Identifying Disease Variants for Familial Crohns Disease

识别家族性克罗恩病的疾病变异

• 批准号: 7942992
• 负责人: Steven R Brant
• 金额: $ 109.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942992
• 关键词: 13q; 13q13.3; 1p35; 1p35.2; 3q29; Accounting; Adult; Affect; Alleles; American; Ashkenazim; Bioinformatics; Biological Assay; Cells; Characteristics; Child; Chromosomes; Chromosomes, Human, Pair 13; Chronic; Code; Complex; Computer Simulation; Confidence Intervals; Crohn' s disease; DNA; Data; Databases; Disease; Disease Attributes; Enzyme-Linked Immunosorbent Assay; Exons; Family; Family history of; Family member; Functional disorder; Future; Gastrointestinal tract structure; Genes; Genetic; Genetic Transcription; Genome; Genotype; Hereditary Disease; Heritability; Human Genome; In Situ Hybridization; Incidence; Inflammation; Inflammatory Bowel Diseases; Intercistronic Region; Introns; Link; Linkage Disequilibrium; Lymphocyte; Minority; Mononuclear; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Nucleic Acid Regulatory Sequences; Patients; Penetrance; Persons; Probability; Promoter Regions; Proteins; Proteomics; RNA; Recruitment Activity; Reverse Transcriptase Polymerase Chain Reaction; Risk; SNP genotyping; Sampling; Simulate; Societies; Susceptibility Gene; Testing; Tissues; Variant; Western Blotting; Work; cancer risk; case control; cost; density; disease phenotype; follow-up; follower of religion Jewish; genetic linkage analysis; genetic pedigree; genetic risk factor; genome-wide; genome-wide linkage; immunocytochemistry; lymphoblastoid cell line; mortality; novel; prevent; programs; protein expression; protein function; public health relevance; therapy development; transmission process

DESCRIPTION (provided by applicant): Crohn's disease (CD) is a complex genetic disorder of chronic inflammation of the gastrointestinal tract that results in increased morbidity, mortality, risk of cancer and cost to patient and society. Twenty to 30% of patients have a CD family history and the disease is four-fold increased in persons of Ashkenazi Jewish (AJ) ancestry. Multiple low penetrance susceptibility genes have been identified and confirmed, but these in total account for only 20% of CD genetic heritability. As part of the NIDDK IBD Genetics Consortium (IBDGC) the applicant performed the first SNP, high density, whole genome linkage study, four-fold larger than any prior linkage study and the only study with adequate numbers of AJ CD pairs (919 CD pairs, 196 pairs AJ). Non-parametric linkage analysis confirmed the IBD1 locus (Lod of 4.86), and identified three additional loci with genome-wide significant linkage: a novel locus at chromosome 13q13.3 (Lod 3.98, simulated whole genome p-value of 0.01) in all CD pedigrees, and loci at chromosomes 1p35.2 and 3q29, in the AJ CD pedigrees (Lod 3.50 and 3.19, respectively and simulated genome p-values of 0.02 and 0.05, respectively). Parametric linkage analysis showed that the 13q and 3q loci follow a recessive, high penetrance mode of inheritance (H-Lod 3.3 - 10% of families linked and H-Lod 3.5, 24% of AJ families linked, respectively) and 1p followed a dominant mode (H-Lod 3.4, 38% of AJ families linked). An ancillary R01 study to identify disease alleles for these three loci is proposed. The applicant will work with the IBDGC to assemble DNA samples on the AJ CD pedigrees and the non-Jewish, chromosome 13 - linked pedigrees and/or within the top quartile of non-parametric linkage evidence. Saturation genotyping will be performed across the 2-lod confidence interval for each locus, with a total of 9000 SNPs. Alleles significantly associated with CD will be identified by using within-pedigree association analysis (independent of linkage) with the program PBAT. Association will be replicated and/or extended in 722 AJ cases and controls, 200 cases to be newly recruited by the IBDGC as part of the ancillary R01, per IBDGC-coordinated plans. Deep re-sequencing of associated genes and regions will be done, in at least 50 CD cases and 50 controls, to identify potential disease alleles. The applicant will use a bioinformatics approach to analyze re-sequencing data for functional relevance. These alleles will then be characterized for association with CD in the 859 total AJ case-control pairs. Lastly, the applicant will determine expression characteristics of genes associated, both analyzing expressed RNA and protein, and how expression correlates with the disease associated versus wildtype alleles. Identifying very high penetrance disease alleles will allow us to determine the specific cause of CD in patients with the disease alleles, and eventually how these alleles cause CD pathophysiology. These discoveries will make possible predicting persons at great risk for developing CD, the potential of preventing the disease in carriers, and the development of therapies, especially for those with CD attributed to these newly identified disease alleles. PUBLIC HEALTH RELEVANCE: Nearly 500,000 Americans, both children and adults, have Crohn's disease, and in approximately one-quarter of those affected, two or more family members have the disease. We have identified three small regions of the human genome, known as "loci," that correlate with familial Crohn's disease. With this study, we will test 9000 gene markers in these regions and identify the specific genes and, by gene sequencing, the specific DNA abnormalities that result in a significant proportion of familial Crohn's disease.

描述（由申请人提供）：克罗恩病（CD）是一种复杂的胃肠道慢性炎症遗传性疾病，导致发病率、死亡率、癌症风险以及患者和社会成本增加。 20% 至 30% 的患者有 CD 家族史，并且德系犹太人 (AJ) 血统的人中该疾病的发病率增加了四倍。多个低外显率易感基因已被鉴定和证实，但这些基因总共只占CD遗传性的20%。作为 NIDDK IBD 遗传学联盟 (IBDGC) 的一部分，申请人进行了第一个 SNP、高密度、全基因组连锁研究，比任何先前的连锁研究大四倍，也是唯一具有足够数量 AJ CD 对（919 个 CD 对）的研究, 196 双 AJ)。非参数连锁分析证实了 IBD1 基因座（Lod 为 4.86），并确定了另外三个具有全基因组显着连锁的基因座：染色体 13q13.3 上的一个新基因座（Lod 3.98，模拟全基因组 p 值为 0.01）。 CD 谱系以及 AJ CD 谱系中染色体 1p35.2 和 3q29 处的基因座 (Lod分别为 3.50 和 3.19，模拟基因组 p 值分别为 0.02 和 0.05）。参数连锁分析表明，13q 和 3q 位点遵循隐性、高外显率遗传模式（H-Lod 3.3 - 10% 的家族连锁，H-Lod 3.5，24% 的 AJ 家族连锁），1p 遵循显性遗传模式。模式（H-Lod 3.4，38% 的 AJ 家族相关）。建议开展一项辅助 R01 研究来鉴定这三个基因座的疾病等位基因。申请人将与 IBDGC 合作，在 AJ CD 谱系和非犹太 13 号染色体连锁谱系上和/或在非参数连锁证据的前四分之一内组装 DNA 样本。将在每个位点的 2-lod 置信区间内进行饱和基因分型，总共有 9000 个 SNP。与 CD 显着相关的等位基因将通过使用 PBAT 程序的谱系内关联分析（独立于连锁）进行鉴定。根据 IBDGC 协调计划，关联将在 722 个 AJ 病例和对照中进行复制和/或扩展，其中 200 个病例将由 IBDGC 新招募，作为辅助 R01 的一部分。将在至少 50 个 CD 病例和 50 个对照中对相关基因和区域进行深度重测序，以确定潜在的疾病等位基因。申请人将使用生物信息学方法来分析重测序数据的功能相关性。然后将在 859 个 AJ 病例对照对中对这些等位基因与 CD 的关联进行表征。最后，申请人将确定相关基因的表达特征，分析表达的RNA和蛋白质，以及表达与野生型等位基因相关疾病的相关性。识别外显率非常高的疾病等位基因将使我们能够确定携带疾病等位基因的患者患 CD 的具体原因，以及最终这些等位基因如何导致 CD 病理生理学。这些发现将使预测罹患 CD 的高风险人群、预防携带者疾病的潜力以及开发治疗方法成为可能，特别是对于那些因这些新发现的疾病等位基因而患有 CD 的患者。 公共卫生相关性：近 500,000 名美国人（包括儿童和成人）患有克罗恩病，其中约四分之一的患者中有两名或两名以上家庭成员患有该病。我们已经确定了人类基因组的三个小区域，称为“基因座”，与家族性克罗恩病相关。通过这项研究，我们将测试这些区域的 9000 个基因标记，并通过基因测序来识别特定基因，并通过基因测序识别导致很大一部分家族性克罗恩病的特定 DNA 异常。