MSH homeobox 1 polymorphisms and the risk of non‐syndromic orofacial clefts: a meta‐analysis

MSH homebox 1 (MSX1) is a susceptibility gene for non‐syndromic orofacial clefts (NSOCs). Here, a meta‐analysis was conducted to assess their associations. A systematic search of PubMed to 1 September 2017, was performed to retrieve all eligible studies. Odds ratios (ORs) were used to calculate the associations. The stability of the results was evaluated by sensitivity analysis. Publication bias was assessed using Begg's funnel plots and the Egger test. In silico Msx1 expression during early mouse craniofacial development was evaluated by the Gene Expression Omnibus. In the overall analysis, MSX1 rs12532 (G>A) contributed to a decreased risk of NSOC. In an analysis stratified according to disease type, rs12532 was associated with the risk of cleft palate only (CPO) but not with the risk of cleft lip with or without cleft palate (CL/P). The association of rs12532 with the occurrence of NSOC in Asian and Caucasian populations but not South American populations was observed in an analysis stratified according to ethnicity. However, no significant associations were detected between any of the other MSX1 SNPs and the risk of NSOC in either the overall or subgroup analysis. The Msx1 gene was widely expressed in mouse craniofacial structures from embryonic day (E)8.5‐E10.5. Taken together, the study indicates that MSX1 rs12532 is associated with the risk of NSOC.     

Replication of two novel susceptibility loci for non‐syndromic orofacial clefts in a Chinese population

Oral Diseases (2011) 17 , 304–308 Objectives: Non‐syndromic orofacial clefts (NSOC) are the most common developmental disorders in human beings. Recently, two genome‐wide association studies in European Caucasians identified three novel NSOC susceptibility loci: rs987525 on 8q24, rs7078160 on 10q25.3, and rs223371 on 17q22. The aim of this study was to determine the association of these polymorphisms with NSOC susceptibility and its subgroups in a Chinese Han population. Material and methods: In this study, 199 NSOC patients and 210 healthy individuals were recruited. SNP rs987525 was not genotyped because of its low frequency in the study subjects. The other two polymorphisms (rs7078160 and rs223371) were respectively genotyped by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) and Taqman‐MGB assay. Results: Overall genotype distributions of rs7078160 and rs223371 polymorphisms were consistent with Hardy–Weinberg equilibrium test. The allele and genotype frequencies of the two polymorphisms were not significantly different between cases and controls. Further analysis indicated that none of the genotypes was associated with increased risk of NSOC. Similar results were also found when all cleft cases were stratified by cleft types. Conclusion: Our findings are consistent with a lack of involvement of the rs7078160 and rs223371 polymorphisms in the development of NSOC in the Chinese Han population.     

Polymorphic variants of genes related to arginine metabolism and the risk of orofacial clefts

Objective

Maternal mid-pregnancy low levels of symmetric dimethylarginine and newborn low levels of citrulline are suspected to be risk factors for orofacial clefts. This study was undertaken to investigate the involvement of polymorphic variants of genes related to arginine metabolism in the susceptibility of clefting.

Design

PCR-RFLP and HRM analyses were used to analyze single nucleotide polymorphisms (SNPs) of ASS1, ASL, and SLC25A13 in 172 children with non-syndromic cleft lip with or without cleft palate (CL/P) and 188 controls without congenital anomalies. The differences in allele and genotype frequencies between cases and controls were determined using standard Chi-square and Fisher exact tests. The odds ratio (OR) and associated 95% confidence intervals (95% CI) for individuals with CL/P versus controls were also calculated. Associations between the investigated polymorphisms and the risk of being born with an orofacial cleft were tested using the nonparametric and genetic model-free Multifactor Dimensionality Reduction (MDR) approach.

Results

Analysis of five SNPs of the ASS1 gene revealed that the G allele of rs7860909 is associated with increased CL/P risk. Compared to individuals with the AA genotype, the G allele carriers had an OR of 1.768 (95% CI: 1.133-2.759; p = 0.012). For the remaining SNPs of all analysed genes, there was no overall evidence for cleft association considering the allele and genotype distribution. However, gene-by-gene interaction analysis conducted using the MDR approach revealed a significant interactive genetic effect of ASS1 (rs666174) and SLC25A13 (rs10252573) on the occurrence of clefting (p = 0.002).

Conclusion

Our results demonstrate moderate evidence for the association of polymorphic variants of genes related to arginine metabolism with abnormal palatogenesis.     

Systemic use of non‐biologics in orofacial diseases: 2. Purine synthesis inhibitors

Systemic non‐biological agents (NBAs) have been extensively used for immunosuppression in clinical medicine, often with considerable efficacy, although sometimes accompanied with adverse effects as with all medicines. With the advent of biological agents, all of which currently are restricted to systemic use, there is a rising need to identify which agents have the better therapeutic ratio. The NBAs include a range of agents, most especially the corticosteroids (corticosteroids). This article reviews the purine synthesis inhibitors (azathioprine and mycophenolate), which are currently the most commonly used systemically immunosuppressive agents in the management of orofacial mucocutaneous diseases. Subsequent articles discuss other corticosteroid‐sparing agents used in the management of orofacial disease, such as calcineurin inhibitors, and the cytotoxic and other immunomodulatory agents.     

Identification of a novel mutation in the PAX9 gene in a family affected by oligodontia and other dental anomalies

The objective of the present work was to study the phenotype and the genotype of three generations of a family affected by oligodontia and other dental anomalies. These family members also presented systemic conditions such as hypercholesterolemia, hypothyroidism, diabetes mellitus, scoliosis, and congenital cardiovascular anomalies. Clinical evaluation, panoramic radiographs, and anamnestic data were used for dental analysis. DNA extraction was carried out from gum samples or buccal swabs. A mutation was identified in six subjects across three generations affected by oligodontia, as well as different phenotypical manifestations, both systemic and oral. The previously undescribed PAX9 mutation was observed in the paired box (exon 2); this was a heterozygote transition of C175 to T, implying the change of arginine 59 for a termination codon. These results strongly suggested that the identified mutation was the etiological cause of the oligodontia. However, in two family members affected by both hypodontia and peg-shaped upper lateral incisors, no mutations in the PAX9 and MSX1 genes were identified. This fact underscores the importance that other presently unknown genes and developmental factors have in tooth development and in the etiology of dental anomalies.