while the CL and CP were more prevalent in women (p=0.000). No association between maternal age and clefts was observed (p=0.747). However, there was evidence of association between father's aged ≥40 years old and NSCL/P (p=0.031). When patients with CP were analyzed separately, no association between the father's age and the child's gender (p=0.728) was observed, i.e. the female gender prevails among patients with CP, regardless of the father's age. Conclusions: This study showed that there were differences in the distribution of the non-syndromic cleft lip and/ or palate and the gender, and fathers aged ≥40 years old may have increased risk of oral cleft. Further studies involving different populations are needed for a better understanding of the effect of maternal and paternal ages as a risk factor for the occurrence of oral clefts.

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“…The role of a second polymorphism within the MTHFR coding region, 1298A>C in NTD susceptibility has been controversial (Koch et al, 1998;van der Put et al, 1998). Several other polymorphisms in the MTHFR gene have been reported to influence the homocysteine levels and thus likely associated with NTD and other related disorders such as cleft lip and palate (Botto and Yang, 2000;Bufalino et al, 2010). Transcobalamin (TCN2) is another gene of interest based on findings of low vitamin B 12 and holo-TC concentrations in women with NTD-affected fetuses.…”

Section: Introductionmentioning

confidence: 99%

Maternal one‐carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India

Godbole

Gayathri

Ghule

et al. 2011

Birth Defects Research

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Maternal polymorphisms in folic acid metabolic genes are associated with nonsyndromic cleft lip and/or palate in the Brazilian population

Abstract: The findings of the present study suggested that genetic variants of folic acid metabolic genes may modulate maternal susceptibility for having an offspring with NSCL/P.

Cited by 43 publications

References 46 publications

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

Parental age is related to the occurrence of cleft lip and palate in Brazilian populations

Maternal one‐carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India

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