Oral Facial Clefts and Gene Polymorphisms in Metabolism of Folate/ One-Carbon and Vitamin A: A Pathway-Wide Association Study

Epidemiology Branch, NIEHS/NIH, Durham, North Carolina 27709, USA.
Genetic Epidemiology (Impact Factor: 2.6). 04/2009; 33(3):247-55. DOI: 10.1002/gepi.20376
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An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi-Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period.
As expected with this high number of statistical tests, there were many associations with P-values<0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, P=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role. Genet. Epidemiol. 2009.

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Available from: Per M Ueland, Oct 05, 2015
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    • "Whether this is mediated through the action of genes involved in folic acid metabolism has not yet been established. A pathway-wide analysis of 108 SNPs and one insertion polymorphism in 29 genes involved in folate/one-carbon metabolism found no convincing evidence that genetic variants in these folate metabolism genes play a causal role in orofacial clefting (Boyles et al., 2009). A second, more recent analysis of 97 SNPs in 14 genes in or interacting with the folate pathway found suggestive evidence of association with six genes in the folate pathway only when a less conservative approach was used for correcting for multiple testing than the stricter Bonferroni correction (Blanton et al., 2011). "
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    ABSTRACT: With an average worldwide prevalence of approximately 1.2/1000 live births, orofacial clefts are the most common craniofacial birth defects in humans. Like other complex disorders, these birth defects are thought to result from the complex interplay of multiple genes and environmental factors. Significant progress in the identification of underlying genes and pathways has benefited from large populations available for study, increased international collaboration, rapid advances in genotyping technology, and major improvements in analytic approaches. Here we review recent advances in genetic epidemiological approaches to complex traits and their applications to studies of nonsyndromic orofacial clefts. Our main aim is to bring together a discussion of new and previously identified candidate genes to create a more cohesive picture of interacting pathways that shape the human craniofacial region. In future directions, we highlight the need to search for copy number variants that affect gene dosage and rare variants that are possibly associated with a higher disease penetrance. In addition, sequencing of protein-coding regions in candidate genes and screening for genetic variation in noncoding regulatory elements will help advance this important area of research.
    The Cleft Palate-Craniofacial Journal 05/2011; 49(1):73-91. DOI:10.1597/10-178 · 1.20 Impact Factor
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    • "A higher occurrence of clefting would be expected if a major maternal effect exists, but no such evidence was found in that study. Finally, in our recent pathway-wide analysis of maternal genes and the risk of CL/P and CP among 29 genes involved in folate/one-carbon metabolism, we found no convincing indication that genetic variants in these folate metabolism genes play an etiologic role in orofacial clefting [45]. "
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    ABSTRACT: Fetal conditions can in principle be affected by the mother's genotype working through the prenatal environment. Genotypes for 1536 SNPs in 357 cleft candidate genes were available from a previous analysis in which we focused on fetal gene effects. After data-cleaning, genotypes for 1315 SNPs in 334 autosomal genes were available for the current analysis of maternal gene effects. Two complementary statistical methods, TRIMM and HAPLIN, were used to detect multi-marker effects in population-based samples from Norway (562 case-parent and 592 control-parent triads) and Denmark (235 case-parent triads). We analyzed isolated cleft lip with or without cleft palate (iCL/P) and isolated cleft palate only (iCP) separately and assessed replication by looking for genes detected in both populations by both methods. In iCL/P, neither TRIMM nor HAPLIN detected more genes than expected by chance alone; furthermore, the selected genes were not replicated across the two methods. In iCP, however, FLNB was identified by both methods in both populations. Although HIC1 and ZNF189 did not fully satisfy our stringency criterion for replication, they were strongly associated with iCP in TRIMM analyses of the Norwegian triads. Except for FLNB, HIC1 and ZNF189, maternal genes did not appear to influence the risk of clefting in our data. This is consistent with recent epidemiological findings showing no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefts in these two populations. It is likely that fetal genes make the major genetic contribution to clefting risk in these populations, but we cannot rule out the possibility that maternal genes can affect risk through interactions with specific teratogens or fetal genes.
    PLoS ONE 07/2010; 5(7):e11493. DOI:10.1371/journal.pone.0011493 · 3.23 Impact Factor
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    ABSTRACT: In order to develop a comprehensive model of the motor control system the time-varying nature of joint dynamics must be addressed. However, it has not previously been possible to quantitatively observe changes in joint dynamics during a transition of state. In this work, a recently developed method for identification of linear time-varying dynamic systems from ensemble data has been used to obtain models of neuromuscular dynamics during a rapid contraction. The method, based on singular value decomposition, provides a series of nonparametric (impulse response function) models of a system's dynamics without a priori knowledge of its dynamic structure or time-variation, thus enabling study of the neuromuscular system during natural activity. Application of this method to simulated and experimental data has shown it to be robust and accurate. Ankle dynamics have been tracked during voluntary isometric contraction of triceps surae, revealing behaviour more complex than second-order, characterized by a decrease in the joint's resistance to low frequency perturbations.
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