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

项目摘要/摘要 2型糖尿病(T2D)患者的骨折风险比年龄匹配的患者高10%-30% 没有T2D。然而，目前的矛盾是，患有T2D的人中会发生脆性骨折，尽管 采用双能X线骨密度仪(DXA)测量骨密度(BMD)。更老的 患有T2D的人骨折发生率高，骨转换率低，而高转换率会增加 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)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 骨折。从DXA图像评估骨质量的间接测量，几何参数 股骨颈和腰椎松质骨评分(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 变化是检测患有T2D的老年人最早的骨骼变化和潜在代谢的关键 T2D受试者骨骼改变的通路。然而，目前关于骨骼健康的研究在 T2D主要是从以非西班牙裔白人为主的人群中收集的，即使是墨西哥人 美国人(MA)是美国最大的西班牙裔/拉丁裔(H/L)亚群，T2D的患病率最高 骨质疏松症。我们建议通过利用我们新的和现有的基因和 基于人群的卡梅伦县拉美裔队列(CCHC)研究的表型数据使用交叉- 横断面和纵向设计。我们的主要目标是研究导致骨丢失和骨质量的原因。 并检查了50岁以上的MA成人样本中代谢和结构表型的变化。 其目的是(1)评估T2D与骨骼特征纵向变化的关联；(2)确定 与骨骼特征纵向变化相关的转录模式；以及(3)识别遗传 骨特征的危险因素，执行共定位，并探索T2D和代谢的因果作用 孟德尔随机化对骨质量的风险。我们 期望 那 对基因和基因的机械论见解 与T2D和代谢障碍相关的转录因子影响导致贫血症的途径 骨骼健康使我们为骨质疏松的早期预防和临床干预确定了新的目标，并 老年MA患者中的骨折。

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.