Genomics of Lupus Associations in the Hispanic 12q24 Linkage

西班牙裔 12q24 连锁中狼疮关联的基因组学

• 批准号: 8249123
• 负责人: John Barker Harley
• 金额: $ 34.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249123
• 关键词: 12q24; Address; Alabama; Albumins; Alleles; American; Biochemical; Biological; Biology; Candidate Disease Gene; Case-Control Studies; Cell physiology; Clinical; Collection; Developmental Process; Disease; Etiology; European; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genetic Processes; Genetic Risk; Genomics; Genotype; Haplotypes; Hepatic; Hispanics; Lod Score; Lupus; Methods; Microsatellite Repeats; Modeling; Molecular; Morphologic artifacts; Nuclear; Oklahoma; Pathogenesis; Patients; Population; Probability; Research Infrastructure; Residual state; Risk; Sample Size; Sampling; Stratification; Susceptibility Gene; Systemic Lupus Erythematosus; Testing; Time; Variant; base; case control; follow-up; gene discovery; gene function; genetic association; genetic pedigree; improved; insight; interest; positional cloning; programs; protein expression; transcription factor

Genes that alter risk represent origins of disease causation and are therefore involved in disease pathogenesis. Many strategies are now available to discover these genes. Candidate gene approaches have given way to reverse genetics as the genotyping capacity has very recently undergone a technical scientific revolution. We identified a convincing linkage at 12q24 in our Hispanic (HI) pedigrees multiplex for systemic lupus erythematosus (lupus or SLE) that we confirmed in our European-American (EA) pedigrees (1) and others confirmed with additional independent samples (2) (p=0.000000014). We screened the linkage support interval with 41 markers in promising candidate genes. Markers in three genes suggested association. Follow up case control studies in HI and EA show association in a transcription factor, with the best haplotype in this gene producing strong evidence for association, an effect that has been independently replicated (p=0.00002). The association remains significant after correction for all the tests actually performed (Bonnferroni) under the overly conservative assumption of marker independence (p=0.003). In Project #2, we will evaluate the genomics of the genetic association and carry these findings toward biological mechanism. We will more than double the sample size studied to date (>6600 HI and EA subjects) to improve power to discriminate the true genetic contributions. We will use currently accepted strategies to eliminate artifacts from sample population stratification. We will physically define the genomic interval containing the association effect. We will use sequencing and genotyping to characterize the possible contributing variants in the interval. We will construct haplotypes and apply standard regression methods to identify the primary association as well as any remaining residual independent associations. The candidate polymorphisms and their surrogates will be evaluated for genomic mechanism(s). Once a genomic model is developed, we will explore gene biology. When successfully completed this P01 project will provide one or more new genes with mechanistic insights into the mechanisms by which lupus is generated. At the same time the infrastructure developed through this P01 project will provide the basis from which to evaluate this and other compelling candidate genes important for lupus in Hispanics (HI). The enlarging sample size from the continuing efforts to expand the existing collections in Alabama and Oklahoma is critical to provide the statistical power with which to winnow the false positive genetic associations from those most likely to be true genetic associations.

改变风险的基因代表疾病起因的起源，因此与疾病有关 发病机制现在有许多方法可以用来发现这些基因。候选基因方法有 由于基因分型能力最近已经经历了技术科学研究， 革命我们在我们的西班牙裔（HI）家系中发现了一个令人信服的12q24连锁， 我们在欧美（EA）家系中证实的红斑狼疮（狼疮或SLE）（1）， 其他人用额外的独立样本证实（2）（p=0.000000014）。我们筛选了 在有希望的候选基因中用41个标记支持区间。三个基因的标记表明 协会在HI和EA中的后续病例对照研究显示转录因子与 最好的单倍型在这个基因产生强有力的证据，协会，效果已独立 重复（p=0.00002）。实际上，在对所有测试进行校正后， 在标记物独立性的过度保守假设下进行（Bonnferroni）（p=0.003）。 在项目#2中，我们将评估遗传关联的基因组学，并将这些发现用于 生物机制我们将把迄今为止研究的样本量增加一倍以上（>6600名HI和EA受试者） 以提高辨别真正基因贡献的能力。我们将使用目前公认的策略， 消除样本群体分层中的伪影。我们将从物理上定义基因组间隔 包含关联效应。我们将使用测序和基因分型来表征可能的 区间中的贡献变量。我们将构建单体型并应用标准回归方法， 识别主关联以及任何剩余的独立关联。候选 将针对基因组机制评价多态性及其替代物。一旦基因组模型 我们将探索基因生物学。当成功完成此P01项目将提供一个或 更多的新基因与机制的见解狼疮的产生机制。在同一 届时，通过P01项目开发的基础设施将为评估这一点提供基础 以及其他对西班牙裔狼疮（HI）重要的引人注目的候选基因。扩大样本量， 继续努力扩大亚拉巴马和俄克拉荷马州现有的收藏品， 统计能力，以剔除假阳性的遗传关联，从那些最有可能 真正的基因关联