Methyl Donor Pathway Genetics in the Development of Orofacial Clefts

口面部裂发展中的甲基供体途径遗传学

基本信息

批准号：
7830432
负责人：
JASPER D RINE
金额：
$ 46.54万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-22 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7830432
关键词：
Address Affect Alleles Area Biological Assay Candidate Disease Gene Case-Control Studies Cleaved cell Cleft Lip Cleft Palate Code Collaborations Congenital Abnormality Coupled Data Data Set Defect Dental Development Diagnostic Disease Disease Association Enzymes Epidemiology Etiology Folate Folic Acid Food Interactions Frequencies Gene Frequency General Population Genes Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Variation Genomics Genotype Heterozygote Homocysteine Homocystine Human Infant Intake Lead Light Metabolic Metabolic Pathway Metabolism Modeling Molecular Genetics Nutrient Nutritional Pathway interactions Phenotype Population Predisposition Pregnancy Prevention strategy Research Risk Role Saccharomyces cerevisiae Scanning Supplementation Testing Variant Vitamins Woman Yeasts base clinical phenotype cofactor cohort craniofacial gene interaction genetic analysis oral condition orofacial prevent remediation trend

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-DE-104: Genotyping of Existing Cohorts in Craniofacial, Dental and Oral Conditions. Orofacial clefts, specifically cleft lip and cleft palate, are common and costly congenital anomalies whose etiologies remain largely unknown. One of the most promising clues to the causes of orofacial clefts is that women who use vitamins containing folic acid in early pregnancy are at much lower risk for cleft-affected pregnancies. Although the underlying mechanisms by which folic acid contributes to these reduced risks are unknown, evidence suggests that folate intake prevents clefts by compensating for susceptibilities in methyl donor metabolism. However, clear identification of genetic determinants in these pathways through association studies has proven elusive. The approach we propose to further define the molecular genetics mechanisms behind orofacial clefts is based on our observations (Proc Natl Acad Sci, 2008, 105:8055 and an ongoing study) that deep sequencing reveals a substantial amount of low-frequency, nonsynonymous variation in folate pathway genes (frequencies < 1%) that has gone unnoticed thus far. Furthermore, a significant fraction of these low-frequency variants affect enzyme function, yet are nutritionally remedial. We hypothesize that genetic susceptibilities in methyl donor metabolism can be etiological for clefts and that these susceptibilities can be conferred by both low-frequency and common variants and by the possible synergy between these. To test this hypothesis, we will sequence the coding regions in 23 methyl donor metabolic genes from a population of 250 cleft-affected infants and 250 controls, for which we also have data on maternal nutritional intake and other epidemiological parameters. We will test all enzyme variants for functional impact and nutritional remediation based on quantitative complementation assays in the yeast S. cerevisiae, and correlate allele distribution and functional studies with clinical phenotype and nutritional data. We hope to better define the causality of orofacial clefts, understand the remedial role of nutritional supplementation, and determine whether additional supplementation may be preventative. This research plan capitalizes on an already existing collaboration that unites a unique combination of expertise for its execution. This proposal should reveal some of the causes of a common form of birth defect known as cleft lip and/or cleft palate. Ultimately, this research may lead to better diagnostic and preventive strategies.

描述（由申请人提供）：此申请解决了广泛的挑战领域（08）基因组学和特定挑战主题，08-DE-104：颅面，牙科和口服条件下现有同类群体的基因分型。口面裂口，特别是唇裂的口腔，是常见且昂贵的先天性异常，其病因在很大程度上尚不清楚。口腔裂缝的最有前途的线索之一是，在怀孕初期使用含有叶酸的维生素的女性的妊娠风险要低得多。尽管叶酸导致这些降低的风险的基本机制尚不清楚，但证据表明，叶酸摄入量通过补偿甲基供体代谢的敏感性来阻止裂口。但是，通过关联研究清楚地鉴定了这些途径中的遗传决定因素已被证明难以捉摸。我们提出的方法是基于我们的观察结果（Proc Natl Acad Sci，2008，1008，105：8055和一项正在进行的研究），该方法是基于我们的观察结果，这些方法是深层测序表明，大量的低频，非频率，非频率变化的基因在弱点基因中（频繁<1％）。此外，这些低频变体的很大一部分会影响酶功能，但在营养方面是补救措施。我们假设甲基供体代谢中的遗传敏感性可能是对裂缝的病因，并且这些敏感性可以由低频和常见变体赋予这些敏感性，并且可以通过它们之间的协同作用。为了检验这一假设，我们将对来自250名受裂口影响的婴儿和250个对照组的23种甲基代谢基因的编码区进行测序，为此，我们还拥有有关母体营养摄入量和其他流行病学参数的数据。我们将根据酵母菌葡萄球菌中的定量互补测定法测试所有酶变体，以进行功能影响和营养补救，并将等位基因分布和功能研究与临床表型和营养数据相关联。我们希望更好地定义口腔裂缝的因果关系，了解补充营养的补救作用，并确定是否可以预防其他补充。该研究计划利用了已经存在的合作，该合作将其执行的独特专业知识结合在一起。该提议应揭示出一种常见形式的先天缺陷的原因，称为唇裂和/或left裂。最终，这项研究可能会导致更好的诊断和预防策略。