非综合征性唇腭裂环境危险因素病例对照研究

目的分析非综合征性唇腭裂(nsCL/P)与孕早期环境暴露因素之间的关系。方法选择在贵阳医学院附属医院和广西百色市人民医院就诊的212例nsCL/P患者作为病例组,221例外伤病人和骨折病人作为对照组。采用自行设计的调查表,通过面对面询问433例研究对象的父母亲获取问卷资料,运用单因素及多因素非条件Logis-tic回归模型分析环境危险因素与非综合征性唇腭裂的关联性。结果病例组父亲和母亲具有高中及以上文化程度的比例(37.7%,27.4%)明显低于对照组(60.6%,57.0%);病例组父亲和母亲为农民的比例(77.4%,77.8%)明显高于对照组(52.5%,52.5%);在调整了父母的文化程度和职业分布影响后,多因素分析结果显示,母亲孕早期被动吸烟(OR=1.643)、母亲孕早期感染史(OR=2.741)、父亲知晓怀孕前饮酒(OR=1.793)明显增加nsCL/P的发病风险。结论怀孕夫妇在孕早期应避免烟酒等不良嗜好并注意防止感染的发生,以减少后代患唇腭裂的风险。     

新疆维、汉族非综合征型唇腭裂危险因素分析

目的 调查新疆维吾尔族、汉族非综合征型唇腭裂(NSCL/P)可疑危险因素,分析维、汉族危险因素异同点并提出有效预防措施.方法 采用病例-对照研究方法,收集新疆维吾尔族、汉族NSCL/P病例、对照共290例,进行危险因素单因素、多因素logistic回归分析.结果 维吾尔族NSCL/P病例-对照研究中,性别(P< 0.05)、母亲平时健康情况(P< 0.05)、孕期有无感冒(P< 0.05)差异有统计学意义;汉族NSCL/P病例-对照研究中,父亲文化程度(P< 0.05)、母亲孕早期工作强度(P< 0.05)、父亲是否饮酒(P< 0.05)差异有统计学意义.结论 维吾尔族和汉族NSCL/P危险因素存在民族差异;性别为男、母亲孕期健康差、母亲孕期感冒是维吾尔族NSCL/P的可能危险因素;父亲文化程度低、母亲孕早期工作过度、父亲饮酒是汉族NSCL/P的可能危险因素.     

非综合征性唇腭裂部分基因SNPs研究进展

非综合征性唇裂伴或不伴腭裂是人类最常见的先天性畸形之一,是一种遗传、环境因素及两者相互作用所致的多基因多因素遗传疾病.单核苷酸多态性是新一代遗传标记,可被用来寻找各种致病基因,目前认为单核苷酸多态性及其特定组合可能是造成以多基因多因素遗传病为代表的复杂性状疾病易感性的重要原因.     

还原叶酸载体基因多态性与先天性心脏病和唇腭裂关联的研究

目的 检验还原叶酸载体基因(RFC1)A80G多态性与先天性心脏病(CHD)和唇腭裂之间的关联,为寻找CHD和唇腭裂危险因素的遗传易感标志物提供流行病学依据。方法 采用RFLP-PCR方法,对67个CHD患儿家庭、82个唇腭裂患儿家庭和100个正常儿童家庭成员的外周血DNA进行RFC1第80位SNP检测,利用核心家庭标本进行以家庭为基础的关联检验(FBAT),并分析了子代RFC1基因型与母亲孕期前后增补叶酸的相互作用。结果 不增补叶酸的母亲生育CHD儿的危险高于增补叶酸的母亲(OR=2 68,95％CI:1 14-6 41),即母亲孕期未增补叶酸与CHD发生危险的关联有统计学意义(x2=6.213,P=0 013);在FBAT检验中,RFC1 G等位基因与CHD发病危险有统计学关联(Z=2 140,P<0 05),表明RFC1 G等位基因可能是CHD发病的遗传易感基因,未发现唇腭裂与RFC1之间的统计学关联。结论 RFC1 G等位基因可能是CHD发生的遗传易感基因之一,子代RFC1基因GG或GA基因型、母亲孕期叶酸缺乏可能增加CHD的发病危险。     

Transforming growth factor α locus and nonsyndromic cleft lip with or without cleft palate: A reappraisal

An association between nonsyndromic cleft lip with or without cleft palate (CL±P) and genetic variation at the transforming growth factor α (TGFA) locus was originally reported in 1989. Subsequent population-based studies of this association have provided conflicting results. The present analyses were undertaken to determine if the cumulative weight of the available data convincingly supports or refutes this association. The published data were analyzed for differences in allele frequencies between Caucasian CL±P patients (i.e., cases) and controls, and for heterogeneity between Caucasian samples. When all data except the original report were considered, there was a statistically significant association between TGFA and CL±P (M.H.O.R. = 1.43; 95% C.I. 1.12–1.80). However, there was evidence of significant heterogeneity in the TGFA allele frequencies between cases, but not controls, from different studies. The data suggest that the observed heterogeneity is unlikely to be attributable to differences in the ethnic composition of the cases among the various studies but may reflect differences in the proportion of cases with bilateral lip defects and/or with positive family histories of CL±P. Definitive conclusions regarding the source(s) of the observed heterogeneity could not, however, be drawn on the basis of the available data. Hence, at present, the evidence regarding an association between genetic variation at the TGFA locus and CL±P remains inconclusive. Genet. Epidemiol. 14:231–240,1997. © 1997 Wiley-Liss, Inc.     

总唇裂发生率变化趋势分析

目的:了解贵州省1996~2003年总唇裂的流行病学特征及发生率的动态变化趋势。方法:采用以医院为单位的整群抽样方法,对贵州省17所医院孕28周至产后7天的围产儿及191例总唇裂病例进行回顾性分析。结果:总唇裂发生率为20.79/万,其中单纯性唇裂为6.64/万,唇裂合并腭裂为14.15/万,单纯性唇裂有升高趋势。城乡总唇裂的发生率(20.23/万、24.41/万)无明显差异;男性发生率为25.36/万,女性为15.70/万,性别比为1.81∶1。不同年龄组产妇间唇裂合并腭裂的发生率有显著性差异,并随产妇年龄增加有升高趋势。结论:1996~2003年贵州省总唇裂发生率无变化,城乡无差异,男性易感性大于女性;唇裂合并腭裂较常见,且产妇年龄对其有影响。     

Genetic epidemiology of cleft lip with or without cleft palate in the population of Hawaii

Orientals consisting of Japanese, Chinese, Koreans, and Filipinos are clearly at higher risk for cleft lip with or without cleft palate [CL(P)] than whites, Puerto Ricans, and Hawaiians/part-Hawaiians in Hawaii. Using the model of diallele cross, CL(P) incidences in incrosses and outcrosses involving 564,002 live births distributed among 669 mating types were analyzed to study the extent of major gene involvement in the difference in the two groups and to investigate maternal effect in the etiology of CL(P). CL(P) cases excluding syndrome cases were classified into two types: all CL(P) cases and CL(P) cases without additional malformations. For either type there was no evidence to suggest that simple major gene plays a dominant role in accounting for racial differences as measured by deviations from additivity in the hybrids. For CL(P) cases without additional defects, a negative "maternal effect" was detected in Filipinos such that higher risk for this racial group depends on when the father is Filipino. Implications of the findings are discussed.     

Spatial and temporal clustering of isolated cleft lip with or without cleft palate in Poland

Background: Geographic variation in the prevalence of isolated cleft lip with or without cleft palate may be due to exogenous environmental factors or genetic variation. In this study, we aim to evaluate the prevalence of isolated cleft lip with or without cleft palate in Polish urban and rural environments in order to identify geographic areas with high prevalence (defect clusters). Methods: We use all cases of congenital malformations reported to the Polish Registry of Congenital Malformations in the years 1998–2008 from the total population of 2,362,502 births. Results: We detect a strong signal of increased prevalence of isolated cleft lip with or without cleft palate in a single region of Poland, the Dolno?l?skie voivodeship. Furthermore, we demonstrate a statistically significant prevalence differences between the urban and rural areas within this region. Through our comprehensive spatiotemporal analysis, we precisely define the cluster of the highest risk that comprises the eastern part of this voivodeship.     

转化生长因子β3基因多态性与唇腭裂关联的核心家庭分析

目的探讨中国部分地区人群非综合征型唇裂伴或不伴腭裂（nsCL／P）与转化生长因子B3基因CA重复序列多态性之间的关系。方法采用PCR-单链构象多态性方法，对170个nsCL／P核心家庭成员DNA标本进行TGFβ3 CA重复序列多态性的检测。利用传递不平衡检验（TDT）、基于单体型的单体型相对危险度检验（HHRR）和运用家系为基础的相关性检验（FBAT）检验分析该突变与nsCL／P发生之间的关系。结果TDT（OR=1．38，95％C10．93—2．06）和HHRR（OR=1．31，95％C10．93—1．84）检验发现，TGFβ3 CA重复序列多态性与nsCL／P发生之间的关联不具有统计学意义（P〉0．05），但是FBAT检验发现在显性和隐性模型中，TGFβ3基因多态性与nsCL／P发病危险之间的关联具有统计学意义（P〈0．05）。结论TGFβ3 CA重复序列多态性可能是中国部分地区人群发生nsCL／P的危险因素，但还有待于扩大样本量进一步加以验证。     

Test of genetic heterogeneity of cleft lip with or without cleft palate as related to race and severity

The question of possible heterogeneity among population groups and phenotypic groups on the role of major gene in the etiology of cleft lip with or without cleft palate [CL(P)] was examined using the uniformly collected data in Hawaii. Complex segregation analysis was used to analyze patterns of family resemblance under the mixed model incorporating the effects of major gene and multifactorial inheritance. Analysis of the entire data showed superior fit of the mixed model including the effects of both major gene and multifactorial inheritance over the model of major gene alone or multifactorial inheritance alone. No significant heterogeneity could be detected between the high-incidence group (Oriental or Japanese) and the low-incidence group (non-Oriental) in the underlying general model, although higher heritability was observed in general. When families were classified into "severe" and "mild" phenotypes based on cleft lip vs. cleft lip and palate or unilateral vs. bilateral cleft in the proband, no significant differences could be detected between the two types in the underlying genetic model.     

IRF6基因rs642961位点多态性与非综合征性唇裂伴或不伴腭裂的相关性研究

目的探讨中国北方人群干扰素调节因子6(IRF6)基因rs642961位点多态性与非综合征性唇裂伴或不伴腭裂(NSCL±P)的相关性。方法收集中国北方人群88个病例核心家庭和116个正常儿童作对照,用四引物扩增受阻突变体系聚合酶链反应(tetra-primer ARMS-PCR)的方法,进行IRF6基因rs642961检测;用人群关联研究、传递不平衡检验(TDT)、单倍型相对风险率(HHRR)、家庭为基础的关联检验(family-based association test,FBAT)等进行统计分析。结果子代、父亲、母亲三个亚组人群的IRF6基因rs642961位点的基因型在NSCL±P组与对照组的分布差异具有统计学意义(P<0.05),OR值及其95%可信区间均不包含1,提示IRF6基因rs642961位点的变异能增加NSCL±P发病的危险。核心家庭资料TDT和HHRR的结果均显示有统计学差异(P<0.05),FBAT分析提示可能存在加性传递模式(P<0.05),进一步支持IRF6基因rs642961位点的突变和NSCL±P发生相关。结论在中国北方人群中,IRF6基因rs642961位点多态性与NSCL±P发病相关。     

Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.     

Cleft lip with or without cleft palate: reanalysis of a three-generation family study from England

The study population consists of 424 three-generation families originally ascertained through nonsyndromic cleft lip with or without cleft palate (CL +/- P) surgical probands by Carter et al [J Med Genet 19:246-261, 1982] in London, England. Carter et al proposed that the multifactorial threshold model (MF/T) could explain the data. The goal of our study was to test that hypothesis, plus alternatives, rigorously. Two approaches were used: 1) Carter et al had proposed that these data were consistent with the predictions of the MF/T as presented by Carter [Br Med Bull 25:52-57, 1969]. However, we tested those predictions using standard chi 2 tests and found statistically significant departures from the predictions in these families. 2) Complex segregation analysis under the mixed model was performed. Again, the MF/T model could be rejected, as could a model of a major locus alone. The best-fitting model included both major locus and multifactorial components. When the data were analyzed in two parts based on the proband's phenotype (CL vs CL + P) there was some evidence of heterogeneity in that there was a significant proportion of sporadic cases in the families of CL probands but not in the families of CL + P probands. Our results provide no support for the MF/T model. The results from segregation analyses of CL +/- P in these families were most consistent with autosomal major gene inheritance plus multifactorial contributions.     

转化生长因子α基因多态性与唇腭裂关联的研究

目的 探讨中国部分地区人群非综合征型唇裂伴或不伴腭裂（nsCL/P）与转化生长因子α基因（TGFα）TaqI位点多态性之间的关系。方法 采用聚合酶链反应限制片段长度多态性分析方法，对149个nsCL／P核心家庭成员DNA标本进行TGFα Taq I突变位点的基因型检测。利用传递失衡检验和以家庭为基础的关联研究（FBAT）方法，分析TGFα Taq I突变与nsCL／P发生之间的关系。结果 未发现TGFα Taq I突变的致病晓等位基因在nsCL／P核心家庭成员中存在传递不平衡（P〉0．05）；采用FBAT分析，未发现C2等位基因及C2C1基因型与nsCL／P发病危险之间关联有统计学意义（P〉0．05）。结论 TGFα Taq I突变可能不是中国部分地区人群nsCL／P发生的易感基因。     

候选基因SNP位点与非综合征性唇腭裂的相关性

目的探讨亲代12个候选基因SNP位点与子代非综合征性唇腭裂(NSCLP)的关系,为开展NSCLP的基因诊断和针对性的防治提供基础资料。方法选取41例NSCLP患儿母亲和109例非患儿母亲分别作为病例组、对照组,提取其血液中DNA,采用改良多重高温连接酶检测法(iMLDR)对CENPJ、c14orf49和YOD1等12个基因的SNP位点进行基因分型,计算各基因型在病例组、对照组中的频率分布,并采用χ2检验分析12个SNP位点基因型与NSCLP的遗传关系。结果 C14orf49、EIF2B3、HEATR8、KIF20B、PARVA、PKP1、RECQL5、REG3A、SEC16A、TEX11基因的10个SNP位点的基因型频率分布在病例组、对照组间的差异均无统计学意义(P值均0.05)。CENPJ基因rs35498994位点的基因型C在病例组、对照组中分布频率分别为46%、33%;YOD1基因chr1_207224322位点的基因型GT和T在病例组分布频率分别为7%、4%,在对照组中分布频率均为0%,以上差异均有统计学意义(P值均0.05)。结论母亲携带CENPJ基因(rs35498994)等位基因C,或YOD1(chr1_207224322)突变基因型GT和T会增加子代患NSCLP的风险。     

转化生长因子α基因多态性和父亲吸烟的交互作用与唇腭裂发生的关联研究

目的探讨中国部分地区人群非综合征型唇裂伴或不伴腭裂（nsCL／P）与转化生长因子α基因（TGFα）TaqI位点多态性之间的关系,及其与父亲吸烟之间的交互作用。方法采用PCR-RFLP方法,对170个nsCL／P核心家庭成员DNA标本进行TGFα TaqI突变位点的基因型检测。利用TDT检验分析该突变与nsCL／P发生之间的关系,采用TDT检验的logistic回归模型分析TGFα基因突变与父亲吸烟之间的交互作用。结果未发现TGFα TaqI突变的致病C2等位基因在nsCL／P核心家庭成员中存在传递不平衡,但是父亲吸烟的nsCL／P核心家庭中C2C1基因型的父母将致病的C2等位基因传递给子代的频率是父亲不吸烟的nsCL／P核心家庭父母的约1／5（0．062～0．711）,控制其他环境因素后发现,父亲是否吸烟与TGFα TaqI突变位点C2等位基因传递之间是偏离乘法模型的负交互作用OR=0．102（0．017～0．619）。结论父亲是否吸烟与中国部分地区人群TGFα基因突变存在交互作用,但还有待于进一步研究加以验证。     

中国人群WNT代谢通路与非综合征型唇腭裂的亲源效应分析

目的 非综合征型唇裂合并或不合并腭裂（NSCL/P）是一类常见的出生缺陷,遗传致病因素一直是其病因学研究的热点。本研究拟基于家系设计在WNT代谢通路基因中探索亲源效应对NSCL/P发病风险的影响。方法 本研究人群为“唇腭裂的基因组学国际合作组研究”项目在中国地区募集的806个NSCL/P核心家系。利用对数线性模型探索WNT基因及其单体型的亲源效应与疾病的关联,采用Wald检验探索亲源效应与环境因素的交互作用。经过Bonferroni多重检验校正后,统计学检验的显著性阈值设为P<3.47×10^-4。结果 质量控制后共纳入7个基因上144个单核苷酸多态性位点进行分析。结果显示,NSCL/P家系中有8个位点具有潜在的亲源效应（P<0.05）,但经Bonferroni多重检验校正后,均未达到统计学显著性水平（P>3.47×10^-4）。NSCL/P家系中位于WNT9A rs4074668-rs12725747单体型（T-A）具有亲源效应,且经Bonferroni校正后差异仍有统计学意义（P=2.74×10^-4）。但该单体型的亲源效应与环境因素（被动吸烟、复合维生素补充）的交互作用并未达到统计学显著水平。结论 WNT代谢通路基因可能通过亲源效应影响NSCL/P的发生风险。位于WNT9A基因rs4074668-rs12725747单体型（T-A）亲源效应与NSCL/P发病风险存在显著关联。未来仍需其他独立样本验证以进一步确认WNT代谢通路在NSCL/P发生中的作用。     

RF6基因多态性与黔北人群非综合征性唇腭裂的相关性研究

目的 探讨黔北地区人群IRF6基因rs2235371和rs2235373 SNP位点的多态性及其与非综合征性唇腭裂的相关性。方法 采用PCR和测序方法对153个对照儿童和123个NSCL/P儿童的IRF6基因中2个SNP位点rs2235371和rs2235373进行扩增和测序;对样本群体进行Hardy-Weinberg平衡分析,比较2组人群的基因型频率、等位基因频率及OR分析;两位点连锁不平衡分析。结果 对照组与病例组人群rs2235371基因型均含有GG、GA和AA型,rs2235373位点均含有CC、CT和TT型。对于2个位点,对照组和病例组均符合Hardy-Weinberg平衡法则(P＞0.05)。2组人群中,rs2235371和rs2235373位点的等位基因和基因型差异均有统计学意义(P＜0.05);rs2235371位点GGvsGA的OR值(95%CI) =1.725(1.025～2.902),GGvsAA的OR值(95%CI) = 2.100(1.109～4.328);rs2235373位点CCvsTT的OR值(95%CI) = 2.263(1.348～5.015),CTvsTT的OR值(95%CI) = 2.061(1.108～2.169);(P＜0.05)。rs2235371和rs2235373位点存在连锁不平衡,GC单倍型是主要的单倍体型,对NSCL/P均有致病风险,OR值(95%CI)= 1.722(1.219～2.431), (P＜0.05)。结论 在黔北地区人群中,IRF6基因 rs2235371和rs2235373位点均具有多态性;rs2235371位点的GG基因型和rs2235373位点的CC、CT基因型与NSCL/P的发生有相关性;rs2235371和rs2235373位点存在连锁不平衡,GC单倍型对NSCL/P有致病风险。     

还原叶酸载体1基因A80G多态性与非综合征型唇腭裂的相关性研究

目的探讨还原叶酸载体(RFC)1基因A80G多态性与非综合症型唇腭裂(NSCL/P)相关性。方法收集97个核心家庭和104个对照家庭,用聚合酶链式反应-限制性片段长度多态性方法,进行RFC1基因A80G位点多态性检测,用人群关联研究分析、NSCL/P核心家庭的TDT、HHRR、FBAT等检验统计分析。结果人群关联研究分析,子代、父亲、母亲病例组和对照组之间基因型和等位基因的分布差异无显著性(P>0.05)。AG基因型相对于AA基因型的比值比OR(95%CI)、P值分别为子代0.87(0.44～1.70)、0.657;父亲1.09(0.54～2.21)、0.788;母亲1.63(0.79～3.36)、0.152。GG基因型相对于AA基因型的OR(95%CI)、P值分别为子代0.48(0.19～1.23)、0.094;父亲0.93(0.38～2.23)、0.850;母亲1.30(0.46～3.67)、0.584。G基因相对于A基因的OR(95%CI)、P值分别为子代1.22(0.78～1.94)、0.386;父亲1.02(0.64～1.61)、0.945;母亲0.91(0.58～1.41)、0.660。携带有突变基因G并不能增加患NSCL/P的危险。NSCL/P核心家庭分析,TDT检验中传递G等位基因给患病子代的为40次,传递A等位基因的为71次,等位基因A比突变等位基因G更易传递给患病子代(χ2=8.658,P<0.05;HHRR检验χ2=10.31,P<0.05;FBAT检验Z=2.942,P<0.05)。结论利用核心家庭资料进行统计分析的结果则认为RFC1基因A80G位点变异存在传递不平衡现象,这与NSCL/P发病危险之间存在有一定的关联关系,等位基因A可能与NSCL/P的高危显性有关系。     

新生儿唇腭裂危险因素的病例对照研究

目的探讨唇腭裂（CLP）的发病原因。方法采用1：1配对的方法,对90例唇腭裂患儿的母亲与非唇腭裂患儿的母亲进行了对照研究,调查范围包括母亲自身危险因素和环境中的危险因素两大方面。结果在所列的7种因素中,有6种因素表现出较高的危险度,依其危险度（OR值）大小排列为：孕期接触工业毒物（9．0）,孕期使用某些化学药物（8.0）,家中饲养猫、狗等宠物（6．0）,父母近亲结婚（6．0）,孕期内受病毒感染（4．5）和孕期内喷洒农药除草剂（4．0）。结论孕期内接触有害物质是CLP的重要致病因素。