Orofacial Cleft Risk Is Increased with Maternal Smoking and Specific Detoxification-Gene Variants

Department of Anesthesiology, Duke University, Durham, North Carolina, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2007; 80(1):76-90. DOI: 10.1086/510518
Source: PubMed


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.

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Available from: Paul A Romitti, Jun 10, 2014
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    • "Further, nutritional and environmental aspects have been the subject of research [21]. The implication of deficits in vitamine B9, B12 [38] [39] [40] [41], zinc [42] and the consumption of tobacco [43] [44] [45], alcohol [46] and coffee [47] seem to show evidence for an elevated risk of CLP. Even emotional vulnerability and distress have been described to be a risk factor [48] [49]. "
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    ABSTRACT: Since a few decades, the prenatal detection of cleft lip is feasible by bi-dimensional ultrasound. The visualization of the fetal lips and nostrils is required in screening programs in developed countries. To date, most of the cleft lips are detected in the prenatal life. The visualization of the hard palate has been the subject of several researches in the past, especially since the development of three-dimensional ultrasound techniques. To date, most of clefts of the hard and/or soft palate are missed in prenatal life. Advances show promising results which permit to describe the anatomy of the primary and the secondary palate in the case of unaffected but also cleft hard palate. Further, the soft palate can be visualized by three-dimensional ultrasound. There is no consensus about a particular technique to view the palate, and there is no professional recommendation for the systematic screening of cleft lip and palate or cleft palate alone. The prenatal detection of a cleft of the lip and/or the palate modifies the prenatal care. The delivered information anticipates the emotional distress of the parents. The multidisciplinary counseling team can give precise information about the extension of the pathology and its prognosis. When the cleft lip is associated to a cleft of the hard palate, the risk of morphological or caryotypical anomalies is elevated; further, the esthetical and functional prognosis is worsened and the surgical followup is more extensive. The chapter resumes the actual state of the art of the prenatal diagnosis of cleft lip and palate. A review is made about the prenatal imaging techniques and the actual professional attitudes concerning the prenatal counseling of the families.
    Full-text · Chapter · Mar 2013
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    • "This may be the first study of PAH exposure and orofacial clefts conducted in humans, and it is generally consistent with many previous studies of cigarette smoking and clefts. Future investigations of PAHs and clefts may benefit from additional measures of exposure such as biomarker data, as well as gathering information on maternal and fetal genotypes related to PAH metabolism(Shimada, 2006; Wassenberg et al., 2005)or genotypes suggested in previous studies of gene-smoking interactions and oral clefts (Shaw et al., 1996; Romitti et al., 1999; Van Rooij et al., 2001; Zeiger et al, 2005; Lammer et al., 2005; Shaw et al., 2005; Shi et al., 2007). "
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    ABSTRACT: Objective :  To evaluate whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons and oral clefts in offspring. This is the first human study of polycyclic aromatic hydrocarbons and clefts of which the authors are aware. Design :  Case-control study. Setting, Participants :  Data for 1997 to 2002 from the National Birth Defects Prevention Study, a large population-based case-control study in the United States, were analyzed. Maternal telephone interviews yielded information on jobs held in the month before through 3 months after conception. Two industrial hygienists independently assessed occupational exposure to polycyclic aromatic hydrocarbons; all jobs rated as exposed or with rating difficulty were reviewed with a third industrial hygienist to reach consensus on all exposure parameters. Logistic regression estimated crude and adjusted odds ratios with 95% confidence intervals for cleft lip with or without cleft palate and cleft palate alone. Results :  There were 2989 controls (3.5% exposed), 805 cases of cleft lip with or without cleft palate (5.8% exposed), and 439 cases of cleft palate alone (4.6% exposed). The odds of maternal occupational exposure to polycyclic aromatic hydrocarbons (any versus none) during pregnancy was increased for cleft lip with or without cleft palate cases as compared with controls (odds ratio, 1.69; 95% confidence interval, 1.18 to 2.40); the odds ratio was 1.47 (95% confidence interval 1.02 to 2.12) when adjusted for maternal education. There was a statistically significant adjusted exposure-response relationship for cleft lip with or without cleft palate (P(trend) = .02). Odd ratios for cleft palate alone were not statistically significant. Conclusions :  Maternal occupational exposure to polycyclic aromatic hydrocarbons was associated with increased risk of cleft lip with or without cleft palate in offspring.
    Full-text · Article · Nov 2012 · The Cleft Palate-Craniofacial Journal
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    • "As craniofacial malformations arise early in embryological development with modest recurrence rates, it has proven difficult to identify specific environmental factors associated with CL/P.15 Maternal smoking during the periconceptual period has been hypothesized to influence markers in the glutathione S-transferase 1 pathway and lead to deficiencies in detoxification.16-20 Folate deficiency has been suggested to influence risk of CL/P in both observational studies and interventional trials using supplementation.21 "
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    ABSTRACT: Objective: The purpose of this cross-sectional study was to compare the severity of unilateral cleft lips in populations of Asia, Sub-Saharan Africa, and Northern Africa and the Middle East. We hypothesize that severity of unilateral cleft lips shows significant variation between these populations. Methods: Medical photographs of 780 patients with primary unilateral cleft lips treated by Operation Smile during November 2007 were reviewed. Photographs of 352 patients from Asia (China, Philippines, Vietnam, Laos, and Cambodia), 112 patients from the Middle East and North Africa (Jordan, Egypt, and Morocco), and 316 patients from Sub-Saharan Africa (Ethiopia, Kenya, and Madagascar) were analyzed. The severity of cleft lips was determined using the Fisher method, which measures the columellar angle as a deviation of the columella from its normal vertical position. The angle was measured using a protractor with its base positioned along a line joining the lateral canthi. An analysis of variance calculated statistical differences between each region and their respective countries. Results: The Asian region was found to have the greatest severity of unilateral cleft lip deformity (P < .05). Analysis-of-variance tests show a significant difference between Asia and other regions studied. When stratifying the data by country, the Philippines and Vietnam showed the highest severity. Conclusions: The results suggest a heterogeneous pattern of global severity. Unilateral cleft lips with the highest severity were predominant in the Asian region. The observed phenotypical differences can be used in future studies of gene variability or environmental factors to determine the cause of this significant disparity.
    Full-text · Article · Feb 2012 · Eplasty
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