中国西部人群IRF6基因V274I位点SNP与非综合征型唇腭裂相关性的研究

目的:探讨干扰素调节因子6(IRF6)基因V274I位点单核苷酸多态性(SNP)与非综合征型唇腭裂的相关性.方法:收集非综合征型唇腭裂患儿332例,患者父亲243例,患者母亲289例,核心家庭224个,对照组正常新生儿174例.采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测IRF6基因V274I多态位点基因型,进行病例对照和传递不平衡(TDT)研究.结果:在中国西部人群中,与正常对照组比较,单纯唇裂和唇腭裂组V274I位点SNP的GG基因型和G等位基因的频率存在显著性差异(P=0.000),而在单纯腭裂组比较没有显著性差异(P=0.699).运用传递不平衡研究发现IRF6基因V274I多态性突变的G等位基因在唇裂和唇腭裂患者中存在过传递(P=0.000).结论:在中国西部人群中IRF6基因V274I SNP位点G等位基因与非综合征型唇腭裂存在强的相关性,而与单纯腭裂没有相关性.     

干扰素调节因子6基因多态性与非综合征型唇腭裂的相关性研究

目的探讨干扰素调节因子6（IRF6）基因rs642961和rs4844880位点单核苷酸多态性与非综合征型唇腭裂的相关性。方法收集宁夏地区非综合征型唇腭裂患者186例,采用聚合酶链反应-限制性片段长度多态性（PCRRFLP）方法检测IRF6基因多态位点rs642961和rs4844880基因型,进行病例对照分析、传递不平衡检验（TDT）。结果与正常对照组比较,唇裂组和唇腭裂组rs642961和rs4844880位点的AA基因型和A等位基因的频率存在统计学差异（P<0.05）,腭裂组均没有意义（P=0.15, P=0.967）;TDT研究发现IRF6基因rs642961位点的A等位基因和rs4844880位点的A等位基因在唇裂和唇腭裂患者中存在过传递（P<0.05）;2个位点在腭裂组均没有统计学意义（P=0.91,P=0.95）。结论IRF6基因多态性与非综合征型唇腭裂存在较强的相关性。     

成纤维细胞生长因子3基因多态性与非综合征型唇腭裂的相关性研究

目的探讨成纤维细胞生长因子3（FGF3）基因rs4980700、rs4631909单核苷酸多态性（SNP）与非综合征型唇腭裂（NSOC）的相关性。方法收集186例非综合征型唇腭裂患者,患者父亲183例,母亲174例,核心家系172个;200例正常新生儿为对照组。采用聚合酶链式反应-限制性片段长度多态性（PCR-RFLP）方法检测FGF3基因rs4980700与rs4631909多态位点基因型,并进行病例对照分析,传递不平衡检验（TDT）和以家系为基础的相关性分析（FBAT）。结果病例组rs4980700多态位点基因型和等位基因频率与对照组比较存在统计学差异（P<0.05）;病例组rs4631909多态位点基因型和等位基因频率与对照组比较存在统计学差异（P<0.05）,而在腭裂组则无统计学差异（P=0.49）。传递不平衡研究发现,FGF3基因rs4980700位点的G等位基因与rs4631909位点的C等位基因在本研究人群非综合征型唇腭裂患者中存在过传递（P<0.05）。FBAT分析rs4980700、rs4631909多态位点与本研究人群非综合征型 唇腭裂存在相关性（P<0.05）。结论FGF3基因rs4980700、rs4631909多态位点与非综合征型唇腭裂存在相关性。     

宁夏回汉族人群Wnt3基因单核苷酸多态性与非综合征型唇腭裂相关性的研究

目的 探讨宁夏回汉族人群中Wnt3基因rs142167和rs7216231位点单核苷酸多态性（SNP）与非综合征型唇腭裂（NSCL/P）的相关性。方法 收集宁夏地区回汉族人群非综合征型唇腭裂患者371例为病例组,其中汉族患者166例,回族患者205例;收集患者父亲196例,患者母亲224例,其中150例患者为NSCL/P核心家系;258例健康新生儿为对照组,其中汉族190例,回族68例。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测Wnt3基因多态位点rs142167和rs7216231基因型,对比分析2组的基因型和等位基因,并进行传递不平衡检验（TDT）和以家系为基础的相关性检验（FBAT）分析。结果 回汉族人群病例组与对照组比较及其民族分层比较,唇裂、腭裂、唇腭裂及总病例组rs142167和rs7216231位点均无统计学差异（P＞0.05）。TDT分析结果显示：rs142167和rs7216231位点的等位基因均不存在过传递（P＞0.05）。FBAT分析结果显示：单倍型G-G具有统计学意义（P<0.05）。结论 Wnt3基因多态性与宁夏地区回汉族人群非综合征型唇腭裂不存在相关性。     

宁夏回汉族人群中FOXE1基因多态性与非综合征型唇腭裂的相关性研究

目的:探讨宁夏回汉人群FOXE1基因rs3758249、rs10217225和rs4460498位点单核苷酸多态性与非综合征型唇腭裂发病的相关性。方法:收集宁夏地区回、汉族非综合征型唇腭裂患者207例,其中回族69例,汉族138例;正常对照组292例,其中,回族72例,汉族220例。采用PCR-RFLP方法检测FOXE1基因rs3758249、rs10217225和rs4460498多态位点的基因型,进行病例对照分析。结果:在回汉人群中,与正常对照组比较,单纯唇裂组和唇腭裂组rs3758249、rs10217225和rs4460498多态位点基因型和等位基因频率存在统计学差异(P0.05);而在单纯腭裂组差异无显著性(P0.05)。分别对汉族和回族人群内病例对照分析,发现唇裂并唇腭裂组rs3758249、rs10217225和rs4460498多态位点基因型在汉族和回族人群中的均存在差异性(P0.05)。病例组内进行回、汉族基因型比较,发现rs10217225多态性在宁夏地区回、汉患者中存在差异性(P0.05),而rs3758249、rs4460498差异没有显著性。结论:在宁夏回汉族人群中,FOXE1基因的rs3758249、rs10217225和rs4460498位点单核苷酸多态性与非综合征型唇腭裂存在相关性;回汉族人群间基因型没有统计学差异。     

山西人群MTHFR基因rs1801133位点多态性与非综合征性唇腭裂的关联性研究

目的:研究亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因rs1801133位点多态性与非综合征性唇腭裂(NSCL/P)的关系。方法:采用聚合酶链反应-限制性片段长度多态性方法,检测334例非综合征性唇腭裂患者和314例正常对照组的MTHFR基因rs1801133位点的多态性。结果:MTHFR基因rs1801133位点基因型频率分布符合Hardy-Weinberg平衡;MTHFR基因rs1801133位点基因型及等位基因的分布在NSCL/P组与对照组之间均无统计学意义(P>0.05)。结论:MTHFR基因rs1801133位点多态性与山西人群非综合征性唇腭裂的发生无关。     

TCN2基因与非综合征性唇腭裂的关系

目的研究叶酸代谢相关基因TCN2与中国人群中非综合征性唇腭裂的关系。方法通过聚合酶链反应-限制性片段长度多态性,在108例非综合征性唇腭裂患者和184名正常对照个体中,对TCN2基因2个单核苷酸多态性（SNP）（rs10418和rs1801198）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软件包分析单个单核苷酸多态性位点以及两个位点单倍型与非综合征性唇腭裂的相关性。结果 2个SNP位点基因型频率分布均符合Hardy-Weinberg平衡;等位基因分布和单倍型组合在非综合征性唇腭裂患者与对照组之间无显著性差异;rs10418 TT基因型能增加非综合征性唇腭裂患病风险。结论 TCN2基因rs10418 TT基因型是非综合征性唇腭裂的危险因素。     

小泛素化修饰基因-1多态性与非综合征型唇腭裂的相关性研究

目的探讨小泛素化修饰基因-1（SUMO-1）rs6709162、rs7599810和rs7580433位点单核苷酸多态性与非综合征型唇腭裂（NSOC）的相关性。方法收集宁夏地区NSOC患者208例、患者父亲189例、患者母亲176例、完整核心家系（患者及其父母）172个进行研究,并收集正常新生儿284例作为对照。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测SUMO-1基因多态位点rs6709162、rs7599810和rs7580433基因型,并进行病例对照分析、传递不平衡检验（TDT）和以家系为基础的相关性检验（FBAT）。结果病例对照研究发现：SUMO-1基因rs7599810位点的TT基因型频率在唇裂、腭裂组与对照组比较有统计学差异（P=0.01,P=0.01）。TDT分析结果：rs7599810位点的T等位基因在唇腭裂组中存在过传递（P=0.00）;rs6709162位点的C等位基因在腭裂和唇腭裂组中存在过传递（P=0.00,P=0.01）;rs7580433位点的G等位基因在唇裂组中存在过传递（P=0.05）。FBAT分析结果：rs7599810位点TT基因型和T等位基因的分布具有统计学意义（P=0.00,P=0.00）。结论SUMO-1基因多态性与NSOC存在相关性。     

THADA基因多态性与非综合征性唇腭裂的相关性研究

目的:探讨中国北方人群甲状腺腺瘤相关基因(THADA) rs7590268、rs13035011和rs6729902位点单核苷酸多态性(SNPs)与非综合征性唇腭裂(NSCL/P)的相关性。方法:应用聚合酶链式反应-连接酶检测反应(PCR-LDR)检测方法,在335例NSCL/P患者和525例健康体检者中,对THADA基因的rs7590268、rs13035011和rs6729902位点进行检测。结果:rs7590268和rs6729902多态性位点等位基因频率在唇裂组与对照组间的分布差异有统计学意义(P＜0.05),rs13035011位点基因型及等位基因频率在病例组和对照组间的分布差异无统计学意义。结论:THADA基因的rs7590268和rs6729902位点单核苷酸多态性可能与中国北方人群非综合征性唇腭裂的发生相关。     

叶酸代谢相关基因多态性与山西地区非综合征性唇腭裂的相关性研究

目的:研究叶酸代谢相关基因MTHFR基因rsl801133、MTHFD1基因rs2236225位点多态性与非综合征性唇腭裂(NSCL/P)的关系。方法:通过聚合酶链反应-限制性片段长度多态性方法,检测265例NSCL/P患者和276例正常对照者的MTHFR基因rsl801133、MTHFD1基因rs2236225位点的多态性。结果:MTHFR基因rsl801133位点、MTHFD1基因rs2236225位点的基因型频率分布符合Hardy-Weinberg平衡;MTHFR基因rsl801133位点、MTHFD1基因rs2236225位点的等位基因频率分布在NSCL/P组与对照组之间差异无统计学意义(P>0.05)。结论:MTHFR基因rsl801133位点、MTHFD1基因rs2236225位点的多态性与NSCL/P的发生无关。     

非综合征型唇腭裂与新疆维吾尔族、汉族 MTHFR 基因多态性的研究

目的：探讨新疆维吾尔族、汉族非综合征型唇腭裂与 MTHFR 基因多态性的关系和民族差异。方法：170例 NSCL／P儿童患者和100例健康儿童对照,SNaPshot 分型方法检测 rs1801131、rs1801133位点多态性,分析基因型、等位基因频率和2个位点联合作用与 NSCL／P 的关系以及民族间差异。结果：rs1801133TT 与 T 等位基因在维、汉两民族间有统计学差异（P ＜0．05）;rs1801133CT 与 CT ＋TT 基因型在总病例组和总对照组间均有统计学差异（P ＜0．05）;rs1801131和 rs1801133的联合分析在维族内、汉族内、两民族间、维汉总人群中病例组和对照组均有统计学差异（P ＜0．05）;rs1801131多态性在维族内、汉族内、两民族间以及维汉总人群中均无统计学差异（P ＞0．05）。结论：rs1801133TT 与 T 等位基因的汉族比维吾尔族更易罹患 NSCL／P;rs1801131AC 和 rs1801133CC 联合作用与 NSCL／P 相关且维吾尔族罹患风险高于汉族;rs1801131多态性与 NSCL／P 不相关并无民族差异;rs1801133CT 与 CT ＋TT 基因型均是避免疾病的保护因素。     

Contribution of polymorphisms in genes associated with craniofacial development to the risk of nonsyndromic cleft lip and/or palate in the Brazilian population

Background and Objective: Nonsyndromic cleft lip and/or palate (NSCL/P) is a complex disease associated with both genetic and environmental factors. One strategy for identifying of possible NSCL/P genetic causes is to evaluate polymorphic variants in genes involved in the craniofacial development. Design: We carried out a case-control analysis of 13 single nucleotide polymorphisms in 9 genes related to craniofacial development, including TBX1, PVRL1, MID1, RUNX2, TP63, TGF?3, MSX1, MYH9 and JAG2, in 367 patients with NSCL/P and 413 unaffected controls from Brazil to determine their association with NSCL/P. Results: Four out of 13 polymorphisms (rs28649236 and rs4819522 of TBX1, rs7940667 of PVRL1 and rs1057744 of JAG2) were presented in our population. Comparisons of allele and genotype frequencies revealed that the G variant allele and the AG/GG genotypes of TBX1 rs28649236 occurred in a frequency significantly higher in controls than in the NSCL/P group (OR: 0.41; 95% CI: 0.25-0.67; p=0.0002). The frequencies of rs4819522, rs7940667 and rs1057744 minor alleles and genotypes were similar between control and NSCL/P group, without significant differences. No significant associations among cleft types and polymorphisms were observed. Conclusion: The study suggests for the first time evidences to an association of the G allele of TBX1 rs28649236 polymorphism and NSCL/P. Key words:Cleft lip, cleft palate, polymorphism, genetic.     

DHFR基因rs11742688位点单核苷酸多态性与中国东北人群唇腭裂相关性研究

目的：探讨二氢叶酸还原酶（DHFR）基因 rs11742688位点单核苷酸多态性与中国东北部人群的非综合征唇腭裂（NSCL／P）的相关性。方法：采用聚合酶链－限制性片段长度多态性方法检测东北地区220例 NSCL／P 及其父母（其中包括138例完整的核心家系）,180例正常儿童作为对照组,进行 HW 平衡检验,用 SPSS 统计学软件对病例组和对照组进行检验及计算 OR 值和95％可信区间。结果：病例对照研究结果显示,东北地区单纯唇裂和唇腭裂 rs11742688位点的 TT 基因型频率差异无显著性（χ2＝0．439,P ＞0．05）。结论：DHFR rs11742688位点 T 等位基因与东北人群的 NSCL／P 无相关性。     

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.     

Further evidence for the involvement of MYH9 in the etiology of 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 birth defects and has a multifactorial etiology that includes both genetic and environmental components. MYH9 , the gene coding for the heavy chain of non-muscle myosin II, has been considered as a good candidate gene in NSCL/P on the basis of its expression profile during craniofacial morphogenesis. Reports in an Italian sample, as well as in an ethnically mixed North American sample, of a positive association between single-nucleotide polymorphisms in the MYH9 gene and NSCL/P have provided further support for the role of MYH9 in the development of NSCL/P. In the present study, we aimed to replicate these findings by conducting a family-based association study with seven single nucleotide polymorphisms in MYH9 using a sample of 248 NSCL/P patients and their parents. Single marker analysis resulted in a highly significant association for rs7078. In haplotype analysis, the most significant result was obtained for the SNP combination (rs7078; rs2071731; rs739097; rs5995288). Our results thus confirm the potential involvement of MYH9 in the etiology of NSCL/P in our patients of Central European origin, although further studies are warranted to determine its exact pathogenetic role.     

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.     

Association between BMP4 gene polymorphisms and cleft lip with or without cleft palate in a population from South China

ObjectivePrevious studies have suggested an association between several polymorphisms of the BMP4 gene and susceptibility to non-syndromic cleft lip with or without cleft palate (NSCL/P) in various populations. However, this association may vary according to ethnic group and the form of NSCL/P. This study analyzed the association between the BMP4 gene polymorphisms rs762642, rs17563, and rs10130587 with the risk of cleft lip only (CLO), cleft palate only (CPO), and cleft lip with palate (CLP) in a population from South China.MethodsThis case-control study included 165 patients with NSCL/P (53 patients with CPO, 52 with CLO, and 60 with CLP) and 52 healthy volunteers. Peripheral blood samples were collected from all subjects to genotype the rs762642, rs17563, and rs10130587 polymorphisms by direct sequencing. Genotype and allelic frequencies of these polymorphisms were compared between healthy volunteers and patients with various forms of NSCL/P.ResultsThe genotype and allelic frequencies of rs762642 differed significantly between subgroups (CPO and CLP) and normal controls, whereas a significant difference was observed only in the CLO subgroup for the rs17563 polymorphism and in the CLO and CLP groups for the rs10130587 polymorphism. In addition, we identified a novel association of a BMP4 gene polymorphism, which was in linkage disequilibrium with the rs10130587 polymorphism, with CLO and CLP.ConclusionThe BMP4 gene polymorphisms rs762642, rs17563, and rs10130587 exhibit different associations with different forms of NSCL/P, suggesting that different forms of NSCL/P may have different etiologies.     

VAX1 gene associated non-syndromic cleft lip with or without palate in Western Han Chinese

ObjectiveNon-syndromic cleft lip with or without palate (NSCL/P) is one of the most common human birth defects, it results from multiple genetic and environmental risk factors. Recently, GWA studies identified associations between NSCL/P and two genetic risk loci, rs7078160 and rs4752028, at VAX1.DesignCurrently, we tried to investigate the roles of the two loci among 302 NSCL/P trios (129 non-syndromic cleft lip only (NSCLO) trios and 173 non-syndromic cleft lip and cleft palate (NSCLP) trios) from Western Han Chinese. The two SNPs were genotyped by SNPscan method; Hardy–Weinberg equilibrium test, allelic TDT and parent-of-origin effect were performed by PLINK software, and genotypic TDT and haplotype by FBAT software.ResultsAllelic TDT analysis revealed allele A at rs7078160 was over-transmitted among NSCL/P group (P = 0.0086, OR_transmission = 1.36, 95%CI: 1.08–1.72). Parent-of-origin effect analysis revealed a paternal special over-transmission of allele A at rs708260 in NSCL/P group (P = 0.0079). Haplotype AC of rs7078160-rs4752028 was significant over-transmitted in the NSCL/P group.ConclusionsOur study firstly confirmed that allele A at rs7078160 at VAX1 gene was a risk factor for NSCL/P in Western Han Chinese population.