To evaluate the association of the polymorphisms in the TGFB3 gene (rs2268626) and the BMP4 gene (rs17563) with nonsyndromic oral clefts.
Design
A hospital-based case-control study was conducted with nonsyndromic oral clefts cases and unaffected controls. Cleft type and tooth agenesis data were collected by clinical examination and confirmed through medical records. Risk factors were obtained through a questionnaire. Genotyping of the selected polymorphisms for TGFB3 and BMP4 were carried out by real-time polymerase chain reaction using the Taqman assay method from a genomic DNA isolated from buccal epithelial cells of all individuals.
Setting
The case group was ascertained through a public reference hospital of oral cleft rehabilitation in Rio de Janeiro, Brazil. The noncleft group consisted of unrelated subjects, with no history of oral cleft in the family, recruited at the Dental Clinic at the Federal University of Rio de Janeiro, Brazil.
Participants
A total of 833 unrelated individuals (450 control individuals and 383 cases with nonsyndromic oral clefts)
Results
No significant association in relation to genotype or allele distributions for TGFB3 polymorphism was found between oral cleft subgroups and the control group. For BMP4, there were significant differences in the genotype frequencies between the oral cleft and control groups (P = .0007). Regarding cleft type, there were statistically significant differences between the cleft lip and control groups (P = .00009).
Conclusion
Our findings provide preliminary evidence suggesting that the risk of nonsyndromic oral clefts may be influenced by variation in the BMP4 gene.
AidarM.LineS.R.A simple and cost-effective protocol for DNA isolation from buccal epithelial cells. Braz Dent J.2007; 18: 148–152.
2.
AntunesL.D.KüchlerE.C.TannureP.N.LotschP.F.CostaM.D.GouvêaC.V.OlejB.GranjeiroJ.M.TGFB3 and BMP4 polymorphism are associated with isolated tooth agenesis. Acta Odontol Scand.2011; 70: 202–206.
3.
ArdingerH.H.BuetowK.H.BellG.I.BardachJ.Van-DemarkD.R.MurrayJ.C.Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet.1989; 45: 348–353.
4.
AshiqueA.M.FuK.RichmanJ.M.Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion. Development.2002; 129: 4647–4660.
5.
BeatyT.H.MurrayJ.C.MarazitaM.L.MungerR.G.RuczinskiI.HetmanskiJ.B.LiangK.Y.WuT.MurrayT.FallinM.D.. A case-control study of nonsyndromic oral clefts in Maryland. Ann Epidemiol.2001; 11: 434–442.
6.
BeatyT.H.MurrayJ.C.MarazitaM.L.MungerR.G.RuczinskiI.HetmanskiJ.B.LiangK.Y.WuT.MurrayT.FallinM.D.. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet.2010; 42: 525–529.
7.
BeatyT.H.RuczinskiI.MurrayJ.C.MarazitaM.L.MungerR.G.HetmanskiJ.B.MurrayT.RedettR.J.FallinM.D.LiangK.Y.. Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate. Genet Epidemiol.2011; 35: 469–478.
8.
BrittoJ.A.EvansR.D.HaywardR.D.JonesB.M.Toward pathogenesis of Apert cleft palate: FGF, FGFR, and TGF beta genes are differentially expressed in sequential stages of human palatal shelf fusion. Cleft Palate Craniofac J.2002; 39: 332–340.
9.
BrunetC.L.SharpeP.M.FergusonM.W.Inhibition of TGF-beta 3 (but not TGF-beta 1 or TGF-beta 2) activity prevents normal mouse embryonic palate fusion. Int J Dev Biol.1995; 39: 345–355.
10.
ButaliA.MosseyP.A.AdeyemoW.L.JezewskiP.A.OnwuamahC.K.OgunleweM.O.UgbokoV.I.AdejuyigbeO.AdigunAlAbdur-RahmanL.O.. Genetic studies in the Nigerian population implicate an MSX1 mutation in complex oral facial clefting disorders. Cleft Palate Craniofac J.2011; 48: 646–653.
11.
ChungK.C.KowalskiC.P.KimH.M.BuchmanS.R.Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate. Plast Reconstr Surg.2000; 105: 485–491.
12.
ClarrenS.K.AndersonB.WolfL.S.Feeding infants with cleft lip, cleft palate, or cleft lip and palate. Cleft Palate J.1987; 24: 244–249.
13.
DixonM.J.MarazitaM.L.BeatyT.H.MurrayJ.C.Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet.2011; 12: 167–178.
GongS.G.GuoC.Bmp4 gene is expressed at the putative site of fusion in the midfacial region. Differentiation.2003; 71: 228–236.
16.
GrantS.F.WangK.ZhangH.GlabersonW.AnnaiahK.KimC.E.BradfieldJ.P.GlessnerJ.T.ThomasK.A.GarrisM.. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr.2009; 155: 909–913.
17.
IchikawaE.WatanabeA.NakanoY.AkitaS.HiranoA.KinoshitaA.KondoS.KishinoT.UchiyamaT.NiikawaN.. PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses. J Hum Genet.2006; 51: 38–46.
18.
JezewskiP.A.VieiraA.R.NishimuraC.LudwigB.JohnsonM.O'BrienS.E.Daack-HirschS.SchultzR.E.WeberA.NepomucenaB.. Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet.2003; 40: 399–407.
19.
JianyanL.ZeqiangG.YongjuanC.KaihongD.BingD.RongshengL.Analysis of interactions between genetic variants of BMP4 and environmental factors with nonsyndromic cleft lip with or without cleft palate susceptibility. Int J Oral Maxillofac Surg.2010; 39: 50–56.
20.
KaartinenV.VonckenJ.W.ShulerC.WarburtonD.BuD.HeisterkampN.GroffenJ.Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet.1995; 11: 415–421.
21.
KimM.H.KimH.J.ChoiJ.Y.NahmD.S.Transforming growth factor-beta3 gene SfaN1 polymorphism in Korean nonsyndromic cleft lip and palate patients. J Biochem Mol Biol.2003; 36: 533–537.
22.
KondoS.SchutteB.C.RichardsonR.J.BjorkB.C.KnightA.S.WatanabeY.HowardE.de LimaR.L.Daack-HirschS.SanderA.. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet.2002; 32: 285–289.
23.
KüchlerE.C.da MottaL.G.VieiraA.R.GranjeiroJ.M.Side of dental anomalies and taurodontism as potential clinical markers for cleft subphenotypes. Cleft Palate Craniofac J.2011; 48: 103–108.
24.
LetraA.MenezesR.GranjeiroJ.M.VieiraA.R.Defining subphenotypes for oral clefts based on dental development. J Dent Res.2007; 86: 986–991.
25.
LinJ.Y.ChenY.J.HuangY.L.TangG.P.ZhangL.DengB.LiM.MaH.LuanR.S.Association of bone morphogenetic protein 4 gene polymorphisms with nonsyndromic cleft lip with or without cleft palate in Chinese children. DNA Cell Biol.2008; 27: 601–605.
26.
LittleJ.CardyA.MungerR.G.Tobacco smoking and oral clefts: a meta-analysis. Bull World Health Organ.2004; 82: 213–218.
27.
LiuW.SunX.BrautA.MishinaY.BehringerR.R.MinaM.MartinJ.F.Distinct functions for Bmp signaling in lip and palate fusion in mice. Development.2005; 132: 1453–1461.
28.
MangoldE.LudwigK.U.BirnbaumS.BaluardoC.FerrianM.HermsS.ReutterH.de AssisN.A.ChawaT.A.MattheisenM.. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet.2010; 42: 24–26.
29.
MorenoL.M.MansillaM.A.BullardS.A.CooperM.E.BuschT.D.MachidaJ.JohnsonM.K.BrauerD.KrahnK.Daack-HirschS.. FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. Hum Mol Genet.2009; 18: 4879–4896.
30.
MorkunienéA.SteponaviciutD.UtkusA.KucinskasV.Few associations of candidate genes with nonsyndromic orofacial clefts in the population of Lithuania. J Appl Genet.2007; 48: 89–91.
31.
MosseyP.A.CastilliaE.Global Registry and Database on Craniofacial Anomalies.Geneva: World Health Organization;2003.
32.
MosseyP.A.LittleJ.MungerR.G.DixonM.J.ShawW.C.Cleft lip and palate. Lancet.2009; 374: 1773–1785.
33.
NawshadA.LaGambaD.HayE.D.Transforming growth factor beta (TGFbeta) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol.2004; 49: 675–689.
34.
ProetzelG.PawlowskiS.A.WilesM.V.YinM.BoivinG.P.HowlesP.N.DingJ.FergusonM.W.DoetschmanT.Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet.1995; 11: 409–414.
35.
RanadeK.ChangM.S.TingC.T.PeiD.HsiaoC.F.OlivierM.PesichR.HebertJ.ChenY.D.DzauV.J.. High-throughput genotyping with single nucleotide polymorphisms. Genome Res.2001; 11: 1262–1268.
36.
ReutterH.BirnbaumS.MendeM.LausterC.SchmidtG.HenschkeH.SaffarM.MartiniM.LausterR.SchiefkeF.. TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate. J Hum Genet.2008; 53: 656–661.
37.
ShiM.ChristensenK.WeinbergC.R.RomittiP.BathumL.LozadaA.MorrisR.W.LovettM.MurrayJ.C.Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants. Am J Hum Genet.2007; 80: 76–90.
38.
SlaytonR.L.WilliamsL.MurrayJ.C.WheelerJ.J.LidralA.C.NishimuraC.J.Genetic association studies of cleft lip and/or palate with hypodontia outside the cleft region. Cleft Palate Craniofac J.2003; 40: 274–279.
39.
SpilsonS.V.KimH.J.E.ChungK.C.Association between maternal diabetes mellitus and newborn oral cleft. Ann Plast Surg.2001; 47: 477–481.
40.
SuazoJ.SantosJ.L.JaraL.BlancoR.Association between bone morphogenetic protein 4 gene polymorphisms with nonsyndromic cleft lip with or without cleft palate in a Chilean population. DNA Cell Biol.2010a; 29: 59–64.
41.
SuazoJ.SantosJ.L.ScapoliL.JaraL.BlancoR.Association between TGFB3 and nonsyndromic cleft lip with or without cleft palate in a Chilean population. Cleft Palate Craniofac J.2010b; 47: 513–517.
42.
SuzukiS.MarazitaM.L.CooperM.E.MiwaN.HingA.JugessurA.NatsumeN.ShimozatoK.OhbayashiN.SuzukiY.. Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip. Am J Hum Genet.2009; 84: 406–411.
43.
TanabeA.TaketaniS.Endo-IchikawaY.TokunagaR.OgawaY.HiramotoM.Analysis of the candidate genes responsible for nonsyndromic cleft lip and palate in Japanese people. Clin Sci (Lond).2000; 99: 105–111.
44.
VieiraA.R.OrioliI.M.CastillaE.E.CooperM.E.MarazitaM.L.MurrayJ.C.MSX1 and TGFB3 contribute to clefting in South America. J Dent Res.2003; 82: 289–292.
45.
WangW.GuanP.XuW.ZhouB.Risk factors for oral clefts: a population-based case-control study in Shenyang, China. Paediatr Perinat Epidemiol.2009; 23: 310–320.
46.
WehbyG.L.CassellC.H.The impact of orofacial clefts on quality of life and healthcare use and costs. Oral Dis.2010; 16: 3–10.
47.
ZuccheroT.M.CooperM.E.MaherB.S.Daack-HirschS.NepomucenoB.RibeiroL.CaprauD.ChristensenK.SuzukiY.MachidaJ.. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med.2004; 19: 351: 769–780.
