To determine the association of single-nucleotide polymorphisms (SNPs) in genes related to craniofacial development, which were previously identified as susceptibility signals for nonsyndromic oral clefts, in Brazilians with nonsyndromic cleft lip and/or palate (NSCL/P).
Design
The SNPs rs748044 (TNP1), rs1106514 (MSX1), rs28372960, rs15251 and rs2569062 (TCOF1), rs7829058 (FGFR1), rs1793949 (COL2A1), rs11653738 (WNT3), and rs242082 (TIMP3) were assessed in a family-based transmission disequilibrium test (TDT) and a structured case-control analysis based on the individual ancestry proportions.
Setting
The SNPs were initially analyzed by TDT, and polymorphisms showing a trend toward excess transmission were subsequently studied in an independent case-control sample.
Participants
The study sample consisted of 189 case-parent trios of nonsyndromic cleft lip with or without cleft palate (NSCL±P), 107 case-parent trios of nonsyndromic cleft palate (NSCP), 318 isolated samples of NSCL±P, 189 isolated samples of NSCP, and 599 healthy controls.
Main Outcome Measure
Association of alleles with NSCL/P pathogenesis.
Results
Preferential transmission of SNPs rs28372960 and rs7829058 in NSCL±P trios and rs11653738 in NSCP trios (P = .04) were observed, although the structured case-control analysis did not confirm these associations. The haplotype T-C-C formed by TCOF1 SNPs rs28372960, rs15251, and rs2569062 was more frequently transmitted from healthy parents to NSCL±P offspring, but the P value (P = .01) did not withstand Bonferroni correction for multiple tests.
Conclusions
With the modest associations, our results do not support the hypothesis that TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3, and TIMP3 variants are risk factors for nonsyndromic oral clefts in the Brazilian population.
AidarM., LineS.R.A simple and cost-effective protocol for DNA isolation from buccal epithelial cells.Braz Dent J.2007; 18: 148–152.
2.
BagordakisE., ParanaibaL.M., BritoL.A., AquinoS.N., MessettiA.C., Martelli-JuniorH., SwertsM.S., GranerE., Passos-BuenoM.R., ColettaR.D.Polymorphisms at regions 1p22.1 (rs560426) and 8q24 (rs1530300) are risk markers for nonsyndromic cleft lip and/or palate in the Brazilian population.Am J Med Genet A.2013; 161a: 1177–1180.
3.
Bastos-RodriguesL., PimentaJ.R., PenaS.D.The genetic structure of human populations studied through short insertion-deletion polymorphisms.Ann Hum Genet.2006; 70: 658–665.
4.
BeatyT.H., HetmanskiJ.B., FallinM.D., ParkJ.W., SullJ.W., McIntoshI., LiangK.Y., VanderkolkC.A., RedettR.J., BoyadjievS.A.. Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations.Hum Genet.2006; 120: 501–518.
5.
BeatyT.H., HetmanskiJ.B., ZeigerJ.S., FanY.T., LiangK.Y., VanderKolkC.A., McIntoshI.Testing candidate genes for non-syndromic oral clefts using a case-parent trio design.Genet Epidemiol.2002; 22: 1–11.
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.
BelovA.A., MohammadiM.Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology.Cold Spring Harb Perspect Biol.2013; 5: 1–28.
8.
BirnbaumS., LudwigK.U., ReutterH., HermsS., SteffensM., RubiniM., BaluardoC., FerrianM., Almeida de AssisN., AlblasM.A.. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24.Nat Genet.2009; 41: 473–477.
9.
BritoL.A., BassiC.F., MasottiC., MalcherC., RochaK.M., SchlesingerD., BuenoD.F., CruzL.A., BarbaraL.K., BertolaD.R.. IRF6 is a risk factor for nonsyndromic cleft lip in the Brazilian population.Am J Med Genet A.2012; 158A: 2170–2175.
10.
BritoL.A., ParanaibaL.M., BassiC.F., MasottiC., MalcherC., SchlesingerD., RochaK.M., CruzL.A., BárbaraL.K., AlonsoN.. Region 8q24 is a susceptibility locus for nonsyndromic oral clefting in Brazil.Birth Defects Res A Clin Mol Teratol.2012; 94: 464–468.
11.
ButaliA., MosseyP.A., AdeyemoW.L., JezewskiP.A., OnwuamahC.K., OgunleweM.O., UgbokoV.I., AdejuyigbeO., AdigunA.I., Abdur-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.
12.
CardosoM.L., BezerraJ.F., OliveiraG.H., SoaresC.D., OliveiraS.R., de SouzaK.S., da SilvaH.P., SilbigerV.N., LuchessiA.D., FajardoC.M.. MSX1 gene polymorphisms in non-syndromic cleft lip and/or palate.Oral Dis.2013; 19: 507–512.
13.
ChiquetB.T., BlantonS.H., BurtA., MaD., StalS., MullikenJ.B., HechtJ.T.Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate.Hum Mol Genet.2008; 17: 2212–2218.
14.
De AquinoS.N., MessettiA.C., BagordakisE., Martelli-JuniorH., SwertsM.S., GranerE., ColettaR.D.Polymorphisms in FGF12, VCL, CX43 and VAX1 in Brazilian patients with nonsyndromic cleft lip with or without cleft palate.BMC Med Genet.2013; 14: 53.
15.
De AquinoS.N., MessettiA.C., HoshiR., BorgesA., VienaC.S., ReisS.R., SwertsM.S.O., GranerE., Martelli-JuniorH., ColettaR.D.Analysis of susceptibility polymorphisms for nonsyndromic cleft lip with or without cleft palate in the Brazilian population.Birth Defects Res A Clin Mol Teratol.2014; 100: 36–42.
16.
DixonJ., JonesN.C., SandellL.L., JayasingheS.M., CraneJ., ReyJ.P., DixonM.J., TrainorP.A.Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities.Proc Natl Acad Sci USA.2006; 103: 13403–13408.
17.
DixonM.J., MarazitaM.L., BeatyT.H., MurrayJ.C.Cleft lip and palate: understanding genetic and environmental influences.Nat Rev Genet.2011; 12: 167–178.
18.
FontouraC., SilvaR.M., GranjeiroJ.M., LetraA.Association of WNT9B gene polymorphisms with nonsyndromic cleft lip with or without cleft palate in Brazilian nuclear families.Cleft Palate Craniofac J.2015; 52: 44–48.
19.
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.
JagomagiT., NikopensiusT., KrjutskovK., TammekiviV., ViltropT., SaagM., MetspaluA.MTHFR and MSX1 contribute to the risk of nonsyndromic cleft lip/palate.Eur J Oral Sci.2010; 118: 213–220.
22.
KadakiaS., HelmanS.N., BadheyA.K., SamanM., DucicY.Treacher Collins syndrome: the genetics of a craniofacial disease.Int J Pediatr Otorhinolaryngol.2014; 78: 893–898.
23.
LaceB., KempaI., PiekuseL., GrinfeldeI., KlovinsJ., PlissL., KruminaA., VieiraA.R.Association studies of candidate genes and cleft lip and palate taking into consideration geographical origin.Eur J Oral Sci.2011; 119: 413–417.
24.
LairdN.M., HorvathS., XuX.Implementing a unified approach to family-based tests of association.Genet Epidemiol.2000; 19: S36–S42.
25.
LudwigK.U., MangoldE., HermsS., NowakS., ReutterH., PaulA., BeckerJ., HerberzR., AlChawaT., NasserE.. Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci.Nat Genet.2012; 44: 968–971.
26.
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.
27.
Martelli-JuniorH., PortoL.V., MartelliD.R., BonanP.R., FreitasA.B., Della ColettaR.Prevalence of nonsyndromic oral clefts in a reference hospital in the state of Minas Gerais, Brazil, between 2000-2005.Braz Oral Res.2007; 21: 314–317.
28.
MasottiC., Armelin-CorreaL.M., SplendoreA., LinC.J., BarbosaA., SogayarM.C., Passos-BuenoM.R.A functional SNP in the promoter region of TCOF1 is associated with reduced gene expression and YY1 DNA-protein interaction.Gene.2005; 359: 44–52.
29.
MenezesR., LetraA., KimA.H., KüchlerE.C., DayA., TannureP.N., Gomes da MottaL., PaivaK.B., GranjeiroJ.M., VieiraA.R.Studies with Wnt genes and nonsyndromic cleft lip and palate.Birth Defects Res A Clin Mol Teratol2010; 88: 995–1000.
30.
MenezesR., LetraA., RuffJ., GranjeiroJ.M., VieiraA.R.Studies of genes in the FGF signaling pathway and oral clefts with or without dental anomalies.Am J Med Genet A.2008; 146a: 1614–1617.
31.
MostowskaA., HozyaszK.K., BiedziakB., WojcickiP., LianeriM., JagodzinskiP.P.Genotype and haplotype analysis of WNT genes in non-syndromic cleft lip with or without cleft palate.Eur J Oral Sci.2012; 120: 1–8.
32.
NikopensiusT., JagomagiT., KrjutskovK., TammekiviV., SaagM., PraneI., PiekuseL., AkotaI., BarkaneB., KruminaA.. Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate.Birth Defects Res A Clin Mol Teratol.2010; 88: 748–756.
33.
NikopensiusT., KempaI., AmbrozaityteL., JagomagiT., SaagM., MatulevicieneA., UtkusA., KrjutskovK., TammekiviV., PiekuseL.. Variation in FGF1, FOXE1, and TIMP2 genes is associated with nonsyndromic cleft lip with or without cleft palate.Birth Defects Res A Clin Mol Teratol.2011; 91: 218–225.
34.
ParanaibaL.M., BufalinoA., Martelli-JuniorH., de BarrosL.M., GranerE., ColettaR.D.Lack of association between IRF6 polymorphisms (rs2235371 and rs642961) and non-syndromic cleft lip and/or palate in a Brazilian population.Oral Dis.2010; 16: 193–197.
35.
PenaS.D., Di PietroG., Fuchshuber-MoraesM., GenroJ.P., HutzM.H., KehdyF.S., KohlrauschF., MagnoL.A., MontenegroR.C., MoraesM.O.. The genomic ancestry of individuals from different geographical regions of Brazil is more uniform than expected.PLoS One.2011; 6: e17063.
36.
PritchardJ.K., StephensM., DonnellyP.Inference of population structure using multilocus genotype data.Genetics.2000; 155: 945–959.
PurcellS., ChernyS.S., ShamP.C.Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits.Bioinformatics.2003; 19: 149–150.
RodriguesK., SenaM.F., RoncalliA.G., FerreiraM.A.Prevalence of orofacial clefts and social factors in Brazil.Braz Oral Res.2009; 23: 38–42.
41.
Snyder-WarwickA.K., PerlynC.A.Coordinated events: FGF signaling and other related pathways in palatogenesis.J Craniofac Surg.2012; 23: 397–400.
42.
StanierP., PauwsE.Development of the lip and palate: FGF signalling.Front Oral Biol.2012; 16: 71–80.
43.
SuazoJ., SantosJ.L., CarrenoH., JaraL., BlancoR.Linkage disequilibrium between MSX1 and non-syndromic cleft lip/palate in the Chilean population.J Dent Res.2004; 83: 782–785.
44.
SullJ.W., LiangK.Y., HetmanskiJ.B., FallinM.D., IngersollR.G., ParkJ.W., Wu-ChouY.H., ChenP.K., ChongS.S., CheahF.. Excess maternal transmission of markers in TCOF1 among cleft palate case-parent trios from three populations.Am J Med Genet A.2008; 146a: 2327–2331.
45.
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.
46.
WangC., ChangJ.Y., YangC., HuangY., LiuJ., YouP., McKeehanW.L., WangF., LiX.Type 1 fibroblast growth factor receptor in cranial neural crest cell-derived mesenchyme is required for palatogenesis.J Biol Chem.2013; 288: 22174–22183.
47.
WehbyG.L., MurrayJ.C.Folic acid and orofacial clefts: a review of the evidence.Oral Dis.2010; 16: 11–19.
48.
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; 351: 769–780.
