• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of ajhgLink to Publisher's site
Am J Hum Genet. Mar 1996; 58(3): 551–561.
PMCID: PMC1914570

Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants.

Abstract

Results of studies to determine whether women who smoke during early pregnancy are at increased risk of delivering infants with orofacial clefts have been mixed, and recently a gene-environment interaction between maternal smoking, transforming growth factor-alpha (TGFa), and clefting has been reported. Using a large population-based case-control study, we investigated whether parental periconceptional cigarette smoking was associated with an increased risk for having offspring with orofacial clefts. We also investigated the influence of genetic variation of the TGFa locus on the relation between smoking and clefting. Parental smoking information was obtained from telephone interviews with mothers of 731 (84.7% of eligible) orofacial cleft case infants and with mothers of 734 (78.2%) nonmalformed control infants. DNA was obtained from newborn screening blood spots and genotyped for the allelic variants of TGFa. We found that risks associated with maternal smoking were most elevated for isolated cleft lip with or without cleft palate, (odds ratio 2.1 [95% confidence interval 1.3-3.6]) and for isolated cleft palate (odds ratio 2.2 [1.1-4.5]) when mothers smoked > or =20 cigarettes/d. Analyses controlling for the potential influence of other variables did not reveal substantially different results. Clefting risks were even greater for infants with the TGFa allele previously associated with clefting whose mothers smoked > or =20 cigarettes/d. These risks for white infants ranged from 3-fold to 11-fold across phenotypic groups. Paternal smoking was not associated with clefting among the offspring of nonsmoking mothers, and passive smoke exposures were associated with at most slightly increased risks. This study offers evidence that the risk for orofacial clefting in infants may be influenced by maternal smoke exposures alone as well as in combination (gene-environment interaction) with the presence of the uncommon TGFa allele.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Andrews J, McGarry JM. A community study of smoking in pregnancy. J Obstet Gynaecol Br Commonw. 1972 Dec;79(12):1057–1073. [PubMed]
  • Ardinger HH, Buetow KH, Bell GI, Bardach J, VanDemark DR, Murray JC. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet. 1989 Sep;45(3):348–353. [PMC free article] [PubMed]
  • Astrup P, Olsen HM, Trolle D, Kjeldsen K. Effect of moderate carbon-monoxide exposure on fetal development. Lancet. 1972 Dec 9;2(7789):1220–1222. [PubMed]
  • Basart AM, Qian JF, May E, Murray JC. A PCR method for detecting polymorphism in the TGFA gene. Hum Mol Genet. 1994 Apr;3(4):678–678. [PubMed]
  • Bronsky PT, Johnston MC, Sulik KK. Morphogenesis of hypoxia-induced cleft lip in CL/Fr mice. J Craniofac Genet Dev Biol Suppl. 1986;2:113–128. [PubMed]
  • Carmichael NG, Backhouse BL, Winder C, Lewis PD. Teratogenicity, toxicity and perinatal effects of cadmium. Hum Toxicol. 1982 Mar;1(2):159–186. [PubMed]
  • Chenevix-Trench G, Jones K, Green AC, Duffy DL, Martin NG. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci. Am J Hum Genet. 1992 Dec;51(6):1377–1385. [PMC free article] [PubMed]
  • Chenevix-Trench G, Jones K, Green A, Martin N. Further evidence for an association between genetic variation in transforming growth factor alpha and cleft lip and palate. Am J Hum Genet. 1991 May;48(5):1012–1013. [PMC free article] [PubMed]
  • Croen LA, Shaw GM, Jensvold NG, Harris JA. Birth defects monitoring in California: a resource for epidemiological research. Paediatr Perinat Epidemiol. 1991 Oct;5(4):423–427. [PubMed]
  • Czeizel A, Nagy E. A recent aetiological study on facial clefting in Hungary. Acta Paediatr Hung. 1986;27(2):145–166. [PubMed]
  • Dixon MJ, Garner J, Ferguson MW. Immunolocalization of epidermal growth factor (EGF), EGF receptor and transforming growth factor alpha (TGF alpha) during murine palatogenesis in vivo and in vitro. Anat Embryol (Berl) 1991;184(1):83–91. [PubMed]
  • Druckrey H, Ivanković S, Preussmann R. Teratogenic and carcinogenic effects in the offspring after single injection of ethylnitrosourea to pregnant rats. Nature. 1966 Jun 25;210(5043):1378–1379. [PubMed]
  • Emanuel I, Culver BH, Erickson JD, Guthrie B, Schuldberg D. The further epidemiological differentiation of cleft lip and palate: a population study of clefts in King County, Washington, 1956-1965. Teratology. 1973 Jun;7(3):271–281. [PubMed]
  • Ericson A, Källén B, Westerholm P. Cigarette smoking as an etiologic factor in cleft lip and palate. Am J Obstet Gynecol. 1979 Oct 1;135(3):348–351. [PubMed]
  • Evans DR, Newcombe RG, Campbell H. Maternal smoking habits and congenital malformations: a population study. Br Med J. 1979 Jul 21;2(6183):171–173. [PMC free article] [PubMed]
  • Fox SH, Brown C, Koontz AM, Kessel SS. Perceptions of risks of smoking and heavy drinking during pregnancy: 1985 NHIS findings. Public Health Rep. 1987 Jan-Feb;102(1):73–79. [PMC free article] [PubMed]
  • Fox SH, Koepsell TD, Daling JR. Birth weight and smoking during pregnancy--effect modification by maternal age. Am J Epidemiol. 1994 May 15;139(10):1008–1015. [PubMed]
  • Givelber HM, DiPaolo JA. Teratogenic effects of N-ethyl-N-nitrosourea in the Syrian hamster. Cancer Res. 1969 May;29(5):1151–1155. [PubMed]
  • Hatch MC, Misra D, Kabat GC, Kartzmer S. Proxy respondents in reproductive research: a comparison of self- and partner-reported data. Am J Epidemiol. 1991 Apr 15;133(8):826–831. [PubMed]
  • Hayward NK, Nancarrow DJ, Bell GI. A Taq I polymorphism for the human transforming growth factor alpha gene (TGFA). Nucleic Acids Res. 1987 Jul 10;15(13):5503–5503. [PMC free article] [PubMed]
  • Hemminki K, Mutanen P, Saloniemi I. Smoking and the occurrence of congenital malformations and spontaneous abortions: multivariate analysis. Am J Obstet Gynecol. 1983 Jan 1;145(1):61–66. [PubMed]
  • Holder SE, Vintiner GM, Farren B, Malcolm S, Winter RM. Confirmation of an association between RFLPs at the transforming growth factor-alpha locus and non-syndromic cleft lip and palate. J Med Genet. 1992 Jun;29(6):390–392. [PMC free article] [PubMed]
  • Hwang SJ, Beaty TH, Panny SR, Street NA, Joseph JM, Gordon S, McIntosh I, Francomano CA. Association study of transforming growth factor alpha (TGF alpha) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants with birth defects. Am J Epidemiol. 1995 Apr 1;141(7):629–636. [PubMed]
  • Kelsey JL, Dwyer T, Holford TR, Bracken MB. Maternal smoking and congenital malformations: an epidemiological study. J Epidemiol Community Health. 1978 Jun;32(2):102–107. [PMC free article] [PubMed]
  • Khoury MJ, Gomez-Farias M, Mulinare J. Does maternal cigarette smoking during pregnancy cause cleft lip and palate in offspring? Am J Dis Child. 1989 Mar;143(3):333–337. [PubMed]
  • Khoury MJ, Weinstein A, Panny S, Holtzman NA, Lindsay PK, Farrel K, Eisenberg M. Maternal cigarette smoking and oral clefts: a population-based study. Am J Public Health. 1987 May;77(5):623–625. [PMC free article] [PubMed]
  • Lambert GH, Nebert DW. Genetically mediated induction of drug-metabolizing enzymes associated with congenital defects in the mouse. Teratology. 1977 Oct;16(2):147–153. [PubMed]
  • Longo LD. Some health consequences of maternal smoking: issues without answers. Birth Defects Orig Artic Ser. 1982;18(3 Pt A):13–31. [PubMed]
  • Malloy MH, Kleinman JC, Bakewell JM, Schramm WF, Land GH. Maternal smoking during pregnancy: no association with congenital malformations in Missouri 1980-83. Am J Public Health. 1989 Sep;79(9):1243–1246. [PMC free article] [PubMed]
  • Manchester D, Jacoby E. Decreased placental monooxygenase activities associated with birth defects. Teratology. 1984 Aug;30(1):31–37. [PubMed]
  • McDonald AD, Armstrong BG, Sloan M. Cigarette, alcohol, and coffee consumption and congenital defects. Am J Public Health. 1992 Jan;82(1):91–93. [PMC free article] [PubMed]
  • Millicovsky G, Johnston MC. Hyperoxia and hypoxia in pregnancy: simple experimental manipulation alters the incidence of cleft lip and palate in CL/Fr mice. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5722–5723. [PMC free article] [PubMed]
  • Patrick DL, Cheadle A, Thompson DC, Diehr P, Koepsell T, Kinne S. The validity of self-reported smoking: a review and meta-analysis. Am J Public Health. 1994 Jul;84(7):1086–1093. [PMC free article] [PubMed]
  • Qian JF, Feingold J, Stoll C, May E. Transforming growth factor-alpha: characterization of the BamHI, RsaI, and TaqI polymorphic regions. Am J Hum Genet. 1993 Jul;53(1):168–175. [PMC free article] [PubMed]
  • Sassani R, Bartlett SP, Feng H, Goldner-Sauve A, Haq AK, Buetow KH, Gasser DL. Association between alleles of the transforming growth factor-alpha locus and the occurrence of cleft lip. Am J Med Genet. 1993 Mar 1;45(5):565–569. [PubMed]
  • Savitz DA, Schwingl PJ, Keels MA. Influence of paternal age, smoking, and alcohol consumption on congenital anomalies. Teratology. 1991 Oct;44(4):429–440. [PubMed]
  • Saxén I. Cleft lip and palate in Finland: parental histories, course of pregnancy and selected environmental factors. Int J Epidemiol. 1974 Sep;3(3):263–270. [PubMed]
  • Schwartz EI, Khalchitsky SE, Eisensmith RC, Woo SL. Polymerase chain reaction amplification from dried blood spots on Guthrie cards. Lancet. 1990 Sep 8;336(8715):639–640. [PubMed]
  • Seidman DS, Ever-Hadani P, Gale R. Effect of maternal smoking and age on congenital anomalies. Obstet Gynecol. 1990 Dec;76(6):1046–1050. [PubMed]
  • Shaw GM, Croen LA, Curry CJ. Isolated oral cleft malformations: associations with maternal and infant characteristics in a California population. Teratology. 1991 Mar;43(3):225–228. [PubMed]
  • Shaw GM, Lammer EJ, Wasserman CR, O'Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet. 1995 Aug 12;346(8972):393–396. [PubMed]
  • Shiang R, Lidral AC, Ardinger HH, Buetow KH, Romitti PA, Munger RG, Murray JC. Association of transforming growth-factor alpha gene polymorphisms with nonsyndromic cleft palate only (CPO). Am J Hum Genet. 1993 Oct;53(4):836–843. [PMC free article] [PubMed]
  • Shiono PH, Klebanoff MA, Berendes HW. Congenital malformations and maternal smoking during pregnancy. Teratology. 1986 Aug;34(1):65–71. [PubMed]
  • Upshall DG. Correlation of chick embryo teratogenicity with the nicotinic activity of a series of tetrahydropyrimidines. Teratology. 1972 Jun;5(3):287–293. [PubMed]
  • Van den Eeden SK, Karagas MR, Daling JR, Vaughan TL. A case-control study of maternal smoking and congenital malformations. Paediatr Perinat Epidemiol. 1990 Apr;4(2):147–155. [PubMed]
  • Werler MM, Lammer EJ, Rosenberg L, Mitchell AA. Maternal cigarette smoking during pregnancy in relation to oral clefts. Am J Epidemiol. 1990 Nov;132(5):926–932. [PubMed]
  • Windham GC, Swan SH, Fenster L. Parental cigarette smoking and the risk of spontaneous abortion. Am J Epidemiol. 1992 Jun 15;135(12):1394–1403. [PubMed]
  • Witter FR, Blake DA, Baumgardner R, Mellits ED, Niebyl JR. Folate, carotene, and smoking. Am J Obstet Gynecol. 1982 Dec 1;144(7):857–857. [PubMed]
  • Zhang J, Savitz DA, Schwingl PJ, Cai WW. A case-control study of paternal smoking and birth defects. Int J Epidemiol. 1992 Apr;21(2):273–278. [PubMed]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    MedGen
    Related information in MedGen
  • OMIM
    OMIM
    OMIM record citing PubMed
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...