Insights from studies with oral cleft genes suggest associations between WNT-pathway genes and risk of oral cancer.
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ABSTRACT:
SUBMITTER: Andrade Filho PA
PROVIDER: S-EPMC3092817 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Clefts of the lip and/or palate (cleft lip/palate) are notable for their complex etiology. The WNT pathway regulates multiple developmental processes including craniofacial development and may play a role in cleft lip/palate and other defects of craniofacial development such as tooth agenesis. Variations in WNT genes have been recently associated with cleft lip/palate in humans. In addition, two WNT genes, Wnt3 and Wnt9B, are located in the clf1 cleft locus in mice.We investigated 13 SNPs located in Wnt3A, Wnt5A, Wnt8A, Wnt11, Wnt3, and Wnt9B genes for association with cleft lip/palate subphenotypes in 463 cleft cases and 303 unrelated controls. Genotyping of selected polymorphisms was carried out using Taqman assays. PLINK 1.06 software was used to test for differences in allele frequencies of each polymorphism between affected and unaffected individuals. Haplotype analysis was also performed.Individuals carrying variant alleles in WNT3 presented an increased risk for cleft lip/palate (p = 0.0003; OR, 1.61; 95% CI, 1.29-2.02) in the population studied.Our results continue to support a role for WNT genes in the pathogenesis of cleft lip/palate. Although much remains to be learned about the function of individual WNT genes during craniofacial development, additional studies should focus on the identification of potentially functional variants in these genes as contributors to human clefting. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.
| S-EPMC2991560 | biostudies-literature
Project description:Genome-wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (CL/P) have identified multiple genes as important in the etiology of this common birth defect. We performed a candidate gene/pathway analysis explicitly considering gene-gene (G × G) interaction to further explore the etiology of CL/P. Animal models have shown the WNT signaling pathway plays an important role in mid-facial development, and various genes in this pathway have been associated with nonsyndromic CL/P in previous studies. We propose a combined approach to search for possible G × G interactions using machine learning and regression-based methods to test for interactions between genes in the WNT family, and between these genes and other genes identified by GWAS in case-parent trios. Using this combined approach of regression-based and machine learning methods in CL/P case-parent trios, we found robust evidence of G × G interaction between markers in WNT5B and MAFB (empiric P-values = 0.0076 among Asian trios and P-values = 0.018 among European trios). Additional evidence for epistatic interaction between markers in WNT5A, IRF6, and C1orf107 was seen among Asian trios, and markers in the 8q24 region and WNT5B among European trios.
| S-EPMC4469492 | biostudies-literature
Project description:Non-syndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect. Genetic and environmental factors have been causally implicated and studies have begun to delineate genetic contributions. The Wnt genes are involved in regulating mid-face development and upper lip fusion and are therefore strong candidates for an etiological role in NSCLP. Furthermore, the clf1 region in A/WyN clefting susceptible mice contains the Wnt3 and Wnt9B genes. To assess the role of the Wnt family of genes in NSCLP, we interrogated seven Wnt genes (Wnt3, Wnt3A, Wnt5A, Wnt7A, Wnt8A, Wnt9B and Wnt11) in our well-defined NSCLP dataset. Thirty-eight single nucleotide polymorphisms were genotyped in 132 multiplex NSCLP families and 354 simplex parent-child trios. In the entire dataset, single-nucleotide polymorphisms (SNPs) in three genes, Wnt3A (P = 0.006), Wnt 5A (P = 0.002) and Wnt11 (P = 0.0001) were significantly associated with NSCLP after correction for multiple testing. When stratified by ethnicity, the strongest associations were found for SNPs in Wnt3A (P = 0.0007), Wnt11 (P = 0.0012) and Wnt8A (P = 0.0013). Multiple haplotypes in Wnt genes were associated with NSCLP, and gene-gene interactions were observed between Wnt3A and both Wnt3 and Wnt5A (P = 0.004 and P = 0.039, respectively). This data suggests that alteration in Wnt gene function may perturb formation and/or fusion of the facial processes and predispose to NSCLP.
| S-EPMC2852032 | biostudies-literature
Project description:Nonsyndromic cleft lip and palate (NSCLP) is one of the most common craniofacial anomalies in humans, affecting more than 135,000 newborns worldwide. NSCLP has a multifactorial etiology with more than 50 genes postulated to play an etiologic role. The genetic pathway comprised of Pbx-Wnt-p63-Irf6 genes was shown to control facial morphogenesis in mice and proposed as a regulatory pathway for NSCLP. Based on these findings, we investigated whether variation in PBX1, PBX2, and TP63, and their proposed interactions were associated with NSCLP. Fourteen single nucleotide variants (SNVs) in/nearby PBX1, PBX2, and TP63 were genotyped in 780 NSCLP families of nonHispanic white (NHW) and Hispanic ethnicities. Family-based association tests were performed for individual SNVs stratified by ethnicity and family history of NSCLP. Gene-gene interactions were also tested. A significant association was found for PBX2 rs3131300 and NSCLP in combined Hispanic families (p = .003) while nominal association was found for TP63 rs9332461 in multiplex Hispanic families (p = .005). Significant haplotype associations were observed for PBX2 in NHW (p = .0002) and Hispanic families (p = .003), and for TP63 in multiplex Hispanic families (.003). An independent case-control group was used to validate findings, and significant associations were found with PBX1 rs6426870 (p = .007) and TP63 rs9332461 (p = .03). Gene-gene interactions were detected between PBX1/PBX2/TP63 with IRF6 in NHW families, and between PBX1 with WNT9B in both NHW and Hispanic families (p?<?.0018). This study provides the first evidence for a role of PBX1 and PBX2, additional evidence for the role of TP63, and support for the proposed PBX-WNT-TP63-IRF6 regulatory pathway in the etiology of NSCLP.
| S-EPMC7325739 | biostudies-literature
Project description:The Wnt-signaling pathway functions in regulating cell growth and thus is involved in the carcinogenic process of several cancers, including colorectal cancer. We tested the hypothesis that multiple genes in this signaling pathway are dysregulated and that miRNAs are associated with these dysregulated genes. We used data from 217 colorectal cancer (CRC) cases to evaluate differences in Wnt-signaling pathway gene expression between paired CRC and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most strongly associated with CRC (fold change (FC) of >1.5 or <0.67) and that were statistically significant after adjustment for multiple comparisons. Of the 138 Wnt-signaling pathway genes examined, 27 were significantly down-regulated (FC<0.67) and 32 genes were significantly up-regulated (FC>1.50) after adjusting for multiple comparisons. Thirteen of the 66 Wnt-signaling genes that were differentially expressed in CRC tumors were associated with differential expression of miRNAs. A total of 93 miRNA:mRNA associations were detected for these 13 genes. Of these 93 associations, 36 miRNA seed-region matches were observed, suggesting that miRNAs have both direct and indirect effects on Wnt-signaling pathway genes. In summary, our data supports the hypothesis that the Wnt-signaling pathway is dysregulated in CRC and suggest that miRNAs may importantly influence that dysregulation.
| S-EPMC5814196 | biostudies-literature
Project description:Here, we describe mutants of Mycoplasma pulmonis that were obtained using a minitransposon, Tn4001TF1, which actively transposes but is then unable to undergo subsequent excision events. Using Tn4001TF1, we disrupted 39 genes previously thought to be essential for growth. Thus, the number of genes required for growth has been overestimated. This study also revealed evidence of gene duplications in M. pulmonis and identified chromosome segregation proteins that are dispensable in mycoplasmas but essential in Bacillus subtilis.
| S-EPMC2974803 | biostudies-literature
Project description:Cleft of the lip and/or palate (CL±P) is the most common congenital craniofacial anomaly affecting around 1 in 700 live births worldwide. Clefts of the human face can be classified anatomically as cleft lip only (CL), cleft palate only (CP), cleft lip and palate (CLP) or a combined group of cleft lip with or without cleft palate (CL±P), based on differences in embryologic development. CL±P has a genetic base and several linkage and association analyses have been performed in order to obtain important information about the role of candidate genes in its onset; not less important are gene-environment interactions that play an increasing role in its aetiology. In CL±P, several loci have been seen associated with the malformation, and, in some cases, a specific gene mapping in a locus has also been identified as susceptibility factor. In CP, one gene has been found, but many more are probably involved. In this short review the genetic studies carried out on CL±P, and the interaction with environmental factors (alcohol, smoking, drugs) are discussed.
| S-EPMC5516428 | biostudies-literature
Project description:BackgroundFetal conditions can in principle be affected by the mother's genotype working through the prenatal environment.Methodology/principal findingsGenotypes for 1536 SNPs in 357 cleft candidate genes were available from a previous analysis in which we focused on fetal gene effects. After data-cleaning, genotypes for 1315 SNPs in 334 autosomal genes were available for the current analysis of maternal gene effects. Two complementary statistical methods, TRIMM and HAPLIN, were used to detect multi-marker effects in population-based samples from Norway (562 case-parent and 592 control-parent triads) and Denmark (235 case-parent triads). We analyzed isolated cleft lip with or without cleft palate (iCL/P) and isolated cleft palate only (iCP) separately and assessed replication by looking for genes detected in both populations by both methods. In iCL/P, neither TRIMM nor HAPLIN detected more genes than expected by chance alone; furthermore, the selected genes were not replicated across the two methods. In iCP, however, FLNB was identified by both methods in both populations. Although HIC1 and ZNF189 did not fully satisfy our stringency criterion for replication, they were strongly associated with iCP in TRIMM analyses of the Norwegian triads.Conclusion/significanceExcept for FLNB, HIC1 and ZNF189, maternal genes did not appear to influence the risk of clefting in our data. This is consistent with recent epidemiological findings showing no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefts in these two populations. It is likely that fetal genes make the major genetic contribution to clefting risk in these populations, but we cannot rule out the possibility that maternal genes can affect risk through interactions with specific teratogens or fetal genes.
| S-EPMC2901336 | biostudies-literature
Project description:ObjectiveTo investigate the association between the risk of tooth agenesis and single-nucleotide polymorphisms (SNPs) of MSX1 and PAX9 genes in nonsyndromic cleft patients.Materials and methodsThe subjects were 126 Korean nonsyndromic cleft patients. Tooth agenesis type (TAT) was classified as none (0); cleft area (1); cleft area + other area (2); and other area (3) based on agenesis of the maxillary lateral incisor (MXLI) and another tooth within or outside the cleft area. TAT was further grouped into two subcategories (0 and 1) and four subcategories (0, 1, 2, and 3). Three SNPs of MSX1 and 10 SNPs of PAX9 were investigated using Fisher's exact test and logistic regression analysis.ResultsAlthough the association between genotype distribution of PAX9-rs7142363 and TAT was significant (P < .05 in four subcategories), genotypic odds ratios (GORs) of SNPs in each TAT were not meaningful. However, for MSX1-rs12532 and PAX9-rs2073247, associations between genotypic distribution and TAT were significant (P < .01 in four subcategories and P < .05 in two subcategories; P < .01 in two subcategories, respectively). In cleft area, GORs of MXLI agenesis in genotypes GA of MSX1-rs12532 and CT of PAX9-rs2073247 were increased by 3.14-fold and 4.15-fold compared with genotype GG of MSX1-rs12532 and CC of PAX9-rs2073247, respectively (P <. 01; P < .05). In cleft area + other area, the GOR of agenesis of MXLI and another tooth in genotype AA of MSX1-rs12532 was increased by fivefold compared with genotype GG (P < .05).ConclusionGenetic disturbances of MSX1 and PAX9 genes are associated with tooth agenesis within and outside the cleft area.
| S-EPMC8722836 | biostudies-literature
Project description:In an effort to comprehensively interrogate genetic variation in the folate pathway for risk of cleft lip with or without cleft palate (CLP), we evaluated 504 common and rare variants in 35 folate-related genes in a panel of 330 infants with CLP and 367 non-malformed controls. Odds ratios (OR) with 95% confidence intervals were computed for common genotypes. A Case-Control Difference metric was calculated for rare variants to highlight differentially occurring alleles. Interactions between variants and a maternal folate intake variable were also evaluated. In gene-only results, significant odds ratios were observed for multiple variants in the BHMT/BHMT2/DMGDH gene cluster, particularly in Hispanic infants. Also in this cluster, rare variant analysis highlighted a substantial case-control difference in BHMT rs60340837 (synonymous Y284Y). In Hispanics, the ALDH1L1 I812V variant (rs4646750) was the most significant risk allele: OR?=?3.8 (95%CI?=?1.6-9.2) when heterozygous. In non-Hispanic white infants, we observed significant risk for AHCYL2 rs1095423 (homozygous OR?=?3.0, 95%CI 1.1-7.8) and the 68?bp CBS insertion (c.844ins68; heterozygous OR?=?2.4, 95%CI?=?1.1-5.3). Rare variant analysis in this group revealed case-control differences in MTRR and several other methionine cycle genes, a process implicated previously in clefting risk. In women with low folate intake specifically, increased risks were observed for CBS rs2851391 (OR?=?3.6, 95%CI?=?1.3-9.6) and the R259P nonsynonymous variant of TCN2 (rs1801198; OR?=?2.8, 95%CI?=?1.2-6.3). This comprehensive study provides further direction on candidate loci to help disentangle the folate-related developmental phenomena in human clefting risk. © 2016 Wiley Periodicals, Inc.
| S-EPMC5634616 | biostudies-literature