Linkage Disequilibrium between MSX1 and Non-syndromic Cleft Lip/Palate in the Chilean Population

Abstract

Non-syndromic cleft lip/palate (NSCLP) is a complex genetic trait. Linkage and association studies have suggested that a clefting locus could be located on chromosome 4p. Sixty Chilean families were recruited for this study; from these, we used unrelated trios to evaluate the possible linkage disequilibrium between MSX1 and NSCLP. An intragenic marker, MSX1-CA, and an extragenic marker, D4S432 at a distance of 0.8 cM from MSX1, were analyzed by means of polymerase chain-reaction with fluorescent-labeled forward primers, followed by electrophoresis on a laser-fluorescent sequencer. We carried out a transmission/disequilibrium test (TDT) for multiple alleles to evaluate the presence of linkage disequilibrium. Results showed a preferential transmission of the 169-bp allele of MSX1 (p = 0.03). Although there was no preferential transmission for the D4S432 marker, the overall extended TDT (ETDT) showed a significant result (p = 0.01). The authors’ findings support the hypothesis of the contribution of MSX1 in the etiology of NSCLP in the Chilean population.

Get full access to this article

View all access options for this article.

References

Beaty TH, Hetmanski JB, Zeiger JS, Fan YT, Lian KY, Vanderkolk CA, et al. -2002-. Testing candidate genes for non-syndromic oral clefts using a case-parent trio design. Genet Epidemiol 22:1–11.

Blanco R, Chakraborty R, Barton S, Carreño H, Paredes M, Jara L -2001-. Evidence of a sex-dependent association between the MSX1 locus and nonsyndromic cleft lip with or without cleft palate in the Chilean population. Hum Biol 73:81–89.

Caporaso N, Rothman N, Wacholder S -1999-. Case-control studies of common alleles and environmental factors. J Natl Cancer Inst Monogr 26:25–30.

Carinci F, Pezzetti F, Scapli L, Martinelli M, Carinci P, Tognon M -2000-. Genetics of nonsyndromic cleft lip and palate: a review of international studies and data regarding the Italian population. Cleft Palate Craniofac J 37:33–40.

Cleves MA, Olson JM, Jacobs KB -1997-. Exact transmission disequilibrium test with multiallelic markers. Genet Epidemiol 14:337–347.

Fallin M, Hetmanski J, Park J, Scott A, Ingersoll R, Fuernkranz H, et al. -2003-. Family-based analysis of MSX1 haplotypes for association with oral clefts. Genet Epidemiol 25:168–175.

Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millaseau P, et al. -1994-. The 1993–94 généthon human genetic linkage map. Nat Genet 7:246–249.

Jezewski PA, Vieira AR, Nishimura C, Ludwig B, Johnson M, O’Brien SE -2003-. Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. J Med Genet 40:399–407.

Jugessur A, Lie RT, Wilcox AJ, Murray JC, Taylor JA, Sugstad OD, et al. -2003-. Variants of developmental genes -TGFA, TGFB3, and MSX1- and their associations with orofacial clefts: a case-parent triad analysis. Genet Epidemiol 24:230–239.

10.

Kaartinen V, Voncken JW, Shuler C, Warburton D, Bu D, Heisterkamp N -1995-. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11:415–421.

11.

Kanno K, Suzuki Y, Yang X, Yamada A, Aoki Y, Kure S, et al. -2002-. 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 47:269–274.

12.

Khoury MJ -1999-. Human genome epidemiology: translating advances in human genetics into population-based data for medicine and public health. Genet Med 1:71–73.

13.

Lidral AC, Romitti PA, Basart AM, Doetschman T, Leysens NJ, Daack-Hirsch S, et al. -1998-. Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. Am J Hum Genet 63:557–568.

14.

Marazita ML, Field L, Cooper M, Tobias R, Maher B, Peanchitlertkajorn S, et al. -2002a-. Nonsyndromic cleft lip with or without cleft palate in China: assessment of candidate regions. Cleft Pal Craniofac J 39:149–156.

15.

Marazita ML, Field L, Cooper M, Tobias R, Maher B, Peanchitlertkajorn S, et al. -2002b-. Genome scan for loci involved in cleft lip with or without cleft palate, in Chinese multiplex families. Am J Hum Genet 71:349–364.

16.

Moreno L, Arcos-Burgos M, Marazita M, Krahn K, Maher B, Cooper M, et al. -2004-. Genetic analysis of candidate loci in non-syndromic cleft lip families from Antioquia-Colombia and Ohio. Am J Med Genet 125-A-:135–144.

17.

Murray JC -1995-. Face facts: genes, environment and clefts -invited editorial-. Am J Hum Genet 57:227–232.

18.

Murray JC -2002-. Gene/environment causes of cleft lip and/or palate. Clin Genet 61:248–256.

19.

Padanilam BJ, Stadler HS, Mills KA, McLeod LB, Solursh M, Lee B -1992-. Characterization of the human HOX7 cDNA and identification of polymorphic markers. Hum Mol Genet 1:407–410.

20.

Poncz M, Solowiejcyk D, Harvel B, Mory Y, Schwartz E, Surrey S -1982-. Construction of human gene libraries from small amounts of peripheral blood: analysis of beta-like globin genes. Hemoglobin 6:27–36.

21.

Satokata I, Maas R -1994-. Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat Genet 6:348–356.

22.

Scapoli L, Martinelli M, Pezzetti F, Carinci F, Bodo M, Tognon M, et al. -2002-. Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate. Hum Genet 110:15–20.

23.

Schultz RE, Cooper ME, Daack-Hirsch S, Shi M, Nepomucena B, Graf KA, et al. -2004-. Targeted scan of fifteen regions for nonsyndromic cleft lip and palate in Filipino families. Am J Med Genet 125A:17–22.

24.

Sham PC, Curtis D -1995-. An extended transmission disequilibrium test for multi-allele marker loci. Ann Hum Genet 59:323–336.

25.

Stata Statistical Software -computer program- -2004-. StataCorp. Release 8.2. College Station, TX: StataCorp LP.

26.

Stein J, Mulliken JB, Stal S, Gasser DL, Malcolm S, Winter R, et al. -1995-. Nonsyndromic cleft lip with or without cleft palate: evidence of linkage to BCL3 in 17 multigenerational families. Am J Hum Genet 57:257–272.

27.

Valenzuela CY -1988-. On sociogenetic clines. Ethol Sociobiol 9:259–268.

28.

Vieira AR, Orioli IM, Castilla EE, Cooper ME, Marazita ML, Murray JC -2003-. MSX1 and TGFB3 contribute to clefting in South America. J Dent Res 82:289–292.

29.

Wyszynski DF, Maestri N, McIntosh I, Smith EA, García-Delgado C, Vinageras-Guarneros E, et al. -1997-. No evidence of linkage for cleft lip with or without cleft palate to a marker near the transforming growth factor alpha locus in two populations. Hum Hered 47:101–109.

30.

Zhao JH, Sham PC, Curtis D -1999-. A program for the Monte Carlo evaluation of significance of the extended transmission/disequilibrium test. Am J Hum Genet 64:1484–1485.

31.

Zollner S, Wen X, Hanchard N, Hervert M, Ober C, Pritchard K -2004-. Evidence for extensive transmission distortion in the human genome. Am J Hum Genet 74:62–72.