Genomic, transcriptomic, and metabolic effects on skeletal health in Mexican Americans

基因组、转录组和代谢对墨西哥裔美国人骨骼健康的影响

• 批准号: 10660283
• 负责人: MIRYOUNG LEE
• 金额: $ 67.56万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660283
• 关键词: Acceleration; Address; Adult; Age; Aging; Black race; Bone Density; Clinical; Cohort Studies; County; Cross-Sectional Studies; Data; Deterioration; Diabetes Mellitus; Dual-Energy X-Ray Absorptiometry; Elderly; Epidemiology; Female; Femur; Fracture; Gene Expression; General Population; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genomics; Glean; Goals; Health; High Prevalence; Hispanic; Hispanic Populations; Image; Individual; Intervention; Knowledge; Latino; Latino Population; Low income; Maps; Measures; Mediating; Mendelian randomization; Metabolic; Metabolic Bone Diseases; Metabolic Pathway; Metabolic dysfunction; Methods; Mexican Americans; Mexico; Minority Groups; Monitor; Neck; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Obesity; Osteoporosis; Participant; Pathway interactions; Patients; Pattern; Persons; Phenotype; Population; Predisposing Factor; Prevention; Public Health; Radiology Specialty; Reporting; Research; Risk; Risk Assessment; Risk Factors; Role; Sampling; Subgroup; Thinness; Time; Trabecular Bone Score; United States; Vertebral column; Visit; aged; bone; bone health; bone loss; bone quality; bone turnover; causal variant; cohort; differential expression; follow-up; fracture risk; fragility fracture; genetic analysis; genetic risk factor; genome wide association study; genomic locus; health disparity; high risk; innovation; insight; longitudinal design; low socioeconomic status; non-diabetic; novel; phenotypic data; population based; premature; risk variant; skeletal; tool; trait; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Individuals with type 2 diabetes (T2D) have a 10%-30% higher risk of fractures than age-matched individuals without T2D. However, the current paradox is that fragility fractures among people with T2D occur despite apparently normal bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA). Older individuals with T2D have high fracture rates have low bone turnover, while high bone turnover increases the risk of fracture in similarly aged non-diabetics. Currently available tools (BMD, markers of bone turnover) are inadequate to screen or monitor bone health in individuals with T2D who have a high prevalence of fragility fractures. Indirect measures of bone quality assessed from DXA images, the geometric parameters of the femoral neck, and the lumbar spine Trabecular Bone Score (LS-TBS) has been recently associated with fracture risk in older individuals. Identifying the best phenotype, genetic risk factors, and associated functional changes is critical to detecting the earliest bone changes in older adults with T2D and the underlying metabolic pathways leading to skeletal changes in participants with T2D. However, current research on skeletal health in T2D is mainly gleaned from research in populations primarily of non-Hispanic Whites, even though Mexican Americans (MA), the largest Hispanic/Latino (H/L) subgroup in the USA, have the highest prevalence of T2D and osteoporosis. We propose to address these research gaps by leveraging our new and existing genetic and phenotypic data on the population-based Cameron County Hispanic Cohort (CCHC) study using cross- sectional and longitudinal designs. Our main goal is to investigate the causal pathways to bone loss and quality and examine changes in metabolic and structural phenotypes in a sample of MA adults aged over 50 years. The aims are to (1) Estimate the association of T2D on longitudinal changes in bone traits; (2) Identify transcriptomic patterns associated with longitudinal changes in bone traits; and (3) Identify genetic risk factors for bone traits, perform colocalization, and explore the causal role of T2D and metabolic risk on bone quality via Mendelian randomization. We expect that mechanistic insights into genetic and transcriptomic factors associated with T2D and metabolic dysfunction that influence pathways leading to poor skeletal health lead us to identify novel targets for early prevention and clinical intervention of osteoporosis and fractures among older MA adults.

项目概要/摘要 2 型糖尿病 (T2D) 患者的骨折风险比同龄人高 10%-30% 没有 T2D。然而，目前的悖论是，尽管 T2D 患者存在脆性骨折，但还是会发生脆性骨折。 通过双能 X 射线吸收测定法 (DXA) 测量的骨矿物质密度 (BMD) 明显正常。年长的 T2D 患者骨折率高，骨转换率低，而骨转换率高则增加了骨折发生率。 年龄相近的非糖尿病患者发生骨折的风险。目前可用的工具（BMD、骨转换标记物）有 不足以筛查或监测脆性患病率较高的 T2D 患者的骨骼健康状况 骨折。从 DXA 图像评估骨质量的间接测量，骨的几何参数 股骨颈和腰椎小梁骨评分 (LS-TBS) 最近与 老年人的骨折风险。确定最佳表型、遗传风险因素和相关功能 变化对于检测患有 T2D 的老年人最早的骨骼变化以及潜在的代谢变化至关重要 导致 T2D 参与者骨骼变化的途径。然而，目前关于骨骼健康的研究 T2D 主要是从对非西班牙裔白人群体的研究中收集到的，尽管墨西哥人 美国人 (MA) 是美国最大的西班牙裔/拉丁裔 (H/L) 亚群，其 T2D 患病率最高 和骨质疏松症。我们建议通过利用我们新的和现有的遗传和 基于人群的卡梅伦县西班牙裔队列 (CCHC) 研究的表型数据使用交叉 截面和纵向设计。我们的主要目标是研究骨质流失和质量的因果途径 并检查 50 岁以上 MA 成年人样本的代谢和结构表型的变化。 目的是 (1) 估计 T2D 与骨骼特征纵向变化的关联； (2) 识别 与骨骼特征纵向变化相关的转录组模式； (3) 识别遗传因素 骨骼特征的危险因素，进行共定位，并探索 T2D 和代谢的因果作用 通过孟德尔随机化对骨质量的风险。我们 预计 那 对遗传和机制的见解 与 T2D 和代谢功能障碍相关的转录组因素影响导致不良的途径 骨骼健康引导我们确定骨质疏松症早期预防和临床干预的新目标 MA 老年人中的骨折。