Dataset Information

Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

ABSTRACT: Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants. In an expanded case set, NAT2 continued to show significant overtransmission of an allele to the fetus, with a final P value of .00003. There was an interaction between maternal smoking and fetal inheritance of a GSTT1-null deletion, seen in both the Danish (P=.03) and Iowan (P=.002) studies, with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples, involving independent populations, that provided substantial power and a framework for future studies that could identify a susceptible population for preventive health care.

SUBMITTER: Shi M

PROVIDER: S-EPMC1785306 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

Shi Min M Christensen Kaare K Weinberg Clarice R CR Romitti Paul P Bathum Lise L Lozada Anthony A Morris Richard W RW Lovett Michael M Murray Jeffrey C JC

American journal of human genetics 20061207 1

Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment int ...[more]

PMID: 17160896

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Project description:Two large studies of case-parent trios ascertained through a proband with a non-syndromic orofacial cleft (OFC, which includes cleft lip and palate, cleft lip alone, or cleft palate alone) were used to test for possible gene-environment (G × E) interaction between genome-wide markers (both observed and imputed) and self-reported maternal exposure to smoking, alcohol consumption, and multivitamin supplementation during pregnancy. The parent studies were as follows: GENEVA, which included 1,939 case-parent trios recruited largely through treatment centers in Europe, the United States, and Asia, and 1,443 case-parent trios from the Pittsburgh Orofacial Cleft Study (POFC) also ascertained through a proband with an OFC including three major racial/ethnic groups (European, Asian, and Latin American). Exposure rates to these environmental risk factors (maternal smoking, alcohol consumption, and multivitamin supplementation) varied across studies and among racial/ethnic groups, creating substantial differences in power to detect G × E interaction, but the trio design should minimize spurious results due to population stratification. The GENEVA and POFC studies were analyzed separately, and a meta-analysis was conducted across both studies to test for G × E interaction using the 2 df test of gene and G × E interaction and the 1 df test for G × E interaction alone. The 2 df test confirmed effects for several recognized risk genes, suggesting modest G × E effects. This analysis did reveal suggestive evidence for G × Vitamin interaction for CASP9 on 1p36 located about 3 Mb from PAX7, a recognized risk gene. Several regions gave suggestive evidence of G × E interaction in the 1 df test. For example, for G × Smoking interaction, the 1 df test suggested markers in MUSK on 9q31.3 from meta-analysis. Markers near SLCO3A1 also showed suggestive evidence in the 1 df test for G × Alcohol interaction, and rs41117 near RETREG1 (a.k.a. FAM134B) also gave suggestive significance in the meta-analysis of the 1 df test for G × Vitamin interaction. While it remains quite difficult to obtain definitive evidence for G × E interaction in genome-wide studies, perhaps due to small effect sizes of individual genes combined with low exposure rates, this analysis of two large case-parent trio studies argues for considering possible G × E interaction in any comprehensive study of complex and heterogeneous disorders such as OFC.

Project description:BackgroundNonsyndromic orofacial cleft is a common birth defect with a complex etiology, including multiple genetic and environmental risk factors. Recent whole genome analyses suggested associations between nonsyndromic orofacial cleft and up to 18 genetic risk loci (ABCA4, BMP4, CRISPLD2, GSTT1, FGF8, FGFR2, FOXE1, IRF6, MAFB, MSX1, MTHFR, MYH9, PDGFC, PVRL1, SUMO1, TGFA, TGFB3, and VAX1), each of which confers a different relative risk in different populations. We evaluate the nonsynonymous variants in these 18 genetic risk loci in nonsyndromic orofacial clefts and normal controls to clarify the specific variants in Taiwanese population.MethodsWe evaluated these 18 genetic risk loci in 103 cases of nonsyndromic orofacial clefts and 100 normal controls using a next-generation sequencing (NGS) customized panel and manipulated a whole-exon targeted-sequencing study based on the NGS system of an Ion Torrent Personal Genome Machine (IT-PGM). IT-PGM data processing, including alignment with the human genome build 19 reference genome (hg19), base calling, trimming of barcoded adapter sequences, and filtering of poor signal reads, was performed using the IT platform-specific pipeline software Torrent Suite, version 4.2, with the plug-in "variant caller" program. Further advanced annotation was facilitated by uploading the exported VCF file from Variant Caller to the commercial software package Ion Reporter; the free online annotation software Vanno and Mutation Taster. Benign or tolerated amino acid changes were excluded after analysis using sorting intolerant from tolerant and polymorphism phenotyping. Sanger sequencing was used to validate the significant variants identified by NGS. Furthermore, each variant was confirmed in asymptomatic controls using the Sequenom MassARRAY (San Diego, CA, USA).ResultsWe identified totally 22 types of nonsynonymous variants specific in nonsyndromic orofacial clefts, including 19 single nucleotide variants, 2 deletions, and 1 duplication in 10 studied genes(ABCA4, MYH9, MTHFR, CRISPLD2, FGF8, PVRL1, FOXE1, VAX1, FGFR2, and IRF6). Nonsynonymous variants in MYH9 and ABCA4, which were detected in 6 and 5 individuals, respectively, were identified to be the most frequent risk loci in nonsyndromic orofacial clefts in the Taiwanese population.ConclusionsNonsynonymous variants in MYH9 and ABCA4 were identified to be the most frequent risk loci in nonsyndromic orofacial clefts in the Taiwanese population. These findings in our study have provided additional information regarding specific variants associated with nonsyndromic orofacial clefts in different population and demonstrate the power of our customized NGS panel, which is clinically useful for the simultaneous detection of multiple genes associated with nonsyndromic orofacial clefts.

Project description:BACKGROUND:Orofacial clefts (OFCs) were among the most familiar birth defects in the world, which had been reported to be influenced by the folic acid ingestion in pregnancy previously. Methylenetetrahydrofolate dehydrogenase1 (MTHFD1) gene was associated with the susceptibility of OFCs through a complex metabolism correlate with folic acid. The aim of our study was to evaluate the correlation of five single-nucleotide polymorphisms (SNPs) within MTHFD1 related to the OFCs risk in a Chinese population. METHODS:By the use of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), we genotyped 5 filtered SNPs (identified by Haploview 4.2 software with HapMap databases) on MTHFD1 gene: 118913T>C, 31136A>G, 58893A>G, 1958G>A and 61869T>C of 216 subjects (108 OFCs cases and 108 healthy controls) from a Chinese population. The association between these SNPs and OFCs risk was investigated by student t-test, one-way analysis of variance (ANOVA) and chi-square test with GraphPad Prism 5.0 software. Furthermore, we also performed a meta-analysis of relevant studies to investigate the association between MTHFD1 1958G>A and the susceptibility of OFCs. RESULTS:Through the genotyping, the AA genotype was found significantly correlated with the susceptibility of OFCs compared with other SNPs on MTHFD1, yielding an OR of 2.71 (95% CI = 1.12-6.58, P = 0.025) under the homozygous model and an OR of 2.37 (95% CI = 1.06-5.30, P = 0.033) under the recessive model. While other selected SNPs 118913T>C and 31136A>G were also associated with an increased OFC risk, the results were not statistically significant (all P > 0.05). However, the overall result of meta-analysis did not support the conclusion that the 1958G>A variant could be a genetic susceptible factor for OFCs (A allele vs. G allele: OR = 1.02, 95% CI = 0.85-1.23, AA vs. GG: OR = 1.06, 95% CI = 0.69-1.63, GA vs. GG: OR = 1.02, 95% CI = 0.81-1.27, AA vs. GG+GA: OR = 0.94, 95% CI = 0.61-1.46, AA+GA vs. GG: OR = 0.94, 95% CI = 0.74-1.19). CONCLUSIONS:The MTHFD1 1958G>A variant was significantly associated with the increased OFCs risk in Chinese population. However, this association was not supported by meta-analysis of all relevant studies. Further investigations about functional impact of this polymorphism were needed.

Dataset Information

Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

Publications

Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

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