Correlating Multiple Sclerosis Phenotypes with Genotypes

多发性硬化症表型与基因型的关联

• 批准号: 7113768
• 负责人: BRUCE C CREE
• 金额: $ 16.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-19 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113768
• 关键词: African American; alleles; biotechnology; blood chemistry; caucasian American; clinical research; data collection methodology /evaluation; family genetics; gene expression; genotype; human genetic material tag; human subject; linkage mapping; multiple sclerosis; pathologic process; phenotype; racial /ethnic difference

DESCRIPTION (provided by applicant): The pathoetiology of multiple sclerosis (MS) involves underlying genetic susceptibility acting in concert with undefined environmental factors. African Americans (AAs) with MS are a unique population that may allow a better understanding of the biology of MS. AA patients have an older age of onset, are at high risk for optic nerve and spinal cord manifestations and suffer from a more severe disease course. Because these characteristics are more prevalent in AAs than in White Americans (WAs), identification of the underlying genes associated with these traits will be more readily accomplished in AAs. Furthermore compared to WA chromosomes, AA chromosomes have smaller blocks of linkage disequilibrium allowing higher resolution genetic mapping in this population. The goals of this proposal are two fold. The first goal is to develop robust and well-characterized cohorts of AA and WA MS patients. To date, 534 AAs and 672 WAs have been recruited and we will recruit a total of 1,000 affected subjects in each group within the first 2 years of this project. The second goal is to use this dataset to identify specific disease alleles that modify disease expression. This dataset has already attained sufficient statistical power to detect phenotypic differences between these populations and, when complete, should have adequate power to make phenotype-genotype correlations. There are currently three loci that have the most consistent association with MS: 6p21, 19q13, and 17q22. Although the HLA-DRB, APOE, and iNOS genes are assumed to account for the effect of these respective loci, the confounding consequences of linkage disequilibrium in WAs prevent definitive mapping of the MS genes. In parallel with this proposal, fine mapping studies will be performed using the AA cohort to determine the genes at these loci associated with MS susceptibility and disease expression. Specific alleles will then be tested for association with MS phenotypes. These studies are expected to substantially improve the understanding of the genetic basis of MS pathogenesis and have practical applications for prognosis and perhaps for therapeutic selection based on an individual's genetic background.

描述（由申请人提供）：多发性硬化症（MS）的病理学涉及与不确定的环境因素一起起作用的遗传易感性。具有MS的非裔美国人（AAS）是一个独特的人群，可以更好地了解MS的生物学。 AA患者的发病年龄较大，视神经和脊髓表现的高风险，并且患有更严重的疾病病程。由于这些特征在AAS中比在美国白人（WAS）中更为普遍，因此在AAS中，对与这些特征相关的基因的识别将更容易完成。此外，与WA染色体相比，AA染色体具有较小的连锁不平衡块，可以使该人群中更高的分辨率遗传映射。该提案的目标是两个折。第一个目标是开发AA和WA MS患者的强大且特征良好的人群。迄今为止，已经招募了534个AAS和672，我们将在该项目的前2年内招募每个组中的1,000名受试者。第二个目标是使用该数据集识别改变疾病表达的特定疾病等位基因。该数据集已经获得了足够的统计能力来检测这些人群之间的表型差异，并且完成后，应具有足够的能力来使表型基因型相关性。目前，有三个基因座与MS：6P21、19Q13和17Q22具有最一致的关联。尽管假定HLA-DRB，APOE和INOS基因可以解释这些基因座的影响，但连锁不平衡的混杂后果是防止MS基因的确定映射。与该提案同时，将使用AA队列进行精细的映射研究，以确定与MS易感性和疾病表达相关的这些基因座的基因。然后，将测试特定的等位基因与MS表型关联。这些研究有望大大提高对MS发病机理的遗传基础的理解，并在预后以及基于个人的遗传背景的治疗选择方面具有实际应用。