A miRNA-binding-site SNP of MSX1 is Associated with NSOC Susceptibility

Abstract

MSX1 is a favorable candidate gene for susceptibility to non-syndromic orofacial clefts (NSOCs). However, the roles of MSX1 genetic variants in the development of NSOC are controversial and vary among human populations. In the present study, the roles of 4 potentially functional single-nucleotide polymorphisms (SNPs) of MSX1 (rs12532 in 3′-untranslated region [UTR], and rs3821947, rs3821949, and rs4464513 in 5′ upstream) were investigated in a case-control study of 602 NSOC cases and 605 healthy controls. The findings showed that rs12532 located within 3′-UTR of MSX1 could influence the risk of developing NSOC. Individuals who carried the variant genotype (rs12532AA genotype) showed a decreased possibility of developing NSOC (AA vs. GG: OR = 0.69, 95% CI = [0.49, 0.98]). Interestingly, similar effects were also observed on cleft lip with palate (CLP), in a stratified analysis (allelic comparison-12532A allele vs. 12532G allele, OR = 0.80, 95% CI = [0.66, 0.99]; genotypic comparison-AA vs. GG, OR = 0.58 95% CI = [0.37, 0.91]). Sequence analysis indicated that this SNP might alter the binding ability of miR-3649, confirmed by luciferase activity assay showing a lower expression level of rs12532 A allele compared with that of the G allele (p < .001 for 293A and COS7 cell lines). Furthermore, an in vivo study showed that MSX1 expression among individuals carrying the AA genotype of rs12532 was markedly lower than that in those with the GG genotype, while the inverse correlation was observed for miR-3649, thus providing a possible interaction between MSX1 and miR-3649 in the etiology of NSOC. Taken together, these findings indicate that SNPs in the miRNA-binding sites might play an important role in the development of NSOCs. Furthermore, if confirmed in subsequent studies, the polymorphisms may be considered as additional markers for the evaluation of infants’ risk of NSOCs.

Keywords

single-nucleotide polymorphism non-syndromic orofacial clefts case-control study genetics microRNA risk factors

Get full access to this article

View all access options for this article.

References

Barrett

Fry

Maller

Daly

(2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263-265.

Beaty

Murray

Marazita

Munger

Ruczinski

Hetmanski

. (2010). A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet 42:525-529.

Cardoso

Bezerra

Oliveira

Soares

Oliveira

de Souza

. (2012). MSX1 gene polymorphisms in non-syndromic cleft lip and/or palate. Oral Dis 19:507-512.

Chen

Yang

Liu

. (2012). Genome-wide association study validation identifies novel loci for atherosclerotic cardiovascular disease. J Thromb Haemost 10:1508-1514.

Cobourne

(2004). The complex genetics of cleft lip and palate. Eur J Orthod 26:7-16.

Dai

Zhu

Mao

Deng

Wang

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

Dixon

Marazita

Beaty

Murray

(2011). Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12:167-178.

Gong

(2001). Phenotypic and molecular analyses of A/WySn mice. Cleft Palate Craniofac J 38:486-491.

Grant

Wang

Zhang

Glaberson

Annaiah

Kim

. (2009). A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24. J Pediatr 155:909-913.

10.

Huang

Deng

Ren

. (2011). Association between MSX1 variants and oral clefts in Han Chinese in western China. DNA Cell Biol 30:1057-1061.

11.

Jagomägi

Nikopensius

Krjutskov

Tammekivi

Viltrop

Saag

. (2010). MTHFR and MSX1 contribute to the risk of nonsyndromic cleft lip/palate. Eur J Oral Sci 118:213-220.

12.

Kim

Park

Baek

(2013). Association between MSX1 SNPs and nonsyndromic cleft lip with or without cleft palate in the Korean population. J Korean Med Sci 28:522-526.

13.

Zhu

Meng

Shi

. (2011). Biological and epidemiological evidence of interaction of infant genotypes at Rs7205289 and maternal passive smoking in cleft palate. Am J Med Genet A 155A:2940-2948.

14.

Mangold

Ludwig

Birnbaum

Baluardo

Ferrian

Herms

. (2010). Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet 42:24-26.

15.

Mossey

Little

Munger

Dixon

Shaw

(2009). Cleft lip and palate. Lancet 374:1773-1785.

16.

Munsie

Lin

Browne

Campbell

Caton

Bell

. (2011). Maternal bronchodilator use and the risk of orofacial clefts. Hum Reprod 26:3147-3154.

17.

Pan

Han

Zhang

Zhou

Cai

. (2013). Association and cumulative effects of GWAS-identified genetic variants for nonsyndromic orofacial clefts in a Chinese population. Environ Mol Mutagen 54:261-267.

18.

Rafighdoost

Hashemi

Narouei

Eskanadri-Nasab

Dashti-Khadivaki

Taheri

(2012). Association between CDH1 and MSX1 gene polymorphisms and the risk of nonsyndromic cleft lip and/or cleft palate in a southeast Iranian population. Cleft Palate Craniofac J 50:e98-e104.

19.

Rahimov

Jugessur

Murray

(2012). Genetics of nonsyndromic orofacial clefts. Cleft Palate Craniofac J 49:73-91.

20.

Ryan

Robles

Harris

(2010). Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer 10:389-402.

21.

Saunders

Liang

(2007). Human polymorphism at microRNAs and microRNA target sites. Proc Natl Acad Sci USA 104:3300-3305.

22.

Seo

Park

Kim

Baek

(2013). Associations between the risk of tooth agenesis and single-nucleotide polymorphisms of MSX1 and PAX9 genes in nonsyndromic cleft patients. Angle Orthod 83:1036-1042.

23.

Sethupathy

Borel

Gagnebin

Grant

Deutsch

Elton

. (2007). Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3′ untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes. Am J Hum Genet 81:405-413.

24.

Suazo

Santos

Jara

Blanco

(2010). Parent-of-origin effects for MSX1 in a Chilean population with nonsyndromic cleft lip/palate. Am J Med Genet A 152A:2011-2016.

25.

van den Boogaard

Dorland

Beemer

van Amstel

(2000). MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans. Nat Genet 24:342-343.

26.

Wehby

Cassell

(2010). The impact of orofacial clefts on quality of life and healthcare use and costs. Oral Dis 16:3-10.

27.

Jolicoeur

Zhang

Fortin

Wang

. (2007). Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers. Nucleic Acids Res 35:4535-4541.

28.

Zhang

Edwards

Zhu

Flemington

Deininger

Zhang

(2012). miRNA-mediated relationships between Cis-SNP genotypes and transcript intensities in lymphocyte cell lines. PLoS One 7:e31429.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.33 MB