Nonsyndromic cleft lip with or without palate (NSCL/P) is one of the most prevalent congenital orofacial defects. It arises from a combination of genetic and environmental factors. This study aims to identify new risk loci around the musculoaponeurotic fibrosarcoma oncogene family, protein B (MAFB) gene in NSCL/P patients from the Western Han Chinese population.
Design
A targeted region sequencing approach was employed to examine the MAFB gene in 159 NSCL/P cases. We conducted both single-variant association and gene-based burden analyses.
Setting
The study was conducted in a stomatological hospital.
Patients, participants
One hundred and fifty-nine NSCL/P cases were analyzed.
Interventions
Blood samples were collected.
Main outcome measures
To explore the association analysis between variants at MAFB and NSCL/P in Western Han Chinese population.
Results
We identified a cluster of significant common variants near the 3’ end of MAFB. Notably, rs6029223 showed significantly associated with NSCL/P (P = 3.82E-09, odds ration [OR]=0.29, 95% confidence interval [CI]: 0.18–0.46), nonsyndromic cleft lip and palate (NSCLP) (P = 5.31E-08, OR=0.25, 95% CI: 0.14–0.44) and nonsyndromic cleft lip only (NSCLO) (P = 1.3E-04, OR=0.34, 95%CI: 0.19–0.62). In Addition, rs79836852 and rs200392238 were significantly associated with both NSCL/P and NSCLP.
Conclusions
Our study revealed that single nucleotide polymorphisms near the 3’ end of the MAFB gene are risk factors for NSCL/P and NSCLP in the Western Han Chinese population. Our findings reinforce the notion that MAFB is a susceptibility gene for NSCL/P.
RahimovFJugessurAMurrayJC. Genetics of nonsyndromic orofacial clefts. Cleft Palate Craniofac J. 2012;49(1):73-91. doi:https://doi.org/10.1597/10-178
2.
DixonMJMarazitaMLBeatyTHMurrayJC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011;12(3):167-178. doi:https://doi.org/10.1038/nrg2933
3.
FanDWuSLiuL, Xia Q, Tian G, Wang W, Ye S, Wang L, Rao J, Yang X, et al.Prevalence of non-syndromic orofacial clefts: based on 15,094,978 Chinese perinatal infants. Oncotarget. 2018;9(17):13981-13990. doi:https://doi.org/10.18632/oncotarget.24238
4.
DaiLZhuJMaoM, Li Y, Deng Y, Wang Y, Liang J, Tang L, Wang H, Kilfoy BA, et al.Time trends in oral clefts in Chinese newborns: data from the Chinese National Birth Defects Monitoring Network. Birth Defects Res Part A Clin Molecular Teratol. 2010;88(1):41-47. doi:https://doi.org/10.1002/bdra.20607
5.
LiZRenALiuJ, Zhang L, Ye R, Li S, Li Z.High prevalence of orofacial clefts in Shanxi Province in northern China, 2003-2004. Am J Med Genet A. 2008;146a(20):2637-2643. doi:https://doi.org/10.1002/ajmg.a.32492
MorenoLMArcos-BurgosMMarazitaML, Krahn K, Maher BS, Cooper ME, Valencia-Ramirez CR, Lidral AC.Genetic analysis of candidate loci in non-syndromic cleft lip families from Antioquia-Colombia and Ohio. Am J Med Genet A. 2004;125a(2):135-144. doi:https://doi.org/10.1002/ajmg.a.20425
9.
BirnbaumSLudwigKUReutterH, Herms S, Steffens M, Rubini M, Baluardo C, Ferrian M, de Assis NA, Alblas MA, et al.Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet.2009;41(4):473-477. doi:https://doi.org/10.1038/ng.333
10.
BeatyTHMurrayJCMarazitaML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, et al.A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet. 2010;42(6):525-529. doi:https://doi.org/10.1038/ng.580
11.
SunYHuangYYinA, Pan Y, Wang Y, Wang C, Du Y, Wang M, Lan F, Hu Z, et al.Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate. Nat Commun. 2015;6:6414. doi:https://doi.org/10.1038/ncomms7414
12.
YuYZuoXHeM, Gao J, Fu Y, Qin C, Meng L, Wang W, Song Y, Cheng Y, et al.Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity. Nat Commun. 2017;8:14364. doi:https://doi.org/10.1038/ncomms14364
13.
HuangLJiaZShiY, Du Q, Shi J, Wang Z, Mou Y, Wang Q, Zhang B, Wang Q, et al.Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft. PLoS Genet. 2019;15(10):e1008357. doi:https://doi.org/10.1371/journal.pgen.1008357
LeslieEJMarazitaML. Genetics of cleft lip and cleft palate. Am J Medical Genet Part C Seminars Medical Genet. 2013;163c(4):246-258. doi:https://doi.org/10.1002/ajmg.c.31381
16.
PaulBJPalmerKJRheaL, Carlson M, Sharp JC, Pratt CH, Murray SA, Dunnwald M.The Mafb cleft-associated variant H131Q is not required for palatogenesis in the mouse. Dev Dynamics. 2021;250(10):1463-1476. doi:https://doi.org/10.1002/dvdy.327
17.
ZhangBDuanSShiJ, Jiang S, Feng F, Shi B, Jia Z.Family-based study of association between MAFB gene polymorphisms and NSCL/P among Western Han Chinese population. Adv Clin Exp Med. 2018;27(8):1109-1116. doi:https://doi.org/10.17219/acem/74388
18.
YuanQBlantonSHHechtJT. Association of ABCA4 and MAFB with non-syndromic cleft lip with or without cleft palate. Am J Med Genet A. 2011;155a(6):1469-1471. doi:https://doi.org/10.1002/ajmg.a.33940
19.
FontouraCSilvaRMGranjeiroJMLetraA. Further evidence of association of the ABCA4 gene with cleft lip/palate. Eur J Oral Sci. 2012;120(6):553-557. doi:https://doi.org/10.1111/eos.12001
20.
LennonCJBirkelandACNuñezJA, Su GH, Lanzano P, Guzman E, Celis K, Eisig SB, Hoffman D, Rendon MT, et al.Association of candidate genes with nonsyndromic clefts in Honduran and Colombian populations. Laryngoscope. 2012;122(9):2082-2087. doi:https://doi.org/10.1002/lary.23394
21.
MiNHaoYJiaoX, Zheng X, Song T, Shi J, Dong C.Association study of single nucleotide polymorphisms of MAFB with non-syndromic cleft lip with or without cleft palate in a population in Heilongjiang Province, northern China. Br J Oral Maxillofac Surg.2014;52(8):746-750. doi:https://doi.org/10.1016/j.bjoms.2014.06.003
22.
YinXMaLLiY, Xu M, Wang W, Wang H, Yuan H, Du Y, Li S, Ma J, et al.Genetic variants of 20q12 contributed to non-syndromic orofacial clefts susceptibility. Oral Dis. 2017;23(1):50-54. doi:https://doi.org/10.1111/odi.12570
23.
HuangLLiangXOuYTangSHeY. Association between 20q12 rs13041247 polymorphism and risk of nonsyndromic cleft lip with or without cleft palate: a meta-analysis. BMC Oral Health. 2020;20(1):39. doi:https://doi.org/10.1186/s12903-020-1003-2
24.
PengLNiuZChenJ, Wan T, Wu D, Yang Y, Wang G, Yang L, Huang W, Chen Z.Association of genetic polymorphisms of VAX1, MAFB, and NTN1 with nonsyndromic cleft lip with or without cleft palate in Chinese population. Mol Genet Genomics. 2022;297(2):553-559. doi:https://doi.org/10.1007/s00438-022-01871-9
25.
WardLDKellisM. Haploreg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(Database issue):D930-D934. doi:https://doi.org/10.1093/nar/gkr917
26.
LudwigKUMangoldEHermsS, Nowak S, Reutter H, Paul A, Becker J, Herberz R, AlChawa T, Nasser E, et al.Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet. 2012;44(9):968-971. doi:https://doi.org/10.1038/ng.2360
27.
PanYZhangWDuY, Tong N, Han Y, Zhang H, Wang M, Ma J, Wan L, Wang L.Different roles of two novel susceptibility loci for nonsyndromic orofacial clefts in a Chinese Han population. Am J Med Genet A. 2011;155a(9):2180-2185. doi:https://doi.org/10.1002/ajmg.a.34170
28.
Lopez-PajaresVQuKZhangJ, Webster DE, Barajas BC, Siprashvili Z, Zarnegar BJ, Boxer LD, Rios EJ, Tao S, et al.A LncRNA-MAF:MAFB transcription factor network regulates epidermal differentiation. Dev Cell. 2015;32(6):693-706. doi:https://doi.org/10.1016/j.devcel.2015.01.028
29.
LiQKimYSuktitipatB, Hetmanski JB, Marazita ML, Duggal P, Beaty TH, Bailey-Wilson JE.Gene-gene interaction among WNT genes for oral cleft in trios. Genet Epidemiol. 2015;39(5):385-394. doi:https://doi.org/10.1002/gepi.21888
30.
XiaoYTaubMARuczinskiI, Begum F, Hetmanski JB, Schwender H, Leslie EJ, Koboldt DC, Murray JC, Marazita ML, et al.Evidence for SNP-SNP interaction identified through targeted sequencing of cleft case-parent trios. Genet Epidemiol. 2017;41(3):244-250. doi:https://doi.org/10.1002/gepi.22023
31.
ShinJOLeeJMChoKW, Kwak S, Kwon HJ, Lee MJ, Cho SW, Kim KS, Jung HS.MiR-200b is involved in Tgf-β signaling to regulate mammalian palate development. Histochem Cell Biol. 2012;137(1):67-78. doi:https://doi.org/10.1007/s00418-011-0876-1
32.
KumariPSinghSKRamanR. A novel non-coding RNA within an intron of CDH2 and association of its SNP with non-syndromic cleft lip and palate. Gene. 2018;658:123-128. doi:https://doi.org/10.1016/j.gene.2018.03.017
33.
KavianiMAzarpiraNKarimiMHAl-AbdullahI. The role of microRNAs in islet β-cell development. Cell Biol Int. 2016;40(12):1248-1255. doi:https://doi.org/10.1002/cbin.10691
34.
ButaliAMosseyPAAdeyemoWL, Jezewski PA, Onwuamah CK, Ogunlewe MO, Ugboko VI, Adejuyigbe O, Adigun AI, Abdur-Rahman LO, et al.Genetic studies in the Nigerian population implicate an MSX1 mutation in complex oral facial clefting disorders. Cleft Palate Craniofac J. 2011;48(6):646-653. doi:https://doi.org/10.1597/10-133
