Association between Interferon Regulatory Factor 6 Gene Polymorphisms and Nonsyndromic Cleft Lip with or without Cleft Palate in a Chinese Population

Abstract

Objective

To further confirm the association between two IRF6 single nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate in a Chinese population.

Participants

A total of 106 nonsyndromic cleft lip with or without cleft palate case trios and 129 control trios.

Intervention

Two IRF6 single nucleotide polymorphisms, rs2235371 and rs642961, were genotyped for all case and control families. Case-control analysis and family-based linkage analysis were both performed for the two single nucleotide polymorphisms.

Results

The genotype and allele frequencies of rs2235371 (odds ratio_{AG+AA vs. GG}, 0.581; 95% confidence interval, 0.345 to 0.976; P = .039) and rs642961 (odds ratio_{AG+AA vs. GG}, 5.389; 95% confidence interval, 2.936 to 9.893; P = 5e-08) were significantly higher in nonsyndromic cleft lip with or without cleft palate patients compared with controls. There was an obvious dosage effect of allele A at rs642961. The transmission of a major allele (G) of rs2235371 and a minor allele (A) of rs642961 was in disequilibrium (P < .05) in complete case-parent trios. The association between the two single nucleotide polymorphisms and nonsyndromic cleft lip with or without cleft palate was confirmed by the Family-Based Association Test for rs642961 (P = .008), but there was no significance for rs2235371 (P = 0.057). Haplotype analysis found that rs2235371 G/rs642961 A haplotype increased the risk of nonsyndromic cleft lip with or without cleft palate (P = 2.42e-07); whereas, rs2235371 A/rs642961 G haplotype reduced the risk of nonsyndromic cleft lip with or without cleft palate (P = 4.37e-05). No evidence of linkage disequilibrium was found between the two single nucleotide polymorphisms (D′ = 0.303, r² = 0.017).

Conclusion

Our results confirmed the involvement of the IRF6 variants rs642961 and rs2235371 in the etiology of nonsyndromic cleft lip with or without cleft palate in a Chinese population.

Keywords

association study case-parent trio interferon regulatory factor 6 (IRF6)nonsyndromic cleft lip with or without cleft palate (NSCL±P)single nucleotide polymorphisms (SNPs)

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References

Barrett

Fry

Maller

Daly

Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21: 263.

Ben

Jabs

E.W.

Chong

S.S.

Genomic, cDNA and embryonic expression analysis of zebrafish IRF6, the gene mutated in the human oral clefting disorders van der Woude and popliteal pterygium syndromes. Gene Expr Patterns. 2005; 5: 629–638.

Blanton

S.H.

Cortez

Stal

Mulliken

J.B.

Finnell

R.H.

Hecht

J.T.

Variation in IRF6 contributes to nonsyndromic cleft lip and palate. Am J Med Genet A. 2005; 137A: 259–262.

Dai

Zhu

Mao

Deng

Wang

Liang

Tang

Wang

Kilfoy

B.A.

. Time trends in oral clefts in Chinese newborns: data from the Chinese National Birth Defects Monitoring Network. Birth Defects Res A Clin Mol Teratol. 2010; 88: 41–47.

Eroshkin

Mushegian

Conserved transactivation domain shared by interferon regulatory factors and Smad morphogens. J Mol Med (Berl). 1999; 77: 403–405.

Ghassibe

Bayet

Revencu

Verellen-Dumoulin

Gillerot

Vanwijck

Vikkula

Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population. Eur J Hum Genet. 2005; 13: 1239–1242.

Hering

Grundmann

The IRF6 p. 274V polymorphism is not a risk factor for isolated cleft lip. Genet Med. 2005; 7: 209.

Huang

Beaty

Sull

Zhu

Wang

Meng

Shi

Association between IRF6 SNPs and oral clefts in West China. J Dent Res. 2009; 88: 715.

Kondo

Schutte

B.C.

Richardson

R.J.

Bjork

B.C.

Knight

A.S.

Watanabe

Howard

de Lima

R.L.

Daack-Hirsch

Sander

. Mutations in IRF6 cause van der Woude and popliteal pterygium syndromes. Nat Genet. 2002; 32: 285–289.

10.

Laird

N.M.

Horvath

Implementing a unified approach to family-based tests of association. Genet Epidemiol. 2000; 19(Suppl 1): S36–S42.

11.

Zhang

Tang

Zeng

Shi

A partitionligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn). Cell Res. 2009; 19: 519–523.

12.

Milunsky

J.M.

Maher

T.A.

Zhao

Roberts

A.E.

Stalker

H.J.

Zori

R.T.

Burch

M.N.

Clemens

Mulliken

J.B.

Smith

. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet. 2008; 82: 1171–1177.

13.

Mossey

P.A.

Little

Epidemiology of oral clefts: an international perspective. In: Wyszynski

D.F.

, eds. Cleft Lip and Palate: From Origin to Treatment. New York: Oxford University Press; 2002: 127–158.

14.

Pan

Zhang

Niu

Wang

Zhang

Wang

IRF6 polymorphisms are associated with nonsyndromic orofacial clefts in a Chinese Han population. Am J Med Genet A. 2010; 152: 2505–2511.

15.

Paranaíba

L.M.

Martelli-Junior

Oliveira Swerts

M.S.

Line

S.R.

Coletta

R.D.

Novel mutations in the IRF6 gene in Brazilian families with van der Woude syndrome. Int J Mol Med. 2008; 22: 507–511.

16.

Paranaíba

L.M.

Bufalino

Martelli-Junior

de Barros

L.M.

Graner

Coletta

R.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.

17.

Park

J.W.

McIntosh

Hetmanski

J.B.

Jabs

E.W.

Vander Kolk

C.A.

Wu-Chou

Y.H.

Chen

P.K.

Chong

S.S.

Yeow

Jee

S.H.

. Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations. Genet Med. 2007; 9: 219–227.

18.

Rahimov

Marazita

M.L.

Visel

Cooper

M.E.

Hitchler

M.J.

Rubini

Domann

F.E.

Govil

Christensen

Bille

Disruption of an AP-2α binding site in an IRF6 enhancer is strongly associated with cleft lip. Nature Genet. 2008; 40: 1341.

19.

Sambrook

Fritsch

E.F.

Maniatis

Molecular cloning: A laboratory manual. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 1989.

20.

Scapoli

Palmieri

Martinelli

Pezzetti

Carinci

Tognon

Carinci

Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population. Am J Hum Genet. 2005; 76: 180–183.

21.

Schorle

Meier

Buchert

Jaenisch

Mitchell

P.J.

Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature. 1996; 381: 235–238.

22.

Shi

Song

Jiao

Qin

Zhou

Single-nucleotide polymorphisms (SNPs) of the IRF6 and TFAP2A in non-syndromic cleft lip with or without cleft palate (NSCLP) in a northern Chinese population. Biochem Biophys Res Commun. 2011; 410: 732–736.

23.

Shi

Y.Y.

SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res. 2005; 15: 97–98.

24.

Spielman

R.S.

McGinnis

R.E.

Ewens

W.J.

Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993; 52: 506–516.

25.

Srichomthong

Siriwan

Shotelersuk

Significant association between IRF6 820G->A and non-syndromic cleft lip with or without cleft palate in the Thai population. J Med Genet. 2005; 42: e46.

26.

Suazo

Santos

J.L.

Jara

Blanco

Linkage disequilibrium between IRF6 variants and nonsyndromic cleft lip/palate in the Chilean population. Am J Med Genet A. 2008; 146: 2706–2708.

27.

Terwilliger

J.D.

Ott

A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations. Hum Hered. 1992; 42: 337–346.

28.

Vieira

A.R.

Unraveling human cleft lip and palate research. J Dent Res. 2008; 87: 119–125.

29.

Dhillon

Collins

A.R.

Day

I.N.

An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res. 2001; 29(17): E88.

30.

Zucchero

T.M.

Cooper

M.E.

Maher

B.S.

Daack-Hirsch

Nepomuceno

Ribeiro

Caprau

Christensen

Suzuki

Machida

. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004; 351: 769–780.