Genetics of Foot Disorders

足部疾病的遗传学

• 批准号: 8303021
• 负责人: Marian T. Hannan
• 金额: $ 60.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303021
• 关键词: Address; Adult; Affect; African; African American; Age; American; Ancillary Study; Biological; Biomechanics; Body mass index; Candidate Disease Gene; Caucasians; Caucasoid Race; Centenarian; Chronic; Clawtoe; Clinical; Collaborations; Communities; Computer Simulation; County; DNA Resequencing; Data; Data Analyses; Data Sources; Deformity; Degenerative polyarthritis; Development; Disease; Disease Progression; Early treatment; Elderly; Epidemiology; Etiology; Family; Flatfoot; Foot Deformities; Framingham Heart Study; Functional disorder; Funding; Future; Gender; Genetic; Genetic Determinism; Genetic Variation; Genotype; Goals; Hallux Valgus; Hammer Toes; Heritability; Individual; Knowledge; Link; Lower Extremity; Maps; Measurement; Measures; Meta-Analysis; Outcome; Phenotype; Physical Examination; Play; Population; Preventive Intervention; Pronation; Protocols documentation; Quality of life; Recording of previous events; Research Personnel; Risk Factors; Role; Running; Sampling; Single Nucleotide Polymorphism; Staging; Supination; Talipes cavus; Testing; Toes; United States National Institutes of Health; Woman; Work; aged; base; clinical care; cohort; disability; effective intervention; family structure; foot; functional disability; functional loss; genetic pedigree; genetic variant; genome wide association study; genome-wide; high risk; indexing; member; pressure; prevent; public health relevance; trait

DESCRIPTION (provided by applicant): Foot disorders affect approximately 20-60% of Americans and are increasingly linked to chronic mobility limitations and disability. Although the importance of genetics is commonly suspected, no linkage, candidate gene association, or genome-wide association studies (GWAS) on foot disorders have been performed. Our preliminary data from the Framingham Foot Study (an ancillary of the Framingham Heart Study [FHS]) show high heritability of hallux valgus, especially in women. We now have the unique opportunity to link data on specific foot disorders and foot biomechanics to a wealth of genetic data in the FHS and the Johnston County OA Project (JoCo OA), two community-based cohorts. By identifying genetic links to foot disorders which can cause functional limitations in later life, targeted preventive interventions can be applied with the goal of preventing or slowing functional loss. The primary objective of this proposed study is to identify genetic determinants of hallux valgus, pes planus, pes cavus, lesser toe deformities (hammer toes, claw toes, or overlapping toes), and foot biomechanics measures: the Center of Pressure Excursion Index (CPEI), and peak plantar load. Specifically, we propose to 1) expand our knowledge of the heritability of these specific foot traits in the FHS; 2) perform a GWAS meta-analysis to identify genetic variants; and 3) replicate the findings in independent samples. Heritability of foot biomechanics measurements will be estimated in the FHS using pedigree structure by a variance component analysis. A GWAS meta-analysis on foot disorders and biomechanics will combine results from FHS and JoCo OA studies (Caucasians) and then replicate (in-silico) the Single Nucleotide Polymorphisms (SNPs) with association test p-values less than 10-5 for available phenotypes in the Genetics of Generalized Osteoarthritis (GOGO) Study (Caucasians). To assess the generalizability of our findings, we will perform association analysis for those SNPs located in the replicated genome-wide associated regions/loci, in African Americans in JoCo OA. The proposed work involves secondary data analysis, using foot disorders and biomechanical traits from our current NIH-funded Study (RO1 AR047853) using identical protocols in both cohorts. This proposal leverages existing unique clinical, epidemiological, biomechanical and genetic data from two large, long-standing community-based cohorts. The proposal capitalizes upon well-established collaborations between productive epidemiologic, biomechanics, and genetics investigators and (to our knowledge) the only data sources of both specific, valid foot data and well-characterized genetic data. These investigators are thus uniquely poised to examine the genetics of foot disorders in adults. PUBLIC HEALTH RELEVANCE: Foot disorders are extremely common in the population and contribute to disability and diminished quality of life. Many of these run in families, suggesting a genetic origin. It is important to identify those who have these conditions, or are at high risk to develop them, because effective interventions exist and can be targeted to appropriate individuals to lessen their impact or potentially prevent their development.

描述(由申请人提供)：足部疾病影响大约20%-60%的美国人，并越来越多地与慢性活动受限和残疾有关。尽管人们普遍怀疑遗传学的重要性，但尚未对足部疾病进行连锁、候选基因关联或全基因组关联研究。我们来自弗雷明翰足部研究(弗雷明翰心脏研究[FHS]的辅助研究)的初步数据显示，拇指外翻的遗传率很高，特别是在女性中。我们现在有了独特的机会，将特定足部疾病和足部生物力学的数据与FHS和约翰斯顿县OA项目(JoCo OA)这两个基于社区的队列中的丰富遗传数据联系起来。通过确定可能导致晚年功能受限的足部疾病的遗传联系，可以应用有针对性的预防性干预措施，以防止或减缓功能丧失。这项拟议研究的主要目标是确定拇外翻、扁平足趾、足底凹陷、小趾畸形(锤趾、爪趾或重叠脚趾)以及足部生物力学指标：压力中心偏移指数(CPEI)和足底峰值负荷的遗传决定因素。具体地说，我们建议1)扩大我们对这些特定足部特征在FHS中的遗传性的了解；2)执行GWAS荟萃分析以识别遗传变异；3)在独立样本中重复发现。足部生物力学测量的遗传力将通过方差分量分析在FHS中使用系谱结构进行估计。一项关于足部疾病和生物力学的GWAS荟萃分析将结合FHS和JoCo OA研究(高加索人)的结果，然后复制(在电子计算机中)单核苷酸多态(SNPs)，其关联测试p值小于10-5，适用于泛发性骨关节炎(Gogo)遗传学研究(高加索人)的可用表型。为了评估我们发现的概括性，我们将在JoCo OA中对位于复制的全基因组相关区域/基因座的非裔美国人中的那些SNP进行关联分析。建议的工作涉及二次数据分析，使用我们目前由NIH资助的研究(RO1AR047853)中的足部疾病和生物力学特征，使用两个队列中相同的方案。这项建议利用了来自两个长期以社区为基础的大型队列的现有独特的临床、流行病学、生物力学和遗传数据。该提案利用了富有成效的流行病学、生物力学和遗传学研究人员之间的良好合作，以及(据我们所知)具体、有效的足部数据和特征良好的基因数据的唯一数据来源。因此，这些研究人员在检查成人足部疾病的遗传学方面具有独一无二的优势。 公共卫生相关性：足部疾病在人群中极为常见，并导致残疾和生活质量下降。其中许多是家族遗传的，这表明它们有基因起源。重要的是确定那些患有这些疾病或有高风险罹患这些疾病的人，因为存在有效的干预措施，并可以针对适当的个人，以减轻其影响或潜在地防止其发展。