Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: Evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts

Romitti, Paul A.; Lidral, Andrew C.; Munger, Ronald G.; Daack‐Hirsch, Sandra; Burns, Trudy L.; Murray, Jeffrey C.

doi:10.1002/(sici)1096-9926(199901)59:1<39::aid-tera9>3.0.co;2-7

Cited by 216 publications

(175 citation statements)

References 40 publications

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“…8,11,19,20 In the present research, no transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, but TGFB3-CA exhibited a trend to excess maternal transmission. Our findings suggest that both the maternal and fetal RR results are in agreement for both TGFB3-CA alleles, as the 163-bp allele had a deleterious recessive effect, whereas the 165-bp allele had a protective recessive effect.…”

Section: Discussioncontrasting

confidence: 49%

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

et al. 2011

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Oral clefts are clinically and genetically heterogeneous disorders that are influenced by both genetic and environmental factors. The present family-based association study investigated the role of the MSX1 and TGFB3 genes in the etiology of non-syndromic oral cleft in a Malay population. No transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, whereas TGFB3-CA exhibited a trend to excess maternal transmission. In sequencing the MSX1 coding regions in 124 patients with oral cleft, five variants were found, including three known variants (A34G, G110G and P147Q) and two novel variants (M37L and G267A). The P147Q and M37L variants were not observed in 200 control chromosomes, whereas G267A was found in one control sample, indicating a very rare polymorphic variant. Furthermore, the G110G variant displayed a significant association between patients with non-syndromic cleft lip, with or without cleft palate, and normal controls (P¼0.001, odds ratio¼2.241, 95% confidence interval, 1.357-3.700). Therefore, these genetic variants may contribute, along with other genetic and environmental factors, to this condition. INTRODUCTIONOral clefts are clinically and genetically heterogeneous disorders, involving both genetic and environmental factors. MSX1 and TGFB3 have emerged as candidate genes for oral cleft, based on expression studies 1,2 and animal models. 3,4 Their involvement is further supported by linkage and association studies in populations of different ethnic origin. [5][6][7][8] Although no deleterious mutation has been reported in TGFB3. 7,9 MSX1 has been suggested to function upstream of TGFB3 in the development of oral cleft. 10 The aim of the current research was to investigate the genetic association of MSX1 and TGFB3 in a Malay population with non-syndromic orofacial cleft. The association study was performed using intragenic CA markers for MSX1 and TGFB3. The coding regions of MSX1 were also directly sequenced.

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Section: Discussioncontrasting

confidence: 49%

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

et al. 2011

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“…[31][32][33][34][35][36][37][38] Reports have classified oral clefts in many different ways, but nearly all have shown a positive association with maternal smoking, with only a few reports not observing this association, 14,39,40 and one report not observing this association for cleft palate alone. 34 The magnitude of the effect estimate observed in our study also is similar to that reported from the wide array of previous studies.…”

Section: Discussionmentioning

confidence: 99%

Maternal smoking and birth defects: Validity of birth certificate data for effect estimation

Honein¹,

Paulozzi²,

Watkins³

2001

Public Health Reports

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SYNOPSISObjectives. The authors sought to assess the validity of birth certificate data for estimating the association between maternal smoking and birth defects. The US standard birth certificate includes check boxes for maternal smoking and for 21 congenital anomalies. The sensitivity and specificity of birth certificate data have been studied, but previous studies have not addressed the validity of these data for estimating the association between birth defects and maternal smoking or other risk factors.Methods. US public-use natality data (1997)(1998) were used to calculate the prevalence ratio (adjusted for maternal age, race/ethnicity, and education) for the association between maternal smoking and 13 defects/defect categories. All analyses were restricted to 45 states, New York City, and the District of Columbia because they collect both maternal smoking and birth defect data.Results. Maternal smoking was associated with an increased prevalence of hydrocephaly (adjusted prevalence ratio [PR] = 1.24; 95% confidence interval [CI] = 1.08,1.43), microcephaly (PR 1.47; 95% CI 1.15,1.88), omphalocele/ gastroschisis (PR 1.37; 95% CI 1.22,1.53), cleft lip/palate (PR 1.35; 95% CI 1.25,1.45), clubfoot (PR 1.62; 95% CI 1.49,1.75), and polydactyly/syndactyly/ adactyly (PR 1.33; 95% CI 1.23,1.43 ). Previous studies have indicated an association between maternal smoking and gastroschisis, oral clefts, and clubfoot with effect estimates of similar magnitude to this study.Conclusions. These findings suggest that birth certificate data may be useful for exploratory or corroborative studies estimating the association between birth defects and some risk factors recorded on birth certificates.

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“…6,21,[39][40][41][42][43] Our results demonstrated that not only the Tgfβ-pathway genes but also other pathway-related genes might interact each other to regulate medial edge epithelium disintegration and complete palatogenesis (Supplementary Figure 2) In several studies, it has been suggested that there is a gene-environment interaction exists between smoking and TGFα expression for the induction of cleft palate. 8,25,[44][45][46][47][48][49] By using our microarray analysis and filtering cleft palate-related genes, we determined that nicotine is the highly susceptible element of smoking to induce down-regulation of TGFα, which may explain the palatal size abnormality observed in nicotine-treated pups. The presence of partial palatal seam in the newborn pups, which otherwise would have disintegrated at 14.5 to 16.5 dpc indicates: (1) the growth of the palate towards each other to form a seam, although in smaller size and shape, is not altered; (2) the genes that causes immaculate seam disintegration might have been effected by nicotine exposure.…”

Section: Discussionmentioning

confidence: 98%

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

Öztürk

Sheldon

Sharma

et al. 2015

NICTOB

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Introduction: Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus. Methods: To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5 mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays. Results: Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools. Conclusions: We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion. Implications: Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.

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Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: Evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts

Cited by 216 publications

References 40 publications

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

Maternal smoking and birth defects: Validity of birth certificate data for effect estimation

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

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