Friday, April 18, 2025
4/18/2025
Genomic, transcriptomic, and metabolic effects on skeletal health in Mexican Americans - 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.
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