Discovering Novel Genetic and Environmental Risk Factors for RA in African Americ

发现非洲裔美国人 RA 的新遗传和环境风险因素

基本信息

批准号：
8641319
负责人：
Richard James Reynolds
金额：
$ 12.81万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641319
关键词：
Accounting Admixture African African American Alabama Algorithms Alleles Amino Acid Sequence Area Asians Autoimmune Diseases Autoimmunity Award Bioinformatics Biological Biology Candidate Disease Gene Cholecalciferol Chromosomes, Human, Pair 6 Chronic Complementarity Determining Regions Complex Computer software Data Development Development Plans Diagnosis Disease Environment Environmental Risk Factor Epitopes Etiology European Evaluation Funding Gene Expression Gene Frequency Genes Genetic Genetic Heterogeneity Genetic Polymorphism Genetic Risk Genetic Variation Genotype Goals HLA-DRB1 Hand Heritability Human Chromosomes Immune Immune response Individual Inflammation International Knowledge Laboratories Linear Models Link Linkage Disequilibrium Major Histocompatibility Complex Major Histocompatibility Complex Gene Measures Mentors Methods Minority Groups Participant Pathway interactions Patients Pattern Performance Play Population Predisposition Prevalence Proteins Receptor Gene Records Registries Relative (related person)Research Research Personnel Research Proposals Rheumatoid Arthritis Risk Role Sampling Sampling Studies Scientist Sensitivity and Specificity Serum Single Nucleotide Polymorphism Smoking Statistical Models Synovial Membrane Testing Training Twin Studies United States National Institutes of Health Vitamin D Vitamin D3 Receptor arthritis registry base career career development case control design genetic risk factor meetings novel population based predictive modeling racial/ethnic difference risk variant skills

项目摘要

DESCRIPTION (provided by applicant): The applicant's career goal is to become an independent investigator in the genetics of autoimmune disorders, particularly rheumatoid arthritis (RA). To meet this goal, the applicant proposes a career development plan with emphasis on didactic training in the pathobiology of autoimmunity and hands-on training using state-of-the-art statistical models that can accommodate the unique challenges presented by high dimensional genetic data. A highly accomplished team of investigators with proven track records as mentors will oversee the applicant's career development. The research component of this project strives to discover novel genetic and environmental factors (and their interactions) that determine susceptibility to RA in African Americans. Data and biological samples from African-American RA participants are available from the NIH-funded Consortium for the Longitudinal Evaluation of African- Americans with RA (CLEAR) Registry (~800 RA cases), while those from healthy African- American controls are from the CLEAR Registry (~300 controls) and from the Birmingham, Alabama area (~500 controls). Genotyping data from these ~800 cases and ~800 controls are already available for 9,484 single nucleotide polymorphisms (SNPs) based on the International Major Histocompatibility Complex (MHC) and Autoimmunity Genetics Network (IMAGEN) SNP array. We will perform genotyping of 3 relevant vitamin D receptor gene (VDR) SNPs and measure serum 25(OH)-vitamin D levels on all 1,600 cases and controls. The aims of the study are: 1) To test the hypothesis that the MHC region harbors genes that have effects on RA risk in African Americans independent of HLA DRB1 SE, and to assess the genetic risk of non-HLA candidate loci in the MHC which have known association in populations of European ancestry; 2) to develop a panel of SNPs that be used to impute with high accuracy the HLA-DRB1 alleles associated with RA; and to validate the association of the SE alleles in African Americans with RA; 3) To test the hypothesis that interactions between vitamin D receptor (VDR) SNPs and vitamin D levels will influence the risk of developing RA in African Americans; and 4) To utilize and evaluate the relative performance of the statistical shrinkage methods, penalized regression (LASSO), and Bayesian versions of the LASSO for testing the multiple main effects, gene by gene and gene by environmental interaction effects on RA risk in African Americans. This project will greatly enhance our understanding of the complex genetic and environmental risk factors for RA in a traditionally understudied population and will provide critical training for Dr. Reynolds' development as an independent scientist.

描述（由申请人提供）：申请人的职业目标是成为自身免疫性疾病遗传学的独立研究者，尤其是类风湿关节炎（RA）。为了实现这一目标，申请人提出了一项职业发展计划，重点是使用最先进的统计模型进行自身免疫和动手培训的病理学培训，以适应高维遗传数据所带来的独特挑战。作为导师的一支良好成就的调查员团队将监督申请人的职业发展。该项目的研究组成部分旨在发现新的遗传和环境因素（及其相互作用），这些因素决定了非裔美国人对RA的易感性。来自非裔美国人RA参与者的数据和生物样本可从NIH资助的联盟获得，用于对具有RA（Clear）注册表（〜800 RA案件）的非裔美国人进行纵向评估（〜800 RA案件），而来自健康的非裔美国人对照组则来自Clear Concormention（〜300个对照）（〜300个控制），来自Birmingham，Alabama，Alabama，Alabama地区（Alabama Arabama地区（〜500 Controls）。来自这些〜800例病例的基因分型数据和〜800个对照的数据已经可用于基于国际主要组织相容性复合物（MHC）和自身免疫遗传学网络（Imagen）SNP阵列的9,484个单核苷酸多态性（SNP）。我们将对所有1,600例病例和对照组进行3种相关维生素D受体基因（VDR）SNP的基因分型，并测量血清25（OH） - 维生素D水平。该研究的目的是：1）检验以下假设：MHC地区具有独立于HLA DRB1 SE的RA风险的基因，并评估MHC中非HLA候选基因群体的遗传风险，而MHC在欧洲祖先人群中已知相关的MHC； 2）开发一组SNP，用于高精度将与RA相关的HLA-DRB1等位基因归为高精度；并验证非洲裔美国人与RA的SE等位基因的关联； 3）为了检验以下假设：维生素D受体（VDR）SNP与维生素D水平之间的相互作用将影响非裔美国人发展RA的风险； 4）利用和评估统计收缩方法的相对性能，惩罚回归（LASSO）和LASSO的贝叶斯版本来测试基因的多种主要影响，以及基因与环境相互作用对非裔美国人RA风险的影响。该项目将大大增强我们对传统研究人群中RA的复杂遗传和环境风险因素的理解，并将为雷诺博士作为独立科学家的发展提供关键的培训。