Genetic Factors in Birth Defects

出生缺陷的遗传因素

• 批准号: 8736884
• 负责人: James Mills
• 金额: $ 67.3万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736884
• 关键词: Affect; Animals; Apical Ectodermal Ridge; BMP2 gene; BMP4; Binding; Binding Sites; Birth; Blood; CTNNB1 gene; CYP26B1 gene; Candidate Disease Gene; Case-Control Studies; Child; Coagulation Process; Collaborations; Confidence Intervals; Congenital Abnormality; Craniosynostosis; DNA; DNA Methylation; Data; Defect; Diet; Etiology; European; FGF10 gene; FGF8 gene; Folate; Future; GDF5 gene; GLI2 gene; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic screening method; Genotype; HIF1A gene; Health; Heterogeneity; Human; Individual; Infant; Institution; Investigation; Lead; Limb Development; Limb structure; Link; Literature; Meta-Analysis; Methylenetetrahydrofolate reductase (NADPH); MicroRNAs; Minor; Mothers; NOS3 gene; Neonatal Screening; New York; Newborn Infant; Not Hispanic or Latino; Obesity; Odds Ratio; Paper; Parents; Plasma; Play; Population; Population Study; Pregnancy; Publication Bias; Publishing; RNA Splicing; Race; Registries; Reporting; Research; Research Personnel; Resources; Risk; Risk Factors; Role; SHH gene; Sampling; Single Nucleotide Polymorphism; Site; Skeletal Development; Spearman Rank Correlation Coefficient; Subgroup; Syndrome; TCF7L2 gene; Testing; VEGFA gene; Variant; WNT7A gene; angiogenesis; base; case control; congenital heart disorder; design; expectation; genetic association; genetic risk factor; genetic variant; genome wide association study; heart disease risk; interest; malformation; offspring; population based; proband; programs; retinoic acid 4-hydroxylase; transcription factor

DNA has been obtained from approximately 20 major malformations for current and future investigations. We have recently expanded our investigations to include searching for copy number variants in rare defects. New York has an exceptionally valuable research resource in having approximately 250,000 births per year from which to identify children with rare defects. In addition to classic candidate gene approaches, cases have been selected for copy number variant studies. Samples have been analyzed by large scale copy number variant array testing. The first defects are now being analyzed for copy number variants. We have also collaborated with large groups doing genome wide association studies. Samples have been tested in cases and controls in collaboration providing subjects for confirmatory genotyping in several studies. Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio OR, 0.96 95% confidence interval, 0.87-1.07). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 95% confidence interval, 1.03-1.51; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 95% confidence interval, 0.91-1.03) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 95% confidence interval, 0.87-1.47). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association. Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 10(-14), odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 10(-11), OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 10(-10), OR = 0.19) and rs17724206 (P = 1.50 10(-8), OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 10(-31) and rs10262453, P = 3.50 10(-14)) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC. Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value < 0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman's rank correlation coefficients between -0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans. We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LDs). Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998-2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR = 1.99; 95% CI = 1.43-2.77; uncorrected P = 0.000043 for rs10805683 heterozygous genotype, and OR = 2.37; 95% CI = 1.48-3.78; uncorrected P = 0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.

DNA已从大约20个主要畸形中获得了当前和将来的研究。 我们最近扩大了调查，以包括搜索稀有缺陷中的拷贝数变体。 纽约拥有非常有价值的研究资源，每年约有25万个出生，可以从中识别出罕见缺陷的儿童。除了经典的候选基因方法外，还选择了拷贝数变体研究的病例。已经通过大型拷贝数变体阵列测试对样品进行了分析。 现在，正在分析第一个缺陷的拷贝数变体。 我们还与从事大型基因组关联研究的大型团体合作。 在几项研究中，已在案例和对照中对样品进行了测试，为验证性基因分型提供了。 甲基四氢叶酸还原酶（MTHFR）基因与先天性心脏病（CHD）的C677T多态性之间的关联是有争议的。我们比较了冠心病病例和对照组之间以及CHD病例和对照的母亲之间的基因型。我们通过进行先前发表的研究的荟萃分析将结果置于上下文中。在具有主要基因型数据和10 056个对照的5814例病例中，没有证据表明MTHFR C677T基因型和CHD风险（优势比或0.96 95％置信区间，0.87-1.07）之间存在关联。所有研究的随机效应荟萃分析（涉及7697例和13个125个对照）表明存在关联（OR，1.25 95％置信区间，1.03-1.51; p = 0.022），但在贡献研究中具有实质异质性（I（2）= 64.4％）和证据。仅对大型研究的荟萃分析（由log的差异定义或<0.05），这些差异共同贡献了所有情况的83％，在没有明显的异质性的情况下，没有任何关联的证据（OR，0.97 95％的置信区间，0.91-1.03）（i（i（2）= 0）。此外，对1781例CHD病例的母亲的荟萃分析（本研究中的829例是基因分型）和19 861个对照表明，孕产妇C677T基因型与后代的CHD风险之间没有相关的证据（OR，1.13 95％置信区间，0.87-1.47）。在来自不同饮食叶酸水平的地区的大型研究中，MTHFR基因型和冠心病风险之间没有显着关联。直接影响血浆叶酸水平的MTHFR C677T多态性与CHD风险无关。关于这种遗传关联，出版偏见似乎实质上污染了文献。 矢状颅骨突变是最常见的颅突变形式，影响了大约5,000名新生儿。据我们所知，我们使用了130个非西班牙裔副父母三重奏（NHW）进行了非基因组矢状颅颅底症（SNSC）的首次基因组关联研究。我们发现BMP2下游的120-KB区域侧面是rs1884302（P = 1.13 10（-14），优势比（OR）= 4.58）和Rs6140226（P = 3.40 10（-11），OR = 0.24），OR = 0.24），在167-kb bbs necy of 167-kb bbs necy of 167-kbb bbss n.1110 rs re。 10（-10），OR = 0.19）和RS17724206（p = 1.50 10（-8），或= 0.22）。我们在172个具有SNSC和548个控件的独立NHW人群中，复制了与基因座（RS1884302，P = 4.39 10（-31）和RS10262453，P = 3.50 10（-14））的关联。 BMP2和BBS9都是在骨骼发育中具有作用的基因，需要功能研究以进一步了解SNSC的病因。 肛门闭锁是严重的病因学的严重先天缺陷，但在动物研究和人类综合征中已经鉴定出候选基因。由于这些基因活性的改变可能会导致厌取性闭锁，因此我们选择了71种被预测为25个候选基因的转录因子结合位点，CPG窗口，剪接位点和miRNA靶位点的常见变体，并测试了它们与厌食性闭合的相关性。该研究人群包括150例肛门闭锁病例和623例没有重大畸形的对照婴儿。预计会影响WNT3A，PCSK5，TCF4，MKKS，GLI2，HOXD12和BMP4中的转录因子结合，剪接和DNA甲基化的变体与基于名义p值<0.05的厌食闭锁相关。据报道，GLI2和BMP4变体与基因表达变化（Spearman的等级相关系数在-0.260和0.226之间）。我们没有找到证据表明孕妇孕前肥胖与MKKS的变异（以前与肥胖相关的基因）的变异，这是出于厌取性闭锁的风险。我们对MKKS支持的结果先前建议与肛门直肠畸形有关。我们的发现表明，需要进行更多的研究来确定改变GLI2和BMP4表达是否在人类的厌取性闭锁中很重要。 我们对选定基因中的单核苷酸多态性（SNP）进行了基于人群的病例对照研究，以找到在肢体缺陷（LDS）病因中起作用的常见变体。这项研究包括389名未知原因LDS的婴儿，1998 - 2005年从纽约州（NYS）的所有出生中选择了980个未受影响的对照。我们使用了纽约州卫生部（DOH）先天性畸形注册表的案件。 Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation （F2，F5，MTHFR）。基因型呼叫率> 97％，SNP被测试，以偏离种族/族裔亚组的Hardy-Weinberg期望。对于每个SNP，估算了所有LDS组合和LD亚型的多重比较，估算了几率（OR）和置信区间（CI）（CI）。 Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR = 1.99; 95% CI = 1.43-2.77; uncorrected P = 0.000043 for rs10805683 heterozygous genotype, and OR = 2.37; 95％CI = 1.48-3.78;未校正的p = 0.00032 rs13170645纯合小型基因型）。我们还观察到在包括CYP26B1和WNT7A在内的其他基因中与SNP的关联的暗示性证据。动物研究表明，FGF10诱导了根尖外胚层的形成，对于肢体发育是必要的。我们的数据表明，FGF10中的常见变体增加了多种非综合肢体缺陷的风险。