非综合征型唇腭裂与MTHFR基因多态性的相关性研究

目的：研究亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）基因位点C677T和A1298C与中国江苏地区汉族人群非综合征型唇腭裂（（nonsyndromic cleft lip with or without cleft palate,NSCL/P）发生的相关性。方法：采用聚合酶链反应-限制性片段长度多态性检测法对200例NSCL/P患者和213例健康人进行基因型检测。结果：MTHFR C677T对照组与病例组在基因型分布无统计学差异（P〉0.05）,TT基因型和携带T等位基因儿童罹患NSCL/P的风险分别是CC基因型儿童的1.84倍及1.57倍。进一步分层分析发现TT基因型和CT基因型能分别显著增加儿童唇裂伴或不伴腭裂和单纯性唇裂的发病风险。MTHFR A1298C病例组和对照组在基因型频率和等位基因频率有统计学差异（P〈0.05）,AC基因型和携带C等位基因的儿童罹患NSCL/P的风险分别比AA基因型儿童降低49%及43%。分层分析中,AC基因型和携带C等位基因可降低罹患唇裂伴腭裂及唇裂伴或不伴腭裂的风险。结论：MTHFR C677T可能为中国江苏地区汉族儿童NSCL/P的危险因素,而MTHFR A1298C有可能是NSCL/P发生的保护因素。     

Influence of methylenetetrahydrofolate reductase polymorphisms in oral cancer patients

J Oral Pathol Med (2011) 40 : 61–66 Background: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. Two common polymorphisms associated with MTHFR gene – C677T and A1298C – influence the thermolabile nature and activity of the enzyme. This study aimed to investigate the role of MTHFR polymorphisms on oral cancer susceptibility and its potential impact on the prognostic outcome. Methods: Oral cancer cases and controls were genotyped using PCR‐RFLP technique for MTHFR C677T and A1298C polymorphisms. Disease susceptibility analysed using regression analysis. The association between clinical outcomes and the polymorphisms were analysed using univariate and multivariate model. Results: The 677CT+TT genotype showed a significant three‐fold reduction in oral cancer risk (RR‐0.35, p‐0.009). 1298CC genotype showed decreased cancer risk when compared to AA+AC genotype (RR‐0.55, p‐0.062). When prognostic significance of MTHFR polymorphism was evaluated, 677CT+TT patients showed improved survival than the CC individuals (RR = 0.56, P = 0.378). The 1298 CC and AC+CC showed an increased risk for treatment failure and poor survival when compared with the wild AA genotype (HR = 4.27, P = 0.001). Conclusion: Here we observed MTHFR C677T to influence oral cancer susceptibility, while A1298C polymorphism associated with patient prognosis. Our data support MTHFR polymorphism to be an independent prognostic marker in oral carcinoma.     

Non-syndromic cleft lip with or without cleft palate in Asian populations: Association analysis on three gene polymorphisms of the folate pathway

ObjectiveOrofacial clefts (OFCs) are one of the most common birth defects in humans. They are the subject of a number of investigations aimed at elucidating the bases of their complex mode of inheritance involving both genetic and environmental factors. Genes belonging to the folate pathway have been among the most studied. The aim of the investigation was to replicate previous studies reporting evidence of association between polymorphisms of folate related genes and the occurrence of non-syndromic cleft lip with or without cleft palate (NSCL/P), using three independent samples of different ancestry: from Tibet, Bangladesh and Iran, respectively.DesignSpecifically, the polymorphisms rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were tested.ResultsA decreased risk of NSCL/P was observed in patients presenting the C677T variant at MTHFR gene (relative risk for heterozygotes = 0.53; 95% confidence interval [C.I.] = 0.32–0.87). The investigated polymorphisms mapping at TCN2 and CBS genes did not provide any evidence of association.ConclusionOverall, these results indicate that NSCL/P risk factors differ among populations and confirm the importance of testing putative susceptibility variants in different genetic backgrounds.     

Association between methylenetetrahydrofolate reductase polymorphisms and non-syndromic cleft lip with or without palate susceptibility: an updated systematic review and meta-analysis

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms are thought to be involved in the development of cleft lip with or without cleft palate (NSCL/P), but published results are contradictory. We therefore designed an updated meta-analysis to pool eligible studies and to evaluate further the possible relations between MTHFR polymorphisms (c.677C > T and c.1298A > C) and susceptibility to NSCL/P. A comprehensive search based on PubMed, Medline, Web of Science, and Embase databases was made up to February 2018. Twenty-three case-control and 10 case-parent trio studies (including 1149 cases and 1161 controls) were retrieved. Odds ratio (OR) with 95% CI were used to estimate the pooled strength of association under different genetic models. The Q test and I² test were used to estimate heterogeneity among studies, the quality of which was assessed using the Newcastle-Ottawa scale. In the MTHFR c.677C > T polymorphism group, there were significant overall results for the recessive (OR 1.231, 95%CI 1.092 to 1.387) and homozygote (OR 1.252, 95%CI 1.078 to 1.456) models. Subgroup analysis by subjects and ethnicity identified only associations in European mothers for the recessive model and the homozygote model. For the c.1298A > C group, there were no significant results for either European or Asian patients for all genetic models. The MTHFR c.677C > T polymorphism might increase susceptibility to NSCL/P in European mothers, but was negatively associated in Asian patients, and the MTHFR c.1298A > C polymorphism is not involved in the development of NSCL/P in either European or Asian patients.     

Haplotype‐based gene–gene interaction of bone morphogenetic protein 4 and interferon regulatory factor 6 in the etiology of non‐syndromic cleft lip with or without cleft palate in a Chilean population

Non‐syndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans, the etiology of which can be dependent on the interactions of multiple genes. We previously reported haplotype associations for polymorphic variants of interferon regulatory factor 6 (IRF6), msh homeobox 1 (MSX1), bone morphogenetic protein 4 (BMP4), and transforming growth factor beta 3 (TGFB3) in Chile. Here, we analyzed the haplotype‐based gene–gene interaction for markers of these genes and NSCL/P risk in the Chilean population. We genotyped 15 single nucleoptide polymorphisms (SNPs) in 152 Chilean patients and 164 controls. Linkage disequilibrium (LD) blocks were determined using the Haploview software, and phase reconstruction was performed by the Phase program. Haplotype‐based interactions were evaluated using the multifactor dimensionality reduction (MDR) method. We detected two LD blocks composed of two SNPs from BMP4 (Block 1) and three SNPs from IRF6 (Block 2). Although MDR showed no statistical significance for the global interaction model involving these blocks, we found four combinations conferring a statistically significantly increased NSCL/P risk (Block 1–Block 2): T‐T/T‐G C‐G‐T/G‐A‐T; T‐T/T‐G C‐G‐C/C‐G‐C; T‐T/T‐G G‐A‐T/G‐A‐T; and T‐T/C‐G G‐A‐T/G‐A‐T. These findings may reflect the presence of a genomic region containing potential causal variants interacting in the etiology of NSCL/P and may contribute to disentangling the complex etiology of this birth defect.     

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目的    研究亚甲基四氢叶酸还原酶（MTHFR）基因 C677T多态性与山东地区非综合征性唇腭裂（NSCL／P）的相关性。方法    于2008 年 9月在山东省优生技术重点实验室采用聚合酶链反应-限制性片段长度多态性（ PCR-RFLP）分析,对2006 年8月至2008年8月曾在齐鲁医院治疗的来自山东地区NSCL／P患儿家庭34户和健康查体的正常儿童家庭46户的家庭成员MTHFR基因的C677T基因型进行检测。结果    携带T等位基因的父母,其子代患NSCL／P的危险性是不携带T等位基因父母的子代的2.420倍;母子都是TT突变纯合子,子代患NSCL／P的危险性是母子为非TT纯合子的4.162倍;子代是TT突变纯合子患NSCL／P的危险性是非TT纯合子的3.812倍。结论    山东地区NSCL／P与MTHFR基因 C677T的多态性相关,与父母的基因型存在联系;T基因在母子组合的研究中有统计学意义,父母传递给子代的T等位基因对后代的患病有重要作用。     

Homozygote C/C at rs12543318 was risk factor for non‐syndromic cleft lip only from Western Han Chinese population

Non‐syndromic cleft lip with or without cleft palate (NSCL/P) is a complex disorder, and it results from both of the genetic modifiers and environmental factors, with genetic modifiers contributes to it more than environmental factors. GWASs made great progress in identifying the candidate genes for NSCL/P, but the findings need to be replicated in other populations. In this study, we selected eleven SNPs from recent GWASs and GWAS meta‐analysis to investigate their associations among 308 NSCL/P trios (134 non‐syndromic cleft lip only (NSCLO) trios and 174 non‐syndromic cleft lip with cleft palate (NSCLP) trios) from Han Chinese population. All SNPs were genotyped using SNPscan method and analyzed the data with FBAT, PLINK, and R package. Allelic TDT analysis showed that allele A at rs12543318 was associated with NSCLO trios (P = .0032, OR = 0.57, 95% CI: 0.39‐0.83), and parent‐of‐origin effect analysis indicated that allele A at rs12543318 was significantly maternally undertransmitted among NSCLO (P = .0046), which implied the potential influence of genomic imprinting; global TDT further confirmed this association. Individual genotypic TDT showed homozygote C/C at rs12543318 was overtransmitted among NSCLO (Z = 3.79, P = .00015) and NSCL/P groups (Z = 3.83, P = .00013), which indicated that it could increase the risk to have cleft babies. Our findings indicated that rs12543318 was associated with NSCLO from Western Han Chinese population, which will give new scientific evidence for later researches in the etiology of NSOCs.     

Association Between Interleukin‐4 Gene −590 C/T, −33 C/T,and 70‐Base‐Pair Polymorphisms and Periodontitis Susceptibility: A Meta‐Analysis

Background: Several studies have investigated the association between interleukin (IL)‐4 gene ?590 C/T, ?33 C/T, or 70–base pair (70‐bp) polymorphisms and periodontitis susceptibility but with conflicting results. Hence, a meta‐analysis was conducted to explore whether these polymorphisms are associated with periodontitis susceptibility. Methods: A comprehensive literature search was conducted of PubMed, Embase, Scopus, ScienceDirect, and Web of Science up to April 5, 2014. After the eligible studies were identified, data were extracted and quality‐assessed before performing the meta‐analysis. Results: The meta‐analysis included 23 eligible case‐control studies from 11 articles involving 12 studies of the ?590 C/T polymorphism (1,220 cases and 2,039 controls), five of the ?33 C/T polymorphism (715 cases and 967 controls), and four of the 70‐bp polymorphism (426 cases and 506 controls). The meta‐analysis showed that none of these IL‐4 gene polymorphisms were significantly associated with periodontitis susceptibility in all study participants. However, subgroup analysis showed that the IL‐4 ?590 T allele (odds ratio [OR] = 1.2, 95% confidence interval [CI] = 1.02 to 1.42, P = 0.03) and TT genotype (OR = 1.68, 95% CI = 1.05 to 2.67, P = 0.03) were associated with periodontitis in whites. Conclusions: Based on current evidence, the IL‐4 ?33 C/T and 70‐bp polymorphisms were not associated with an increased risk of periodontitis. However, the IL‐4 ?590 T allele and TT genotype were associated with increased risk of periodontitis in whites.     

Lack of association between IRF6 polymorphisms (rs2235371 and rs642961) and non‐syndromic cleft lip and/or palate in a Brazilian population

Oral Diseases (2010) 16 , 193–197 Background: Interferon regulatory factor 6 (IRF6) gene has emerged as a potential susceptibility gene for non‐syndromic cleft lip and/or palate (NSCL/P) in different populations. The aim of this study was to determine the association of IRF6 rs2235371 and rs642961 polymorphisms with NSCL/P in a Brazilian population. Methods: Two hundred and twenty‐eight patients affected by NSCL/P and 126 healthy individuals were genotyped by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay. Results: Overall genotype distributions of rs2235371 and rs642961 polymorphisms were as expected by Hardy‐Weinberg equilibrium test. The rs2235371 polymorphic genotype GA was identified in 10.1% of the patients with NSCL/P and in 10.3% of the control group, revealing no statistical difference. Similarly, the frequency of rs642961 minor genotypes (GA and AA) was quite similar between control group (28.6%) and NSCL/P group (25.4%), without significant difference. Conclusion: Our findings are consistent with a lack of involvement of IRF6 rs2235371 and rs642961 polymorphisms in the NSCL/P pathogenesis in the Brazilian population.     

亚甲基四氢叶酸还原酶C677T多态性与非综合征性唇腭裂的关系

目的研究亚甲基四氢叶酸还原酶基因C677T多态性与非综合征性唇腭裂的关系。方法利用聚合酶链反应-限制性片段长度多态性方法（PCR-RFLP）,在168例非综合征性唇腭裂患者和192名正常对照中,对MTHFR基因C677T单核苷酸多态性（SNP,rs1801133）进行检测。利用拟合优度卡方检验,分析基因型分布频率是否符合Hardy-Weinberg平衡定律;应用UNPHASED软件包分析多态性位点与非综合征性唇腭裂的相关性。结果MTHFRC677T多态性基因型频率分布符合Hardy-Weinberg平衡;MTHFR C677T等位基因分布在NSCL／P组与对照组之间有显著性差异（P〈0.05）,正常组中T等位基因的频率明显高于NSCL／P组。结论MTHFR C677T多态性位点在中国人群中与非综合征性唇腭裂形成的发生相关联。     

Quantitative Assessment of the Associations Between Interleukin‐8 Polymorphisms and Periodontitis Susceptibility

Background: This review assesses the associations of interleukin‐8 gene (IL‐8) ?251A/T (rs4073) and ?845T/C (rs2227532) polymorphisms with susceptibility to periodontitis. Methods: Several electronic databases were searched for eligible articles. Twelve studies involving 2,233 cases and 2,655 controls were retrieved and analyzed. Odds ratios (ORs) along with 95% confidence intervals (CIs) were calculated to assess the strength of relationship between the IL‐8 polymorphisms and periodontitis risk. Results: No significant association was found for IL‐8 ?251A/T polymorphism with periodontitis in the overall analysis and stratification by periodontitis type and smoking status. Subgroup analysis by ethnicity revealed that ?251A/T T allele and TT genotype were associated with decreased risk of periodontitis in a Brazilian mixed population (T allele versus A allele: OR 0.80, 95% CI 0.68 to 0.94, P_{heterogeneity} = 0.30; TT versus AA: OR 0.65, 95% CI 0.46 to 0.93, P_{heterogeneity} = 0.39; TT versus AA/AT: OR 0.58, 95% CI 0.35 to 0.98, P_{heterogeneity} = 0.01). In addition, ?251A/T T allele was associated with increased periodontitis risk in Asians. Pooled estimates showed that the ?845T/C polymorphism was associated with periodontitis susceptibility in overall analysis and the chronic periodontitis subgroup. In addition, marginal associations were observed between ?845T/C polymorphism and periodontitis in a Brazilian mixed population. Moreover, this association was also confirmed to be significant in Brazilian non‐smokers. Conclusion: This meta‐analysis indicated that both IL‐8 ?251A/T and ?845T/C polymorphisms may be involved in the development of periodontitis in a Brazilian mixed population, whereas the ?251A/T allele T appeared to be a risk factor for periodontitis in Asians.     

Evidence of the folate-mediated one-carbon metabolism pathway genes in controlling the non-syndromic oral clefts risks

The folate-mediated one-carbon metabolism pathway is thought to play an important role in the etiology of non-syndromic oral clefts (NSOFC), although none of the genes in this pathway has shown significant signals in genome-wide association studies (GWAS). Recent evidence indicated that enhanced understanding could be gained by aggregating multiple SNPs effect simultaneously into polygenic risk score (PRS) to assess its association with disease risks. This study is aimed to assess the association between the genetic effect of folate-mediated one-carbon metabolism pathway and NSOFC risks using PRS based on a case–parent trio design. A total of 297 SNPs mapped from 18 genes in the folate-mediated one-carbon metabolism pathway were aggregated from a GWAS of 2458 case–parent trios recruited from an international consortium. We found a PRS based on the folate-mediated one-carbon metabolism pathway was significant among all NSOFC trios (OR = 1.95, 95% CI: 1.66–2.28, p = 2.39 × 10⁻¹⁶), as well as two major subtypes, non-syndromic cleft lip with or without cleft palate (NSCL/P) trios (OR = 1.71, 95% CI: 1.50–1.96, p = 7.66 × 10⁻¹⁵) and non-syndromic cleft palate only (NSCPO) trios (OR = 1.51, 95% CI: 1.36–1.68, p = 2.1 × 10⁻¹⁴). Similar results were also observed in further subgroup analyses stratified into Asian and European trios. The averaged PRS of the folate-mediated one-carbon metabolism pathway varied between the NSOFC case group and its comparison group (p < 0.05) with higher average PRS in the cases. Moreover, the top 5% pathway PRS group had 2.25 (95% CI: 1.85–2.73) times increased NSOFC risk, also 3.09 (95% CI: 2.50–3.81) and 2.06 (95% CI: 1.39–3.02) times increased risk of NSCL/P and NSCPO compared to the remainder of the distribution. The results of our study confirmed the folate-mediated one-carbon metabolism pathway was important in controlling risk to NSOFC and this study enhanced evidence towards understanding the genetic risks of NSOFC.     

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目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因A1298C多态性与山西人群非综合征性唇腭裂（nonsyndromic cleft lip with or without cleft palate,NSCL／P）的相关性。方法选取2010年9月至2012年4月山西地区150例NSCL／P患者及其父母作为病例组（其中有135个完整的NSCL／P核心家系）,150例正常新生儿作为对照组,应用聚合酶链式反应一限制性片段长度多态性（PCR—RFLP）分析方法,对MTHFR基因A1298C位点的多态性进行检测,利用人群关联研究分析、病例组核心家系的传递不平衡检验（TDT）、单体型的相对危险度（HHRR）分析来研究该突变与NSCL／P的相关性。结果病例组和对照组人群基因型均未偏离Hardy-Weinberg遗传平衡定律（P〉0．05）;病例组与对照组进行子代间比较,AA、AC、CC3种基因型分布差异有统计学意义（P〈0．05）,A等位基因和c突变等位基因的分布差异均有统计学意义（P〈0．05）;NSCL／P核心家系TDT检验,差异有统计学意义（P〈0．05）,表明突变等位基因c存在着传递失衡的现象;HHRR检验结果表明,MTHFR基因A1298C位点多态性由双亲传递给患病子女的等位基因（C／A）频率差异有统计学意义（P〈0．05）。结论MTHFR基因A1298C位点多态性与山西人群NSCL／P的发生存在关联。     

Susceptibility locus for non‐syndromic cleft lip with or without cleft palate on chromosome 10q25 confers risk in Estonian patients

Nikopensius T, Birnbaum S, Ludwig KU, Jagomägi T, Saag M, Herms S, Knapp M, Hoffmann P, Nöthen MM, Metspalu A, Mangold E. Susceptibility locus for non‐syndromic cleft lip with or without cleft palate on chromosome 10q25 confers risk in Estonian patients. Eur J Oral Sci 2010; 118: 317–319. © 2010 The Authors. Journal compilation © 2010 Eur J Oral Sci Non‐syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects and has a multifactorial etiology that includes both genetic and environmental factors. Recently, two novel susceptibility loci and three suggestive loci for NSCL/P were identified by a genome‐wide association scan (GWAS) in a German population with subsequent independent replication in a mixed European population. The aim of the present study was to investigate whether these newly detected loci confer similar effects in the North‐East European Baltic population. A total of 101 NSCL/P patients and 254 controls from Estonia were included. A significant association was observed for rs7078160 (P = 0.0016) at chromosome 10q25, which confirms the association of this locus with NSCL/P in the Baltic population. No significant association was found for the other four loci, a result that may have been attributable to the limited power of the sample.     

Polymorphism in ADH and MTHFR genes in oral squamous cell carcinoma of Indians

Objectives: Alcohol consumption is known to increase the risk for several cellular disorders like oral cancer. The risk may be reinforced by polymorphism in genes like alcohol dehydrogenase. Therefore, this study is designed to asses the polymorphic status in ADH1B (formerly ADH2), ADH1C (formerly ADH3) and MTHFR genes in order to correlate the susceptibility to oral squamous cell carcinoma (OSCC). Subjects and methods: DNA from 126 OSCC samples were amplified using primers for ADH1B, ADH1C and MTHFR genes. The amplicons were analyzed for ADH1B*1, ADH1C*2 and MTHFR C677T allelic polymorphism by restriction digestion using appropriate enzymes. Results: ADH1B*1/*1 genotype in cancer patients who were heavy drinkers showed a negligible risk association with an odds ratio of 1.62; 95% CI = 1.08–2.14. In OSCC patients, ADH1C*2/*2 genotypes showed a relatively higher risk (odds ratio 2.65; 95% CI = 1.78–3.53) in heavy drinkers and a less significant risk (1.6; 95% CI = 1.15–2.03) in moderate drinkers and negligible risk in light drinkers (1.23; 95% CI = 0.77–1.63). In contrast, MTHFR 677TT genotype showed a high risk association for OSCC in heavy drinkers (odds ratio 3.0; 95% CI = 2.02–4.0). Interestingly, the combination of ADH1B*1/*1/ MTHFR 677TT genotypes in alcoholic cancer patients showed a high risk (odds ratio 4.16; 95% CI = 2.78–5.53). A similar risk (odds ratio 4.16; 95% CI = 1.18–5.53) was shown by ADH1B*1/*2/*2/*2MTHFR 677TT genotype combination. The ADH1C*2/*2 /MTHFR 677TT genotype combination showed the maximum risk (odds ratio 20; 95% CI = 13.45–26.64) in the heavy drinker group. This combination showed a high risk in moderate drinkers (odds ratio 5.88; 95% CI = 4.24–7.50) and relatively lower risk in light drinkers (odds ratio 2.77; 95% CI = 1.74–3.68). Conclusions: The ADH1C*2/*2/MTHFR 677TT genotype combination appears to be more susceptible for OSCC, since it showed a 20‐fold increase in risk in heavy drinkers and a 5.9‐ and 2.8‐fold increase in risk respectively in moderate drinkers and light drinkers. This study suggests the association of ADH1C*2/*2/MTHFR 677TT genotype combination as a risk factor for OSCC in alcoholics.     

IRF6 gene variants in Central European patients with non‐syndromic cleft lip with or without cleft palate

Variants in the interferon regulatory factor 6 (IRF6) gene have repeatedly been associated with non‐syndromic cleft lip with or without cleft palate (NSCL/P). A recent study has suggested that the functionally relevant variant rs642961 is the underlying cause of the observed associations. We genotyped rs642961 in our Central European case–control sample of 460 NSCL/P patients and 952 controls. In order to investigate whether other IRF6 variants contribute independently to the etiology of NSCL/P, we also genotyped the non‐synonymous coding variant V274I (rs2235371) and five IRF6‐haplotype tagging single nucleotide polymorphisms (SNPs). A highly significant result was observed for rs642961 (P = 1.44 × 10^?6) in our sample. The odds ratio was 1.75 [95% confidence interval (CI): 1.38–2.22] for the heterozygous genotype and 1.94 (95% CI: 1.21–3.10) for the homozygous genotype, values that are similar to those reported in a previously published family‐based study. Our results thus confirm the involvement of the IRF6 variant, rs642961, in the etiology of NSCL/P in the Central European population. We also found evidence suggestive of an independent protective effect of the coding variant V274I. In order to understand fully the genetic architecture of the IRF6 locus, it will be necessary to conduct additional SNP‐based and resequencing studies using large samples of patients.     

Evaluating SKI as a candidate gene for non‐syndromic cleft lip with or without cleft palate

Non‐syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital malformations and has a multifactorial etiology. Findings in mice suggest that the v‐ski sarcoma viral oncogene homolog (SKI) gene is a candidate gene for orofacial clefting. In humans, a significant association between rs2843159 within SKI and NSCL/P has been reported in patients from the Philippines and South America. In the South American patients, the association was driven by the subgroup of patients with non‐syndromic cleft lip only (NSCLO). Here we investigated the association with rs2843159 in a Mayan Mesoamerican population (172 NSCL/P patients and 366 controls). In addition, we analyzed the phenotypic subgroups NSCLO and non‐syndromic cleft of lip and palate (NSCLP). A trend towards association between rs2843159 and NSCL/P was observed in the Mayan cohort (P = 0.097), and we found a stronger association in the NSCLP subgroup (P = 0.072) despite a limited sample size. To investigate whether other common variants within the SKI gene contribute to NSCL/P susceptibility in European and Asian populations, we also analyzed genotypic data from two recent genome‐wide association studies using set‐based statistical approaches. These analyses detected a trend toward association in the European population. Our data provide limited support for the hypothesis that common SKI variants are susceptibility factors for NSCL/P.     

Association between MAFB rs17820943 and rs6072081 polymorphism and risk of nonsyndromic cleft lip with or without cleft palate: a meta-analysis

While there have been previous studies examining the relation between the rs17820943 and rs6072081 polymorphisms in the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene and rates of nonsyndromic cleft lip with or without cleft palate (NSCL/P), at present the results of these studies have been inconsistent. This meta-analysis therefore aimed to conduct a more robust assessment of the association between the MAFB rs17820943 and rs6072081 polymorphisms and NSCL/P risk. The Embase, Web of Science, PubMed, the China National Knowledge Internet (CNKI), and Wanfang databases were systematically searched to identify relevant studies. In total, five studies incorporating 2769 patients and 2885 controls were identified assessing the rs17820943 polymorphism and three studies incorporating 1242 patients and 1310 controls assessing the rs6072081 polymorphism were identified. This analysis revealed the MAFB rs17820943 and rs6072081 polymorphisms to be linked to a significantly reduced NSCL/P risk (rs17820943: C vs T: OR = 0.76, 95% CI = 0.70-0.82; CC vs CT: OR = 0.75, 95% CI = 0.67-0.85; CC vs TT: OR = 0.58, 95% CI = 0.49-0.67; CC + CT vs TT: OR = 0.67, 95% CI = 0.59-0.77; CT + TT vs CC: OR = 1.43, 95% CI = 1.28-1.60; rs6072081: A vs G: OR = 0.77, 95%CI = 0.68-0.86; AA vs AG: OR = 0.76, 95%CI = 0.64-0.90; AA vs GG: OR = 0.58, 95%CI = 0.45-0.74; AA + AG vs GG: OR = 0.68, 95%CI = 0.54-0.84; AG + GG vs AA: OR = 1.40, 95% CI = 1.19-1.65). The results of the present meta-analysis indicate that in an East Asian population, for both rs17820943 and rs6072081 were associated with NSCL/P.     

Association of MTHFR gene C677T mutation with recurrent aphthous stomatitis and number of oral ulcers

Objectives

Recurrent aphthous stomatitis (RAS) is a common ulcerative disease of the oral mucosa. Methylenetetrahydrofolate reductase (MTHFR) gene variants are associated with thrombophilia and vasculopathy that may result in oral ulceration. Oral ulcers are also the most common feature of Behcet’s disease (BD). Association of MTHFR gene C677T mutation with BD has been reported in different populations. The aim of the present study was to investigate the possible association between MTHFR gene C677T mutation and RAS and evaluate if there was an association with clinical features in a relatively large cohort of Turkish patients.

Materials and methods

The study included 188 patients affected by RAS and 200 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR gene C677T mutation.

Results

The genotype and allele frequencies of C677T mutation showed statistically significant differences between RAS patients and controls (p?=?0.002 and p?=?0.0004, respectively). After stratifying RAS patients according to clinical characteristics of oral ulcers, a significant association was observed between C677T mutation and number of oral ulcers of RAS patients (p?=?0.006).

Conclusions

As a result, a high association between MTHFR gene C677T mutation and RAS was observed in the present study. Also number of oral ulcers was found to be associated with MTHFR C677T mutation in RAS patients.

Clinical Relevance

If our observation can be substantiated with further studies, evaluation for MTHFR mutations and perhaps folate supplementation may become necessary in selected patients.