IRF6 rs2235375 single nucleotide polymorphism is associated with isolated non-syndromic cleft palate but not with cleft lip with or without palate in South Indian population / Polimorfismo de nucleotídeo único do gene IRF6 rs2235375 está associado com à fenda palatina isolada não sindrômica, mas não com fenda labial com ou sem fenda palatina em população do sul da Índia

Abstract Introduction Transcription factors are very diverse family of proteins involved in activating or repressing the transcription of a gene at a given time. Several studies using animal models demonstrated the role of transcription factor genes in craniofacial development. Objective We aimed to investigate the association of IRF6 intron-6 polymorphism in the non-syndromic cleft lip with or without palate in a South Indian population. Methods 173 unrelated nonsyndromic cleft lip with or without cleft palate patients and 176 controls without clefts patients were genotyped for IRF6 rs2235375 variant by allele-specific amplification using the KASPar single nucleotide polymorphism genotyping system. The association between interferon regulatory factor-6 gene intron-6 dbSNP208032210:g.G>C (rs2235375) single nucleotide polymorphism and non-syndromic cleft lip with or without palate risk was investigated by chi-square test. Results There were significant differences in genotype or allele frequencies of rs2235375 single nucleotide polymorphism between controls and cases with non-syndromic cleft lip with or without palate. IRF6 rs2235375 variant was significantly associated with increased risk of non-syndromic cleft lip with or without palate in co-dominant, dominant (OR: 1.19; 95% CI 1.03-2.51; p = 0.034) and allelic models (OR: 1.40; 95% CI 1.04-1.90; p = 0.028). When subset analysis was applied significantly increased risk was observed in cleft palate only group (OR dominant: 4.33; 95% CI 1.44-12.97; p = 0.005). Conclusion These results suggest that IRF6 rs2235375 SNP play a major role in the pathogenesis and risk of developing non-syndromic cleft lip with or without palate.

Resumo Introdução Fatores de transcrição constituem uma família de proteínas muito diversa envolvida na ativação ou repressão da transcrição de um gene, em um determinado momento. Vários estudos usando modelos animais demonstraram o papel dos genes do fator de transcrição no desenvolvimento craniofacial. Objetivo Nosso objetivo foi investigar a associação do polimorfismo IRF6 intron-6 na fenda labial não sindrômica com ou sem fenda palatina em uma população do sul da Índia. Método Um total de 173 pacientes com fenda labial não sindrômica com ou sem fenda palatina e 176 controles sem fendas foram genotipados para a variante IRF6 rs2235375 por amplificação alelo-específica utilizando o sistema KASPar de genotipagem de polimorfismo de nucleotídeo único. A associação entre o polimorfismo de nucleotídeo único Fator 6 Regulatório do Interferon (IRF6) intron-6 dbSNP208032210:g.G>C (rs2235375) e o risco de fenda labial não sindrômica com ou sem fenda palatina foi investigado pelo teste qui-quadrado. Resultados Houve diferenças significativas nas frequências de genótipos ou alelos do rs2235375 SNP entre controles e casos com fenda labial não sindrômica com ou sem fenda palatina. A variante IRF6 rs2235375 foi significativamente associada ao aumento do risco de fenda labial não sindrômica com ou sem fenda palatina em modelos codominantes, dominantes (OR: 1,19; IC 95%: 1,03-2,51; p = 0,034) e alélicos (OR: 1,40; IC 95%: 1,04-1,90; p = 0,028). Quando a análise do subgrupo foi realizada, um risco significativamente aumentado foi observado no grupo Fenda Palatina Isolada (OR dominante: 4,33; IC 95%: 1,44-12,97; p = 0,005). Conclusões Esses resultados sugerem que o polimorfismo de nucleotídeo único IRF6 rs2235375 desempenha um papel importante na patogênese e no risco de desenvolvimento de fenda labial não sindrômica com ou sem fenda palatina.

Association of single nucleotide polymorphisms in AXIN2, BMP4, and IRF6 with Non-Syndromic Cleft Lip with or without Cleft Palate in a sample of the southeast Iranian population

Abstract Non-syndromic cleft lip with or without palate (NSCL/P) is a common congenital malformation worldwide, with complex etiology. It has been proposed that interaction of genes and environmental factors play a role in the predisposition to this disease. Objectives: The aim of this study was to examine the association between AXIN2 (axis inhibition protein 2) rs7224837, BMP4 (bone morphogenetic protein 4) rs17563, and IRF6 (interferon regulatory factor 6) rs861019 and 2235371 polymorphisms and NSCL/P in an Iranian population. Material and Methods: This case-control study was carried out on 132 unrelated NSCL/P patients and 156 healthy subjects. The variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The findings suggest that BMP4 rs17563 polymorphism significantly decreased the risk of NSCL/P in codominant (OR=0.36, 95%CI=0.17-0.79, p=0.012, CT vs CC and OR=0.11, 95%CI=0.01-0.88, p = 0.019, TT vs CC), dominant (OR=0.30, 95%CI=0.15-0.62, p = 0.0007, CT+TT vs CC), recessive (OR=0.12, 95%CI=0.02-0.99, p = 0.023, TT vs CC+CT), overdominant (OR=0.39, 95%CI = 0.18-0.84, p=0.021, CT vs CC+TT), and allele (OR=0.28, 95%CI=0.15-0.55, p<0.0001, T vs C) inheritance models. Our findings did not support an association between AXIN2 rs7224837 and IRF6 rs861019 polymorphism and risk/protection of NSCL/P. The IRF6 2235371 variant was not polymorphic in our population. Conclusion: The results indicate that the BMP4 rs17563 variant is likely to confer a protective effect against the occurrence of NSCL/P in a sample of the southeast Iranian population.

Cleft lip and cleft palate in Jangxi province: A case-control study on familial occurrence of 1 967 cases / 实用口腔医学杂志

Objective:To assess whether familial occurrence has an influence on the morphological characteristics of patients with nonsyndromic cleft lip and/or palate (NsCL/P).Methods:A case-control analysis was performed on the morphological characteristics of familial group and sporadic group,using medical records of 1967 patients with NsCL/P treated in the Affiliated Stomatological Hospital of Nanchang University from 2002 to 2014.Results:164 (8.34％) cases presented a positive history of cleft in their families.The cleft types,the positive familial rate of cleft lip only (CLO),cleft lip and alveolar ridge(CLA),cleft lip and palate (CLP) and cleft palate only (CPO) were 8.11％,8.54％,6.19％ and 9.65％ respectively.A positive family history of NsCL/P was associated with 0.66 times risk of CPO (P =0.036,OR =0.66,95％ CI 0.44-0.98) compared to those of CLO,CLA and CLP.In familial group of CLP,the lateral incidence of male patients was different from that of female patients (P ＜ 0.001).There was no significant difference between familial group and sporadic group on birth weights,parental child-bearing age and clinical manifestations of patients.Conclusion:Familial occurrence might have an influence on cleft type,laterality and gender of the patients with NSCL/P.

Bioinformatics analysis of dysregulated miRNAs in the tissue of children with nonsyndromic cleft lip and/or cleft palate / 实用口腔医学杂志

Objective:To screen the differentially expressed miRNAs in umbilical cord tissue of children with nonsyndromic cleft lip and/or cleft palate( NSCL/P) using miRNA microarray and comprehensive bioinformatics analysis for the prediction of related the bio-logical process and signaling pathways. Methods:Umbilical cord tissues of 4 cases of healthy newborns' and 4 lip or palate tissues of 4 cases with NSCL/P without other disease aged younger than 2 years were collected. The differentially expressed miRNAs were screened by miRNA microarray. Targets of dysrugulated miRNAs were predicted by TARGETSCAN-VERT, MIRDB and RNA22-HSA. All the gene sets were analyzed by gene ontology and pathway enrichment. Results: MiRNA microarray demonstrated that 254 miRNAs were dysregulated(181 miRNAs were up-regulated and 73 downregulated,P <0. 05). The dysregulated miRNAs targets contained 5029 genes. The dysregulated miRNAs targets were enriched in anatomical structure development,cell adhesion,cell proliferation,cell motili-ty and other biological processes. The dysregulated miRNAs targets were enriched in Wnt, mTOR, cGMP-PKG, TGFβ, PI3K-Akt and other signaling pathways. Conclusion:The target genes set of miRNAs are enriched in multiple biological processes and signaling path-ways related to NSCL/P, which indicate that genetic and environmental factors may influence the development process of NSCL/P.

Association of rs1 1 742688 polymorphism of DHFR gene with non-syndromie cleft lip with or without cleft palate in the northeast of China / 实用口腔医学杂志

Objective:To investigate the association between dihyrofolate reductase(DHFR)gene rs1 1 742688 polymorphism and non-syndrom cleft lip with or without cleft palate (NSCL/P)in northest Chinese population.Methods:PCR-restriction fragment length polymorphism(PCR-RFLP)was used to identify the rs1 1 742688 polymorphism of DHFR gene of 220 NSCL/P patients(inclu-ding 1 38 core families)and 1 80 healthy controls.Hardy-Weinberg test and SPSS statistical software were used to calculate the data, OR and 95% confidence intervalarents.Results:In case-contral analysis,there was no significant difference in TT genotype of rs1 1 742688 between NSCL/P subjects and the controls(χ2 =0.439,P >0.05)in.Conclusion:The polymorphism of rs1 1 742688 in DHFR gene is not associated with NSCL/P in northest Chinese population.

Association of the MTHFR gene polymorphism with non-syndromes cleft lip with or without cleft palate in XinJiang Uyghur and Han population / 实用口腔医学杂志

Objective:To explore the relationship of NSCL/P with MTHFR gene polymorphism in Xinjiang Uyghur and Han popula-tion and the ethnic difference.Methods:rs1801131 and rs1801133 polymorphism was detected by SNaPshot genotype method in 170 children with NSCL/P and 100 healthy controls of Uyghur and Han population.Results:Rs1801133 TT and T allele was statistically difference between 2 nationalities(P 0.05).Conclusion:Rs1801133 TT and T allele in Han nationality are more likely to suffer from NSCL/P than in Uyghur,rs1801133 CT and CT +TT genotypes are protective factors.Rs1801131AC and rs1801133CC conjoint is relevant to NSCL/P,and the risk in Uyghur is higher than in Han.MTHFR rs1801131 gene polymorphism may not be relat-ed with NSCL/P in Uyghur or Han.

The association of MAFB gene polymorphism with nonsyndromic cleft lip with or without cleft palate in Ningxia Hui and Han population / 实用口腔医学杂志

Objective:To study the association between non-syndrome cleft lip and palate (NSCL/P)and MAFB (rs6072081, rs6065259,rs17820943,rs11696257)gene polymorphism in NingXia Hui and Han population.Methods:512 cases of NSCL/P,258 case of Hui nationality and 254 of Han,174 cases of complete 3 core family members(patients and their parents),142 cases of single parents families(patients and their single parents),were collected in patient group.505 cases of healthy newborns were collected in control group.The MAFB gene SNPs were determined with TaqMan SNPs genotyping methods and the data were analyzed by case-con-trol analysis,transmission disequilibrium test(TDT)and family based association test(FBAT).Results:Case-control analysis found that,there was a statistical significance of the genotypes and allele frequency between patients and the controls in MAFB of the 4 locus (P 0.05).Conclusion:The 4 locus single nucle-otide polymorphism was associated with NSCL/P in Ningxia population.

Association between folate metabolism-related genes and non-syndromic cleft lip and palate in the popu-lation of Shanxi Province / 实用口腔医学杂志

Objective:To investigate the association of the rsl801133 polymorphisms of the methylenetetrahydrofolate reductase (MTHFR)gene and rs2236225 polymorphisms of the methylenetetrahydrofolate dehydrogenase(MTHFD1)gene with non-syndromic cleft lip with or without cleft palate (NSCL/P)in Chinese population of Shanxi Province.Methods:The rsl801133 polymorphism of MTHFR gene and rs2236225 polymorphism of MTHFD1 gene were examined by PCR-RFLP in 265 patients with NSCL/P and 276 healthy controls.Data were statistically analysed.Results:The genotypic distribution of rsl801133 and rs2236225 was not deviated from the Hardy-Weinberg equilibrium.There was no significant difference in allele frequencies of rsl801133 and rs2236225 variants between patients with NSCL/P and healthy individuals(P <0.05).Conclusion:The polymorphism of MTHFR gene and MTHFD1 gene was not associated with NSCL/P in Chinese population of Shanxi Province.

Lower incidence of nonsyndromic cleft lip with or without cleft palate in females: Is homocysteine a factor.

In India, as in other parts of the world, nonsyndromic cleft lip with or without cleft palate (NSCL±P) is a highly prevalent birth defect, its incidence in males being twice that in females. A case–control association study has been carried out with respect to homocysteine level and MTHFR C677T, A1298C and SLC19A1 (RFC1) G80A genotypes from an eastern Indian cohort to investigate whether Hcy and other Hcy-pathway genes also contribute to the risk level. While MTHFR 677T and SLC19A1 80G are individually and cumulatively risk factors, SLC19A1 80A appears to be protective against MTHFR 677T risk allele. Elevated Hcy associates with NSCL±P both in case mothers and cases. Significantly, this difference shows a gender bias: the level of elevation of Hcy in female cases is distinctly higher than in males, and more case females are hyperhomocyteinemic than the case males. It implies that compared with the males, higher level of Hcy is needed for NSCL±P to manifest in the females. We consider this as one of the possible factors why the incidence of this disorder in females is much lower than in males.

Significant association between SNPs in IRF6 and non-syndromic cleft lip with or without cleft palate in West China / 实用口腔医学杂志

Objective:To study the association between the rs2013162 and rs2235375 polymorphisms in IRF6 and risk of NSCL/P in west Chinese population. Methods: The study group consisted of 332 NSCL/P patients, their parents (289 mothers, 243 fathers and 206 complete families), and 174 controls. PCR-RFLP method was used to identify genotypes and both case-parent and case-control designs were carried out on samples from west China. Results: There were significant differences in the frequency distributions of both genotypes and alleles when cases were compared with control infants at the rs2235375(P<0.01, P<0.01 respectively). We found strong evidence of over-transmission of the G allele at rs2235375 in cleft case-parent trios(P<0.01). Five specific haplotypes showed significant over-and under-transmission. Conclusion: These results suggest IRF6 variants play a role in NSCL/P in west Chinese populations.