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.

项目总结/摘要 2型糖尿病（T2 D）患者的骨折风险比年龄匹配的个体高10%-30% 没有T2 D。然而，目前的矛盾是，尽管T2 D患者发生了脆性骨折， 通过双能X线吸收测定法（DXA）测量的骨矿物质密度（BMD）明显正常。老年 具有高骨折率的T2 D个体具有低骨转换，而高骨转换增加了T2 D患者的骨密度。 相似年龄的非糖尿病患者的骨折风险。目前可用的工具（BMD，骨转换的标志物）有 不足以筛查或监测脆性患病率较高的T2 D患者的骨骼健康 骨折从DXA图像评估的骨质量的间接测量， 股骨颈和腰椎骨小梁评分（LS-TBS）最近被认为与 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 变化对于检测老年T2 D患者最早的骨变化和潜在的代谢变化至关重要。 导致T2 D参与者骨骼变化的途径。然而，目前对骨骼健康的研究， T2 D主要是从非西班牙裔白人人群的研究中收集的，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）亚组，T2 D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基因和 基于人群的卡梅隆县西班牙裔队列（CCHC）研究的表型数据，使用交叉 分段和纵向设计。我们的主要目标是调查导致骨质流失和骨质疏松的原因 并检查50岁以上MA成人样本中代谢和结构表型的变化。 目的是（1）估计T2 D与骨骼性状纵向变化的相关性;（2）确定 与骨性状纵向变化相关的转录组模式;（3）确定遗传 骨特征的风险因素，进行共定位，并探讨T2 D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 想到 的 对基因和 与T2 D和代谢功能障碍相关的转录组因子，这些因子影响导致不良 骨骼健康使我们确定了骨质疏松症早期预防和临床干预的新靶点， 老年人的骨折。