The objective of this case-control study was to evaluate the possible association between nonsyndromic cleft lip/palate (NSCLP) and 10 genetic markers in four chromosomal regions in the admixed Spanish-Amerindian Chilean population.
Setting
Study participants included 56 patients with NSCLP identified and interviewed for positive family history during the course of clinical examinations at different rehabilitation centers in the cities of Santiago and Talca, Chile. A control group of 59 normal individuals without known familial antecedents of clefting was obtained from blood bank donors of the University Hospital, University of Chile. Cases and controls belonged to low- to low-middle socioeconomic strata.
Results
Ten markers from chromosome 4p, 4q, 6p, 17q, and 19q were assessed (MSX1, D4S175, D4S192, F13A1, EDN1, D6S89, D6S105, D6S109, D17S579, BCL3). Four of them showed significant deviations from Hardy-Weinberg expectations in controls, according to the exact test (D4S192, BCL3, F13A1, and D6S89). The case-control comparison by means of the CLUMP program showed significant differences only in BCL3, and D6S109 almost reached statistical significance.
Conclusions
Most of the genetic regions with positive results in Caucasian populations may not be involved in NSCLP in Chile, regardless of the positive evidence for the candidate region on chromosome 19. Similar findings have been reported recently in the Chinese population.
BlancoR.Arcos-BurgosM.ParedesM.PalominoH.JaraL.CarreñoH.ObrequeV.MuñozA.Complex segregation analysis of nonsyndromic cleft lip/ palate in the Chilean population.Genet Mol Biol.1998; 21: 139–144.
2.
BlancoR.RosalesC.J.Diferencias étnicas y dimorfismo sexual de la fisura labiopalatina.Rev Med Chile.1988; 24: 216–225.
3.
CarinciF.PezzettiF.ScapoliL.PadulaE.BacilieroU.CurioniC.TognonM.Nonsyndromic cleft lip and palate: evidence of linkage to microsatellite markers on 6p2.Am J Hum Genet.1995; 56: 337–339.
4.
ChungC.S.BixlerD.WatanabeKoguchiH.Fogh AndersenP.Segregation analysis of cleft lip with or without cleft palate: a comparison of Danish and Japanese data.Am J Hum Genet.1986; 39: 603–611.
5.
DaviesA.F.StephensR.J.AlavesenM.G.HeatherL.DixonM.MageeA.FlinterF.RagoussiJ.Evidence of a locus for orofacial clefting on human chromosome 6p24 and STS content map of the region.Hum Mol Genet.1995; 4: 121–128.
6.
DemenaisF.ChungC.S.Bonnaiti-PelieD.BriardM.L.FeingoldJ.An epidemiological and genetic study of facial clefting in France II. Segregation analysis.J Med Genet.1984; 21: 436–440.
7.
De PaepeA.Dominantly inherited cleft lip and palate.J Med Genet.1989; 26: 794.
8.
FarrallM.HolderS.Familial recurrence-pattern analysis of cleft lip with or without cleft palate.Am J Hum Genet.1992; 50: 270–277.
9.
GooldR.D.diSibioG.L.XuH.LangD.B.DadgarJ.MagraneG.G.DugaiczykA.SmithK.A.CoxD.R.MastersS.B.MyersR.M.The development of sequence-tagged sites for human chromosome 4.Hum Mol Genet.1993; 2: 1271–1288.
10.
GuoS.W.ThompsonE.A.Performing the exact test of Hardy-Weinberg proportions for multiple alleles.Biometrics.1992; 48: 371–372.
11.
HallJ.M.FriedmanL.GentherC.LeeM.K.WeberJ.L.BlackD.M.KingM.C.Closing in on a breast cancer gene on chromosome 17q.Am J Hum Genet.1992; 50: 1235–1242.
12.
HechtJ.Dominant CLP families.J Med Genet.1990; 27: 597.
13.
HechtJ.YangP.MichelsV.BuetowK.H.Complex segregation analysis of nonsyndromic cleft lip and palate.Am J Hum Genet.1991; 49: 674–681.
14.
KannoK.SuzukiY.YangX.YamadaA.AokiKureS.MatsubaraY.Lack of evidence for a significant association between nonsyndromic cleft lip with or without cleft palate and the retinoic acid receptor alpha gene in the Japanese population.J Hum Genet.2002; 47: 269–274.
15.
KittlesR.A.ChenW.PanguluriR.K.AhaghotuC.LacksonA.AdebamowoC.A.CYP3A4-V and prostate cancer in African Americans: causal or confounding association because of population stratification?Hum Genet.2002; 110: 553–560.
16.
LidralA.MurrayJ.BuetowK.BasartA.ScheareH.ShiangR.NavalA.LaydaE.MagteeK.MageeW.Studies of the candidate genes TGFB2, MSX1, TGFA, and TGFB3 in the etiology of cleft lip and palate in the Philippines.Cleft Palate Craniofac J.1997; 34: 1–6.
17.
LidralA.C.RomittiP.A.BasartA.M.DoetschmanT.LeysensN.J.Daack-HirschS.SeminaE.V.JohnsonL.R.MachidaJ.BurdsA.ParnellT.J.RubensteinL.R.MurrayJ.C.Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.Am J Hum Genet.1998; 63: 557–568.
18.
MarazitaM.L.FieldL.CooperM.TobiasR.MaherB.PeanchitlertkajornS.LiuY.Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families.Am J Hum Genet.2002a; 71: 349–364.
19.
MarazitaM.L.FieldL.CooperM.TobiasR.MaherB.PeanchitlertkajornS.LiuY.Nonsyndromic cleft lip with or without cleft palate in China: assessment of candidate regions.Cleft Palate Craniofac J.2002b; 39: 149–156.
20.
MarazitaM.L.GolksteinA.M.SmalleyS.L.SpenceM.A.Cleft lip with or without cleft palate: reanalysis of a three-generation family study from England.Genet Epidemiol.1986; 3: 335–342.
21.
MarazitaM.L.HuD.N.SpenceM.A.LiuY.E.MelnickM.Cleft lip with or without cleft palate in Shanghai, China: evidence for an autosomal major locus.Am J Hum Genet.1992; 51: 648–653.
NemanaL.J.MarazitaM.L.MelnickM.A genetic analysis of cleft lip with or without cleft palate in Madras, India.Am J Med Genet.1992; 42: 5–10.
24.
NorthB.V.CurtisD.ShamP.C.A note on the calculation of empirical P values from Monte Carlo procedures.Am J Hum Genet.2002; 71: 439–441.
25.
PadanilamB.J.StadlerH.S.MillsK.A.McLeodL.B.SolurshM.LeeB.RamírezF.BuetowK.H.MurrayJ.C.Characterization of the human HOX7 cDNA and identification of polymorphic markers.Hum Mol Genet.1992; 1: 407–410.
26.
PagesJ.C.DrieuC.BlancheH.BeckemannJ.CannH.M.A short tandem repeat polymorphism at the endothelin 1 (EDN1) locus.Hum Mol Genet.1993; 2: 90.
27.
PalominoH.Cerda-FloresR.M.BlancoR.PalominoH.M.BartonS.A.de An-dradeM.ChackrabortyR.Complex segregation analysis of facial clefting in Chile.J Craniofac Genet Dev Biol.1997; 17: 57–64.
28.
PalominoH.M.PalominoH.CauviD.Variación sociogenética en la susceptibilidad a las fisuras faciales en Santiago, Chile.Odontol Chile.1990; 38: 86–92.
29.
PolymeropoulosM.H.RatchD.S.XiaoH.MerrilC.R.Tetranucleotide repeat polymorphism at the human coagulation factor XIII A subunit gene (F13A1).Nucleic Acids Res.1991; 19: 4306.
30.
PonczM.SolowiejcykD.HarvelB.MoryY.SchwartzE.SurreyS.Construction of human gene libraries from small amounts of peripheral blood: analysis of beta-like globin genes.Hemoglobin.1982; 6: 27–36.
31.
RanumL.P.W.ChungM.Y.DuvickL.A.ZoghbiH.Y.OrrH.T.Dinucleotide repeat polymorphism at the D6S109 locus.Nucleic Acids Res.1991a; 19: 1171.
32.
RanumL.P.W.DuvickL.A.StephenR.S.ShutJ.LittM.OrrH.Localization of the autosomal dominant HLA-linked spinocerebellar ataxia (SCAI) locus, in two kindreds, within an 8cM subregion of chromosome 6p.Am J Hum Genet.1991b; 49: 31–41.
33.
RayA.K.LeighL.MarazitaL.M.Nonsyndromic cleft lip with or without cleft palate in West Bengal, India: evidence for an autosomal major locus.Am J Hum Genet.1993; 52: 1006–1011.
34.
RothhammerF.LasserreE.BlancoR.CovarrubiasE.DixonM.Microevolution in human Chilean populations. Shovel-shape, mesial palatal version and other dental traits in Pewenche Indians.Z Morphol Anthropol.1968; 60: 162–169.
35.
SantosJ.L.Pérez-BravoF.CarrascoE.CalvillánM.AlbalaC.Association between HLA-DQB1 alleles and type 1 diabetes in a case-parents study conducted in Santiago, Chile.Am J Epidemiol.2001; 153: 794–798.
36.
SassaniR.BartlettS.P.FengH.Goldner-SauveA.HaqA.H.BurtonK.H.GasserD.L.Association between alleles of the transforming growth factor-alpha locus and the occurrence of cleft lip.Am J Med Genet.1993; 45: 565–569.
37.
SchaidD.J.JacobsenS.J.Biased test of association: comparisons of allele frequencies when departing from Hardy-Weinberg proportions.Am J Epidemiol.1999; 149: 706–711.
38.
SchneiderS.RoessliD.ExcoffierL.Arlequin: A Software for Population Genetics Data Analysis.Geneva: University of Geneva, Genetics and Biometry Laboratory, Department of Anthropology;2000.
39.
ShamP.C.CurtisD.An extended transmission disequilibrium test for multi-allele marker loci.Ann Hum Genet.1995; 59: 323–336.
40.
SpielmanR.EwensW.The TDT and other family-based tests for linkage disequilibrium and association.Am J Hum Genet.1996; 59: 983–989.
41.
Stata Corp. Stata Statistical Software. Release 7.0. College Station, TX: Stata Corp.; 2001.
42.
St. George-HyslopPHOhnoHGusellaJFMckeithanT.The BCL3 locus and chromosome 19 displays and informative microsatellite polymorphism.Nucleic Acids Res.1992; 20: 927.
43.
TempleK.CalvertM.PlintD.ThompsonE.PembreyM.Dominantly inherited cleft lip and palate in two families.J Med Genet.1989; 26: 386–389.
ValenzuelaC.HarbZ.Socioeconomic assortative mating in Santiago, Chile: a demonstration using stochastic matrices of mother-child relationship applied to ABO blood groups.Soc Biol.1977; 24: 225–233.
46.
ValenzuelaC.Y.AcuñaM.HarbZ.Sociogenetic gradient in the Chilean population [in Spanish].Rev Med Chil.1987; 115: 295–299.
47.
WeberJ.J.KwitekA.F.MayP.E.ZoghbiH.Y.Dinucleotid repeat polymorphism at the D6S105 locus.Nucleic Acids Res.1991; 19: 968.
