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Background: Orofacial clefts (OFCs) are common birth defects with complex etiology. Genome wide association studies for OFC have identified SNPs in and near MAFB. MAFB is a transcription factor critical for structural development of digits, kidneys, skin, and brain. MAFB is also expressed in the craniofacial region. Previous sequencing of MAFB in a Filipino population revealed a novel missense variant significantly associated with an increased risk for OFC. This MAFB variant, leading to the amino acid change H131Q, was knocked into the mouse Mafb, resulting in the Mafb H131Q allele. The Mafb H131Q construct was engineered to allow for deletion of Mafb ("Mafb del ")., Results: Mafb del/del animals died shortly after birth. Conversely, Mafb H131Q/H131Q mice survived into adulthood at Mendelian ratios. Mafb del/del and Mafb H131Q/H131Q heads exhibited normal macroscopic and histological appearance at all embryonic time points evaluated. The periderm was intact based on expression of keratin 6, p63, and E-cadherin. Despite no effect on craniofacial morphogenesis, H131Q inhibited the Mafb-dependent promoter activation of Arhgap29 in palatal mesenchymal, but not ectodermal-derived epithelial cells in a luciferase assay., Conclusions: Mafb is dispensable for murine palatogenesis in vivo, and the cleft-associated variant H131Q, despite its lack of morphogenic effect, altered the expression of Arhgap29 in a cell-dependent context., (© 2021 American Association of Anatomists.)

While there have been previous studies examining the relation between the rs17820943 and rs6072081 polymorphisms in the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene and rates of nonsyndromic cleft lip with or without cleft palate (NSCL/P), at present the results of these studies have been inconsistent. This meta-analysis therefore aimed to conduct a more robust assessment of the association between the MAFB rs17820943 and rs6072081 polymorphisms and NSCL/P risk. The Embase, Web of Science, PubMed, the China National Knowledge Internet (CNKI), and Wanfang databases were systematically searched to identify relevant studies. In total, five studies incorporating 2769 patients and 2885 controls were identified assessing the rs17820943 polymorphism and three studies incorporating 1242 patients and 1310 controls assessing the rs6072081 polymorphism were identified. This analysis revealed the MAFB rs17820943 and rs6072081 polymorphisms to be linked to a significantly reduced NSCL/P risk (rs17820943: C vs T: OR=0.76, 95% CI=0.70-0.82; CC vs CT: OR=0.75, 95% CI=0.67-0.85; CC vs TT: OR=0.58, 95% CI=0.49-0.67; CC+CT vs TT: OR=0.67, 95% CI=0.59-0.77; CT+TT vs CC: OR=1.43, 95% CI=1.28-1.60; rs6072081: A vs G: OR=0.77, 95%CI=0.68-0.86; AA vs AG: OR=0.76, 95%CI=0.64-0.90; AA vs GG: OR=0.58, 95%CI=0.45-0.74; AA+AG vs GG: OR=0.68, 95%CI=0.54-0.84; AG+GG vs AA: OR=1.40, 95% CI=1.19-1.65). The results of the present meta-analysis indicate that in an East Asian population, for both rs17820943 and rs6072081 were associated with NSCL/P., (Copyright © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Non-syndromic cleft lip/palate (NSCL/P) has an etiology, including both genetic and environmental factors. Herein, we evaluated the association of rs13041247 and rs11696257 v-maf musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ) polymorphisms with the risk of NSCL/P in a meta-analysis. Methods: The PubMed/Medline, Scopus, Cochrane Library, Web of Science, and HuGE Navigator databases were systematically searched to retrieve relevant articles published up to January 2019. The Newcastle-Ottawa scale was applied for quality evaluation of retrieved articles. The 95% confidence interval (CI) and crude odds ratio (OR) were calculated for each study using the Review Manager 5.3 software to show the association between MAFB polymorphisms and risk of NSCL/P. The comprehensive meta-analysis 2.0 software was used to calculate the publication bias. In addition, sensitivity analysis was carried out to show the stability of results. Results: Of 102 articles retrieved from the databases, 10 articles were analyzed in this meta-analysis. Ten articles, including eleven studies reporting rs13041247 MAFB polymorphism, included 3082 NSCL/P patients and 4104 controls. Three studies that reported rs11696257 MAFB polymorphism involved 845 NSCL/P patients and 927 controls. The rs11696257 MAFB polymorphism was not associated with the risk of NSCL/P, but the CC and TC genotypes of rs13041247 polymorphism were associated with the risk of NSCL/P. Nevertheless, the C allele and CC and TC genotypes were associated with a significant decline in the risk of NSCL/P in population-based studies. Conclusions: The results of this meta-analysis demonstrated that the risk of NSCL/P was related to rs13041247 polymorphism, not rs11696257 MAFB polymorphism. Well-designed studies are required to assess the interaction of MAFB and other genes with environmental factors in different ethnic groups.

Background: Non-syndromic cleft lip with or without cleft palate (NSCL/P) are the most common human congenital birth defects with a complex etiology. MAFB has been reported as a candidate gene involved in the pathogenesis of NSCL/P from genome-wide association study (GWAS) findings, and no replication studies have been performed in Western Han Chinese., Objectives: The aim of this study was to investigate the associations of MAFB among NSCL/P trios in Western Han Chinese., Material and Methods: We selected 6 single nucleotide polymorphisms (SNPs) (rs6072081, rs6065259, rs17820943, rs13041247, rs11698025 and rs6102085) near MAFB based on previous GWAS findings and recruited 298 case-parents trios with NSCL/P from Western Han Chinese population, while genotypes were done by SNPscan technology., Results: Strong evidence of an association was found at rs17820943 (p = 0.0023; odds ratio - ORtranmission = 0.7 and 95% confidence interval [CI]: 0.55-0.88) and rs13041247 (p = 0.0023; ORtranmission = 0.7 and 95% CI: 0.55-0.88) among NSCL/P; genotypic transmission-disequilibrium test (TDT) analysis further confirmed this. C/C homozygote at rs17820943 (z = 3.44 and p = 0.00058) and T/T homozygote at rs13041247 (z = 3.14 and p = 0.0017) was over-transmitted among NSCL/P, which indicated they could increase the risk of having an affected baby. Sliding window haplotype analysis showed that haplotypes consisting of C allele at rs17820943 and T allele at rs13041247 were still over-transmitted among NSCL/P (lowest p = 0.0021)., Conclusions: This study further confirmed that the targeted SNPs at MAFB were associated with NSCL/P trios from Western Han Chinese population, which provides more scientific evidence for the future research and genetic counseling.

Objective: Previous genomewide association studies (GWAS) identified a region near MAFB at chr20q12 associated with non-syndromic orofacial clefts (NSOC) susceptibility. However, whether other SNPs in this area could independently contribute to non-syndromic orofacial clefts in Chinese populations remained obscure., Materials and Methods: We selected 24 SNPs based on a haplotype-tagging SNP strategy and evaluated their associations with risk of non-syndromic orofacial clefts in a large-scale two-stage case-control study with 1278 cases and 1295 controls. Genotyping was performed with Sequenom and TaqMan assay. Associations between the SNPs and risk of non-syndromic orofacial clefts were estimated from unconditional logistic regression analyses., Results: Overall, six SNPs were found to be the susceptible factors of non-syndromic orofacial clefts. The most significant and independent SNP was rs6129653 (additive model of P value = 1.4E-06). In subgroup analysis, its significant associations with cleft lip only (CLO) and cleft lip and palate (CLP) were observed. Furthermore, in silico bioinformatics analysis indicated that rs6129653 was located in the transcriptionally active region and associated with MAFB expression in human brain tissues., Conclusions: Rs6129653 was an independent locus of non-syndromic orofacial clefts among Chinese populations possibly due to its potential of distal transcriptional regulation of MAFB expression., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nonsyndromic clefts of the lip and palate (NSCLP) are complex genetic traits. Together, they are classified as one of the most common birth defects with a prevalence of 1/700 live births. Genome-wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (NSCL[P]) revealed significant association for common single nucleotide polymorphisms near genes involved in craniofacial development i.e., MAFB, PAX7, VAX1, ARHGAP29 (ABCA4 locus), and IRF6. Sequencing of protein coding regions of the NSCL(P) GWAS candidate genes or adjacent genes suggest a role for rare functional variants. Replication studies in the African population did not observe any significant association with the GWAS candidate genes. On the other hand, the role of rare functional variants in GWAS candidate genes has not been evaluated in the African population. We obtained saliva samples from case triads in Nigeria and Ethiopia for Sanger sequencing of the GWAS candidate genes (MAFB, PAX7, VAX1, ARHGAP29, and IRF6) in order to identify rare functional variants. A total of 220 African samples (140 Nigerians and 80 Ethiopians) were sequenced and we found the following new rare variants- p.His165Asn in the MAFB gene, p.Asp428Asn in the PAX7, a splice-site variant that creates a new donor splice-site in PAX7. We also found three previously reported missense variants p.Gly466Ser in PAX7; p.Leu913Ser and Arg955His in ARHGAP29. No de novo mutations were found. Future genome-wide association and sequencing studies should be conducted using samples from Africa in order to identify new molecular genetic factors that contribute to the etiology of NSCLP., (© 2014 Wiley Periodicals, Inc.)

Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. MAFB (v-maf musculoaponeurotic fibrosarcoma oncogene homolog B) is a new gene that may be involved in susceptibility to cleft lip with or without cleft palate (CL/P). To further assess its role in NSCLP, we investigated 3 identified single nucleotide polymorphisms in MAFB (rs13041247, rs6065259, and rs11696257) and examined them for association with NSCLP in 344 patients and 324 healthy controls in a northern Chinese Han population with a high incidence of the syndrome. Peripheral blood samples were taken when patients enrolled in the study and DNA samples were extracted from the blood. The 3 single nucleotide polymorphisms were genotyped using a mini-sequencing method (Snapshot(®) Multiplex System for SNP genotyping, Life Technologies Ltd, Paisley, UK). We found that rs6065259 was the most important single nucleotide polymorphism in MAFB (OR6065259-AA=0.45; 95% CI: 0.28 to 0.71; p=0.0027), followed by rs13041247; however, no association was found between rs11696257 and NSCLP. Our study provides further evidence regarding the role of MAFB variations in the development of NSCLP in this northern Chinese Han population., (Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Non-syndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. Numerous genes and environmental factors, and their interactions, are thought to play a role in the susceptibility to CL/P. A recent genome-wide association study with several populations revealed markers in/near transcription factor vmaf musculoaponeurtoic fibrosarcoma oncogene homolog B (MAFB) and ATP-binding cassette sub-family A member 4 (ABCA4) genes as new susceptibility loci for CL/P. We hypothesized that these genes could also contribute to CL/P in a Brazilian population, and hence we evaluated if the associated single-nucleotide polymorphisms (SNPs) in MAFB (rs13041247 and rs11696257) and ABCA4 (rs560426 and rs481931) were associated with CL/P in our case-control data set. We genotyped 812 Caucasian individuals (400 cases and 412 controls) from Brazil. Allele frequencies were compared for cases and controls as well as for cleft subgroups and controls. ABCA4 rs540426 showed strong associations with CL/P, unilateral and right CL/P, and bilateral CL/P, whereas the SNP rs481931 showed borderline associations with CL/P and bilateral CL/P . No association was found for MAFB. Our results support a potential role for ABCA4 in the etiology of CL/P in individuals from Brazil., (© 2012 Eur J Oral Sci.)

Objectives/hypothesis: Orofacial clefts are the most common craniofacial birth defects in humans, with the majority of orofacial clefts occurring as nonsyndromic cleft lip with or without cleft palate (NSCLP). We previously demonstrated associations between single-nucleotide polymorphisms (SNPs) in the IRF6 gene and NSCLP in the Honduran population. Here we investigated other candidate genes and chromosomal regions associated with NSCLP identified from genome-wide association studies (GWAS), including MAFB, ABCA4, 8q24, 9q22, 10q25, and 17q22 in two independent Hispanic populations., Study Design: Case-control and family-based association testing., Methods: Honduran families with two or more members with NSCLP (multiplex) were identified. DNA was collected from affected and unaffected family members (488) and 99 gender-matched controls. NSCLP Colombian families were identified; DNA was collected from 26 proband-parent trios. All participants were genotyped for 17 SNPs in six chromosomal regions. Case-control association and family-based association testing (FBAT) analyses were conducted., Results: Seven SNPs demonstrated association in at least one model in the Honduran population. In the Colombian families, five SNPs demonstrated significance in FBAT when patients with isolated cleft palate (CP) were included; four overlapped with SNPs demonstrating significance in the Honduran population, two with the same allele. One SNP retained significance with CP excluded., Conclusions: This study supports the previous GWAS findings and is the first to suggest a role for FOXE1, ABCA4, and MAFB in orofacial clefting in two separate Hispanic populations., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Objective: To reveal the association between the single nucleotide polymorphism (SNP) of v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene rs17820943 locus and non-syndromic cleft lip with or without cleft palate (NSCL/P) in the southern Chinese Han population., Methods: Genotyping of MAFB gene rs17820943 polymorphism was carried out in 300 patients with NSCL/P, 354 normal controls, and an additional 168 case-parent trios with matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry. Then based on the genotyping results, both a case-control association study and a case-parent trio association study were performed., Results: Significant differences were found in the allele and genotype frequencies of rs17820943 locus between case and control groups (Pallele = 0.001 and Pgenotype = 0.002, respectively). To be specific, the odds radio (OR) values and 95% confidence interval (95% CI) of allele T (frequencies of cases:controls = 0.358:0.448) and genotype TT (frequencies of cases:controls = 0.110:0.195) were ORT = 0.69 (95% CI: 0.55-0.86) and OR(TT) = 0.43 (95% CI: 0.26-0.70), respectively. Subsequent case-parent trio analysis also indicated an association between MAFB rs17820943 variant and the risk of NSCL/P (ORT(T vs. C) = 0.55, 95% CI: 0.41-0.75, P value of transmission disequilibrium test was 0.000)., Conclusion: Polymorphism of MAFB gene rs17820943 locus is associated with NSCL/P in the southern Chinese Han population; MAFB rs17820943 variant may be a susceptible gene of NSCL/P.

Nonsyndromic orofacial clefts (NSOC) are the most common developmental anomalies in human beings. Recently, a large-scale genome-wide association study identified two novel NSOC susceptibility loci: rs13041247 near MAFB and rs560426 near ABCA4. In the present study, we recruited 396 NSOC cases and 384 healthy controls to replicate their associations with risk of NSOC as well as their subgroups in a Chinese Han population. We found the overall genotype and allele frequencies of rs13041247, but not rs560426 were significantly different between cases and controls. Further logistic regression analysis showed rs13041247 CT, CC, and CT/CC were associated with decreased NSOC susceptibility, compared with rs13041247 TT wide-type homozygote. Moreover, the apparent protection against cleft lip with or without cleft palate (CL/P), cleft lip with cleft palate (CLP), and cleft lip only (CLO) was also identified in stratified analysis. However, none of any rs560426 genotypes or alleles was associated with risk of NSOC or their subgroups. Taken together, our findings confirmed the contribution of MAFB in the etiology of NSOC in a Chinese Han population., (Copyright © 2011 Wiley-Liss, Inc.)

Case-parent trios were used in a genome-wide association study of cleft lip with and without cleft palate. SNPs near two genes not previously associated with cleft lip with and without cleft palate (MAFB, most significant SNP rs13041247, with odds ratio (OR) per minor allele = 0.704, 95% CI 0.635-0.778, P = 1.44 x 10(-11); and ABCA4, most significant SNP rs560426, with OR = 1.432, 95% CI 1.292-1.587, P = 5.01 x 10(-12)) and two previously identified regions (at chromosome 8q24 and IRF6) attained genome-wide significance. Stratifying trios into European and Asian ancestry groups revealed differences in statistical significance, although estimated effect sizes remained similar. Replication studies from several populations showed confirming evidence, with families of European ancestry giving stronger evidence for markers in 8q24, whereas Asian families showed stronger evidence for association with MAFB and ABCA4. Expression studies support a role for MAFB in palatal development.