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：
8845973
负责人：
Richard James Reynolds
金额：
$ 12.8万
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/8845973
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 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 adaptive immunity 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，特别是类风湿性关节炎（RA）。为了实现这一目标，申请人提出了一项职业发展计划，重点是自身免疫病理学方面的教学培训和使用最先进的统计模型的实践培训，这些模型可以适应高维遗传数据带来的独特挑战。一个由具有良好业绩记录的优秀调查员组成的导师团队将监督申请人的职业发展。该项目的研究部分致力于发现决定非裔美国人对 RA 易感性的新遗传和环境因素（及其相互作用）。非裔美国人 RA 参与者的数据和生物样本可从 NIH 资助的非裔美国人 RA 纵向评估联盟 (CLEAR) 登记处（约 800 例 RA 病例）获得，而健康非裔美国人对照者的数据和生物样本则来自CLEAR 登记处（约 300 个对照）和来自阿拉巴马州伯明翰地区（约 500 个对照）。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，来自这约 800 个病例和约 800 个对照的 9,484 个单核苷酸多态性 (SNP) 的基因分型数据已经可用。我们将对所有 1,600 名病例和对照的 3 个相关维生素 D 受体基因 (VDR) SNP 进行基因分型，并测量血清 25(OH)-维生素 D 水平。本研究的目的是： 1) 检验 MHC 区域包含对非裔美国人 RA 风险产生影响的基因这一假设，与 HLA DRB1 SE 无关，并评估 MHC 中非 HLA 候选基因座的遗传风险与欧洲血统人群有已知的关联； 2) 开发一组 SNP，用于高精度估算与 RA 相关的 HLA-DRB1 等位基因；并验证非裔美国人的 SE 等位基因与 RA 的关联； 3) 检验维生素 D 受体 (VDR) SNP 与维生素 D 水平之间的相互作用会影响非裔美国人患 RA 风险的假设； 4) 利用和评估统计收缩方法、惩罚回归 (LASSO) 和 LASSO 的贝叶斯版本的相对性能，以测试非裔美国人 RA 风险的多重主效应、逐个基因和逐个基因的相互作用效应。该项目将极大地增强我们对传统上研究不足的人群中 RA 的复杂遗传和环境风险因素的理解，并将为 Reynolds 博士作为独立科学家的发展提供重要的培训。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Periodontitis and Porphyromonas gingivalis in Patients with Rheumatoid Arthritis.

类风湿关节炎患者的牙周炎和牙龈卟啉单胞菌。

DOI：
发表时间：
2014-01-08
期刊：
影响因子：
0
作者：
Mikuls, Ted R;Payne, Jeffrey B;Yu, Fang;Thiele, Geoffrey M;Reynolds, Richard J;Cannon, Grant W;Markt, Jeffrey;McGowan, David;Kerr, Gail S;Redman, Robert S;Reimold, Andreas;Griffiths, Garth;Beatty, Mark;Gonzalez, Shawneen;Bergman, Debra A;Ha
通讯作者：
Ha

Modelling heterogeneity among fitness functions using random regression.

使用随机回归对适应度函数之间的异质性进行建模。

DOI：
发表时间：
2016-01
期刊：
影响因子：
0
作者：
Reynolds, Richard J;de Los Campos, Gustavo;Egan, Scott P;Ott, James R
通讯作者：
Ott, James R

HLA-DRB1 Amino Acid Positions and Residues Associated with Antibody-positive Rheumatoid Arthritis in Black South Africans.

与南非黑人抗体阳性类风湿性关节炎相关的 HLA-DRB1 氨基酸位置和残基。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Govind, Nimmisha;Reynolds, Richard J;Hodkinson, Bridget;Ickinger, Claudia;Ramsay, Michele;Bridges Jr, S Louis;Tikly, Mohammed
通讯作者：
Tikly, Mohammed