OBJECTIVETo investigate the association between interferon regulatory factor 6 (IRF6) gene polymorphism and non-syndromic oral clefting (NSOC).

METHODSExperimental group consisted of 186 Ningxia NSOC patients, their parents (183 fathers and 174 mothers), 172 core families (patient+parents), and control group consisted of 200 normal children. DNA was extracted and PCR-restriction fragment length polymorphism (PCR-RFLP) was used to identify the genotypes of the samples, case-control analyses and transmission-disequilibrium test (TDT) were carried out.

RESULTSCompared with control group, there were significant differences in both rs642961's and rs4844880's AA genotype and A allele among NSOC patients (P < 0.05), but no difference in cleft palate (P = 0.15, P = 0.967, respectively). In TDT analysis, the A allele of rs642961 had a strong over-transmission in NSOC (P < 0.05), so did the rs4844880'A allele (P < 0.05), but neither of them had significant difference in cleft palate (P = 0.91, P = 0.95, respectively).

CONCLUSIONIRF6 gene polymorphism is associated with NSOC.

Case-Control Studies ; Cleft Palate ; genetics ; Humans ; Interferon Regulatory Factors ; genetics ; Polymorphism, Genetic

OBJECTIVETo identify mutations of interferon regulatory factor 6 (IRF6) gene in Van der Woude syndrome (VWS) patients in China.

METHODSThree Chinese VWS families were screened to IRF6 gene mutation via PCR and sequence techniques. After amplification of exons 1-8 and their flanking splice junctions and part of exon 9 of the IRF6 gene by polymerase chain reaction, mutations were detected by direct sequencing.

RESULTSThree novel mutations, one in each family, were identified in all the affected members in the three families. There were one missense mutation 1214 (T-->C) in exon 9, two nonsense mutations 981 (T-->A) in exon 7 and 1234 (C-->T) in exon 9. All affected members of the three families were heterozygous for their respective mutation.

CONCLUSIONMutations in IRF6 gene were found in all VWS patients. This observation supports the hypothesis that IRF6 is the gene responsible for VWS across different populations.

Asian Continental Ancestry Group ; genetics ; Cleft Lip ; genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Interferon Regulatory Factors ; genetics ; Male ; Mutation ; Pedigree

OBJECTIVE: This study aimed to investigate the clinical phenotype and genetic characteristics of Chinese families with Van der Woude syndrome (VWS). METHODS: Clinical manifestations between 14 families and within each family were recorded. Possible inheritance modes and pathogenic genes were analyzed. Phenotypic distribution and gene frequencies were calculated. RESULTS: Of the pedigrees investigated, an autosomal dominant inheritance pattern was suggested. All patients had typical symptoms. The pathogenic gene was interferon regulatory factor 6 (IRF6). Phenotypic distribution frequencies were as follows: lip pits (91.9%), cleft lip and/or palate (73.0%), and hyperdontia (8.1%). There were significant differences in clinical phenotypes among individuals of different families and individuals of the same family. CONCLUSIONS VWS in a Chinese population was dominantly inherited with high penetrance and variable expressivity. The pathogenic gene was IRF6. VWS in a Chinese population was genotyped as VWS1.
Abnormalities, Multiple ; genetics ; Cleft Lip ; genetics ; Cleft Palate ; genetics ; Cysts ; genetics ; Humans ; Interferon Regulatory Factors ; genetics ; Lip ; abnormalities ; Mutation ; Pedigree ; Syndrome

The morbidity and mortality of myeloproliferative neoplasms (MPNs) are primarily caused by arterial and venous complications, progression to myelofibrosis, and transformation to acute leukemia. However, identifying molecular-based biomarkers for risk stratification of patients with MPNs remains a challenge. We have previously shown that interferon regulatory factor-8 (IRF8) and IRF4 serve as tumor suppressors in myeloid cells. In this study, we evaluated the expression of IRF4 and IRF8 and the JAK2V617F mutant allele burden in patients with MPNs. Patients with decreased IRF4 expression were correlated with a more developed MPN phenotype in myelofibrosis (MF) and secondary AML (sAML) transformed from MPNs versus essential thrombocythemia (ET). Negative correlations between the JAK2V617F allele burden and the expression of IRF8 (P < 0.05) and IRF4 (P < 0.001) and between white blood cell (WBC) count and IRF4 expression (P < 0.05) were found in ET patients. IRF8 expression was negatively correlated with the JAK2V617F allele burden (P < 0.05) in polycythemia vera patients. Complete response (CR), partial response (PR), and no response (NR) were observed in 67.5%,10%, and 22.5% of ET patients treated with hydroxyurea (HU), respectively, in 12 months. At 3 months, patients in the CR group showed high IRF4 and IRF8 expression compared with patients in the PR and NR groups. In the 12-month therapy period, low IRF4 and IRF8 expression were independently associated with the unfavorable response to HU and high WBC count. Our data indicate that the expression of IRF4 and IRF8 was associated with the MPN phenotype, which may serve as biomarkers for the response to HU in ET.
Biomarkers ; Humans ; Hydroxyurea/therapeutic use* ; Interferon Regulatory Factors/genetics* ; Janus Kinase 2/genetics* ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Phenotype ; Primary Myelofibrosis/genetics* ; Thrombocythemia, Essential/genetics*

Objective: To understand the relationship between AOX1, IRF4 gene methylation status in peripheral blood leukocyte DNA, as well as its interaction with environmental factors, and the risk of breast cancer. Methods: A case-control study was conducted among 401 breast cancer patients and 555 cancer-free controls selected from 2010 to 2014. Methylation sensitive-high resolution melting curve analysis was used to detect the methylation status of AOX1 and IRF4. The multiplication interaction effect between genes' methylation and environmental factors on the risk of breast cancer was analyzed by using unconditional logistic regression, and Excel software was used to analyze the additive interaction effect. Results: Individuals without AOX1 methylation had a 1.37-fold (95%CI: 1.02-1.84) higher breast cancer risk compared to individuals with AOX1 methylation. AOX1 methylation interacted with fungi intake (OR=2.06, 95%CI: 1.12-3.79) and physical activity (OR=2.18, 95%CI: 1.16-4.09) synergistically, on the risk for breast cancer, but no additive interaction effects were observed. Non-methylation of IRF4 could increase the risk for breast cancer, with statistical significance (OR=1.71, 95%CI: 0.99-7.43). Neither multiplication nor additive interactions were observed between IRF4 methylation and environmental factors. Conclusion: Non-methylation of AOX1 and IRF4 were a risk factors for breast cancer.
Aldehyde Oxidase/genetics* ; Breast Neoplasms/genetics* ; Case-Control Studies ; DNA Methylation/genetics* ; Female ; Genetic Predisposition to Disease ; Humans ; Interferon Regulatory Factors/genetics* ; Leukocytes/metabolism*

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with non-syndromic cleft lip and cleft palate (NSCLP). METHODS: With informed consent obtained, members of the pedigree were subjected to clinical examination and history taking to exclude syndromic cleft lip and palate. One affected member was subjected to whole-exome sequencing and bioinformatics analysis. Candidate variant was verified by Sanger sequencing and co-segregation analysis of her family members and 100 unrelated healthy individuals. RESULTS: Whole-exome sequencing and co-segregation analysis showed that all affected members of this pedigree have carried a heterozygous missense c.253A>G (p.Cys85Arg) variant in exon 4 of the IRF6 gene, which has co-segregated with the phenotype and was not found among the 100 unrelated healthy individuals. CONCLUSION The missense c.253A>G variant in exon 4 of the IRF6 gene probably underlay the NSCLP in this pedigree.
Brain/abnormalities* ; China ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Female ; Humans ; Interferon Regulatory Factors/genetics* ; Mutation, Missense ; Pedigree ; Whole Exome Sequencing

OBJECTIVE: To explore the genetic characteristics of a Chinese pedigree affected with van der Woude syndrome (VWS). METHODS: A proband who had visited the Drum Tower Hospital Affiliated to Nanjing University Medical School in May 2020 for "two previous pregnancies with cleft lip and palate" was selected as the study subject. Trio-whole exome sequencing (trio-WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of her pedigree members (8 individuals from four generations) and bioinformatic analysis. Chromosomal microarray analysis (CMA) was used to rule out copy number variations in the fetuses. RESULTS: Trio-WES revealed that the proband and her father had both harbored a heterozygous c.742G>T (p.G248C) missense variant of the IRF6 gene, for which her mother was of the wild type. The variant was located in a region with important functions and has not been reported previously. Prediction with several software suggested that it is likely to have a significant impact on the protein structure/function and is highly correlated with the specific phenotypes in this pedigree. Sanger sequencing confirmed co-segregation of the genotypes and phenotypes in the pedigree. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), this variant was rated as likely pathogenic (PM1+PM2_Supporting+PP1+PP3+PP4). Based on the above results, pre-implantation genetic diagnosis was carried out for the proband, which has led to birth of a healthy offspring with normal results for both site testing and CMA. CONCLUSION The IRF6: c.742G>T (p.G248C) heterozygous variant probably underlay the VWS in this pedigree. Above finding has also enabled reproductive guidance for the proband.
Humans ; Female ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Pedigree ; DNA Copy Number Variations ; East Asian People ; Interferon Regulatory Factors/genetics* ; Mutation

The objective of this study was to investigate expression of interferon regulatory factors (ICSBP/IRF8) and the potential role of DNA methylation in silencing ICSBP/IRF8 gene in multiple myeloma (MM) cell line U266 and bone marrow mononuclear cells from 10 MM patients (MM-BMMNC). The bone marrow mononuclear cells from 10 healthy persons (N-BMMNC) were collected and used as normal controls. Expression of ICSBP/IRF8 gene was detected by real-time fluorescence quantitative PCR (using 2(-ΔΔCT) to calculate); DNA methylation level of the ICSBP/IRF8 gene was measured using methylation-specific PCR (using the ratio of interest gene ICSBP/IRF8 and internal reference β-actin expression as results). The results showed that as compared with N-BMMNC the lower expression of ICSBP/IRF8 gene was found in U266 cells and MM-BMMNC, the hypermethylation of the CpG island in the ICSBP/IRF8 promoter was observed, there were significant differences between N-BMMNC and MM-BMMNC or U266 cells (P < 0.05). It is concluded that the expression of ICSBP/IRF8 gene can be silenced in the MM-BMMNC and U226 cells. As the hypermethylation of CpG island in ICSBP/IRF8 promoter is a frequent event in MM cells, the ICSBP/IRF8 gene silencing caused by DNA methylation may take part in the pathogenesis and development of MM.
Bone Marrow Cells ; metabolism ; Case-Control Studies ; Cell Line, Tumor ; DNA Methylation ; Gene Silencing ; Humans ; Interferon Regulatory Factors ; genetics ; metabolism ; Multiple Myeloma ; genetics ; metabolism

The rs10954213 polymorphism and the haplotype diversity in interferon regulatory factor 5 (IRF5) play a special role in systemic lupus erythematosus (SLE) but with inconclusive results. We conducted a meta-analysis integrating case-control and haplotype variant studies in multiple ethnic populations to clearly discern the effect of these two variants on SLE. Eleven studies on the relation between rs10954213 polymorpisms in IRF5 and SLE were included and we selected a random effect model to calculate the pooled odds ratios (ORs) and the corresponding 95% confidence interval (95% CI). A total of 6982 cases and 8077 controls were involved in the meta-analysis. The pooled results indicated that A allele was significantly associated with increased risk of SLE as compared with the IRF5 rs10954213 G allele (A vs. G, P<0.00001) in all subjects. The same pattern of the results was also obtained in the European, African American, and Latin American. Asian population had a much lower prevalence of the A allele (49.1%) than any other population studied, and Europeans had the highest frequency of the IRF5 rs10954213 A allele (62.1%). The significant association of increased SLE risk and TCA haplotype was indicated in the contrast of TCA vs. TTA as the pooled OR was 2.14 (P=0.002). The same result was also found in the contrast of TCA vs. TTG as the pooled OR was 1.45 (P=0.004). This meta-analysis suggests that the A allele of rs10954213 and TCA haplotype (rs2004640-rs2070197-rs10954213) in IRF5 is associated with the increased risk of SLE in different ethnic groups, and its prevalence is ethnicity dependent.
Female ; Genetic Association Studies ; Genetic Markers ; genetics ; Genetic Predisposition to Disease ; epidemiology ; genetics ; Genetic Variation ; genetics ; Haplotypes ; genetics ; Humans ; Interferon Regulatory Factors ; genetics ; Lupus Erythematosus, Systemic ; epidemiology ; genetics ; Male ; Polymorphism, Single Nucleotide ; genetics ; Prevalence

OBJECTIVETo investigate the molecular mechanisms of the expression regulation of retinoic acidinduced gene G (RIG-G) by interferon alpha (IFNalpha).

METHODSRIG-G promoter region was analyzed by bioinformatics. The functional activities of RIG-G promoter with or without IFNalpha were detected by luciferase reporter assay and electrophoretic mobility shift assay (EMSA).

RESULTSRIG-G promoter region contained two well-conserved IFN-stimulated response elements (ISREs). Both ISRE I and ISRE II showed their effective binding abilities with signal transducer and activator of transcription 1 (STAT1). In HT1080 cells, in contrast with the empty plasmid pXP2, pXP2-A reporter construct containing intact ISRE I and ISRE II showed a significant higher baseline expression (1741.2 +/- 517.5) which could be further enhanced up to three-four folds by IFNalpha (5338.7 +/- 1226.9, P < 0.05). However, the luciferase activity of pXP2-A as well as its IFNalpha inducibility could be abrogated in STAT1-deficient U3A cells (from 1741.2 +/- 517.5 to 406.1 +/- 103.2, P < 0.05), indicating that the STAT1 protein was a prerequisite for the activities of ISRE I and ISRE II.

CONCLUSIONISREs present in RIG-G promoter region are molecular basis of IFNalpha induced RIG-G expression. RIG-G is a target gene directly regulated by STAT1 protein and should play a key role in IFNalpha signaling pathways.

Base Sequence ; Cells, Cultured ; Gene Expression Regulation ; drug effects ; physiology ; Humans ; Interferon Regulatory Factor-1 ; genetics ; metabolism ; Interferon Regulatory Factors ; genetics ; metabolism ; Interferon-alpha ; pharmacology ; physiology ; Interferons ; physiology ; Molecular Sequence Data ; Promoter Regions, Genetic ; drug effects ; genetics ; physiology ; STAT1 Transcription Factor ; metabolism