BMP4 Was Associated with NSCL/P in an Asian Population

Chen, Qianqian; Wang, Hong; Hetmanski, Jacqueline B.; Zhang, Tianxiao; Ruczinski, Ingo; Schwender, Holger; Liang, Kung Yee; Fallin, M. Daniele; Redett, Richard J.; Raymond, Gerald V.; Chou, Yah‐Huei Wu; Chen, Philip Kuo-Ting; Yeow, Vincent; Chong, Samuel S.; Cheah, Foong Koon; Jabs, Ethylin Wang; Scott, Alan F.; Beaty, Terri H.

doi:10.1371/journal.pone.0035347

Cited by 25 publications

(17 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A recent study reported that overexpression of the inhibitory Smad, Smad7, in neural crest cells repressed both TGFβ and BMP signaling, augmented apoptosis in branchial arches, and resulted in craniofacial anomalies [66]. Mutations in genes encoding a number of TGFβ superfamily members such as, TGFB3 [67], TGFBR1 ( ALK5 ) or TGFBR2 [68], ALK2/ACVR1 [69], ALK3/BMPR1A [70], BMP2 [71], BMP4 [72], BMP7 [73] and GDF11 [74] have been linked to CP formation. In the present study, genes encoding 40 members of the TGFβ superfamily (noted in “Results” and Table S1), were found to be differentially regulated subsequent to in utero AzaD exposure.…”

Section: Discussionmentioning

confidence: 99%

Determinants of orofacial clefting I: Effects of 5-Aza-2′-deoxycytidine on cellular processes and gene expression during development of the first branchial arch

Mukhopadhyay

Seelan

Rezzoug

et al. 2017

Reproductive Toxicology

View full text Add to dashboard Cite

In this study, we identify gene targets and cellular events mediating the teratogenic action(s) of 5-Aza-2′-deoxycytidine (AzaD), an inhibitor of DNA methylation, on secondary palate development. Exposure of pregnant mice (on gestation day (GD) 9.5) to AzaD for 12 hrs resulted in the complete penetrance of cleft palate (CP) in fetuses. Analysis of cells of the embryonic first branchial arch (1-BA), in fetuses exposed to AzaD, revealed: 1) significant alteration in expression of genes encoding several morphogenetic factors, cell cycle inhibitors and regulators of apoptosis; 2) a decrease in cell proliferation; and, 3) an increase in apoptosis. Pyrosequencing of selected genes, displaying pronounced differential expression in AzaD-exposed 1-BAs, failed to reveal significant alterations in CpG methylation levels in their putative promoters or gene bodies. CpG methylation analysis suggested that the effects of AzaD on gene expression were likely indirect.

show abstract

Section: Discussionmentioning

confidence: 99%

Determinants of orofacial clefting I: Effects of 5-Aza-2′-deoxycytidine on cellular processes and gene expression during development of the first branchial arch

Mukhopadhyay

Seelan

Rezzoug

et al. 2017

Reproductive Toxicology

View full text Add to dashboard Cite

show abstract

“…BMP4 is among the genes known to be functionally involved in craniofacial development. Building upon its biological function, as well as evidence from animal experimental studies [17] – [20] and human linkage studies [21] , [22] , BMP4 has been considered a leading candidate gene for NSCL/P and intensely studied in association studies using case-control [24] , [28] , [29] and case-parent trio designs [25] – [27] . Four of the 9 published candidate gene studies provided supportive evidence for association between BMP4 and NSCL/P, where the identified SNPs included rs17563 [24] , [28] , [29] , rs10130587 [25] , rs762642 [26] and rs2855530 [27] .…”

Section: Discussionmentioning

confidence: 99%

“…122 single nucleotide variants (SNVs) in and around BMP4 were genotyped using the Illumina Human610-Quad v.1_B Bead Chip at the Center for Inherited Disease Research at the Johns Hopkins University of the US [8] . Based on the genomic structure of NM_130850.2 or NM_ 001202.3 for BMP4 ( http://genome.ucsc.edu/ ) [25] , these SNVs are located 3′ (n = 114), introns (intron_1 for rs762642 and intron_3 for rs2071047 ) and 5′ (n = 6) of the gene, respectively.…”

Section: Methodsmentioning

confidence: 99%

Joint Testing of Genotypic and Gene-Environment Interaction Identified Novel Association for BMP4 with Non-Syndromic CL/P in an Asian Population Using Data from an International Cleft Consortium

et al. 2014

Self Cite

View full text Add to dashboard Cite

BackgroundNon-syndromic cleft lip with or without cleft palate (NSCL/P) is a common disorder with complex etiology. The Bone Morphogenetic Protein 4 gene (BMP4) has been considered a prime candidate gene with evidence accumulated from animal experimental studies, human linkage studies, as well as candidate gene association studies. The aim of the current study is to test for linkage and association between BMP4 and NSCL/P that could be missed in genome-wide association studies (GWAS) when genotypic (G) main effects alone were considered.Methodology/Principal FindingsWe performed the analysis considering G and interactions with multiple maternal environmental exposures using additive conditional logistic regression models in 895 Asian and 681 European complete NSCL/P trios. Single nucleotide polymorphisms (SNPs) that passed the quality control criteria among 122 genotyped and 25 imputed single nucleotide variants in and around the gene were used in analysis. Selected maternal environmental exposures during 3 months prior to and through the first trimester of pregnancy included any personal tobacco smoking, any environmental tobacco smoke in home, work place or any nearby places, any alcohol consumption and any use of multivitamin supplements. A novel significant association held for rs7156227 among Asian NSCL/P and non-syndromic cleft lip and palate (NSCLP) trios after Bonferroni correction which was not seen when G main effects alone were considered in either allelic or genotypic transmission disequilibrium tests. Odds ratios for carrying one copy of the minor allele without maternal exposure to any of the four environmental exposures were 0.58 (95%CI = 0.44, 0.75) and 0.54 (95%CI = 0.40, 0.73) for Asian NSCL/P and NSCLP trios, respectively. The Bonferroni P values corrected for the total number of 117 tested SNPs were 0.0051 (asymptotic P = 4.39*10−5) and 0.0065 (asymptotic P = 5.54*10−5), accordingly. In European trios, no significant association was seen for any SNPs after Bonferroni corrections for the total number of 120 tested SNPs.Conclusions/SignificanceOur findings add evidence from GWAS to support the role of BMP4 in susceptibility to NSCL/P originally identified in linkage and candidate gene association studies.

show abstract

“…Recently, Chen et al [20] tested for possible association between markers in BMP4 gene and nonsyndromic CL±P in 297 Asian and Maryland trios. Their results does not support the evidence of linkage and association for the SNP rs17563.…”

Section: Discussionmentioning

confidence: 99%

“…Lately, Chen et al [20] provided further evidence of association between BMP4 gene and nonsyndromic CL±P. They tested for possible association between markers in and around the BMP4 gene and nonsyndromic CL±P in Asian and Maryland trios.…”

Section: Introductionmentioning

confidence: 99%

Preliminary Analysis of the Nonsynonymous Polymorphism rs17563 in BMP4 Gene in Brazilian Population Suggests Protection for Nonsyndromic Cleft Lip and Palate

Araujo

Simioni

Félix

et al. 2012

Plastic Surgery International

View full text Add to dashboard Cite

Cleft lip with or without palate (CL±P) is common congenital anomalies in humans. Experimental evidence has demonstrated that bone morphogenetic protein 4 gene (Bmp4) is involved in the etiology of CL±P in animal models. The nonsynonymous polymorphism rs17563 T>C (p.V152A) in the BMP4 gene has been associated to the risk of nonsyndromic CL±P in Chinese population and microforms from different ethnic backgrounds. The aim of this study was to investigate the role of BMP4 gene in CL±P in Brazilian sample using genetic association approach. Our sample was composed by 123 patients with nonsyndromic CL±P and 246 controls, in which absence of CL±P was confirmed in 3 generations. The rs17563 polymorphism was genotyped by PCR-RFLP technique. Logistic regression was performed to evaluate allele and genotype association. Our data showed statistical power to detect association (86.83%) in this sample. Logistic regression results showed significant association between C allele and CL±P (P = 0.00018, OR = 0.40, and 95% CI = 0.25–0.65), as well as CC genotype and CL±P (P = 0.00018, OR = 0.35, and 95% CI = 0.19–0.66). So, there is a strong association between nonsyndromic CL±P and BMP4 rs17563 polymorphism in our sample and the C allele had a protective effect against the occurrence of nonsyndromic CL±P.

show abstract

BMP4 Was Associated with NSCL/P in an Asian Population

Cited by 25 publications

References 28 publications

Determinants of orofacial clefting I: Effects of 5-Aza-2′-deoxycytidine on cellular processes and gene expression during development of the first branchial arch

Determinants of orofacial clefting I: Effects of 5-Aza-2′-deoxycytidine on cellular processes and gene expression during development of the first branchial arch

Joint Testing of Genotypic and Gene-Environment Interaction Identified Novel Association for BMP4 with Non-Syndromic CL/P in an Asian Population Using Data from an International Cleft Consortium

Preliminary Analysis of the Nonsynonymous Polymorphism rs17563 in BMP4 Gene in Brazilian Population Suggests Protection for Nonsyndromic Cleft Lip and Palate

Contact Info

Product

Resources

About