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Investigating the Genetic Basis of Metabolic Disease and Familial Dysceramidemia in Pacific Islanders

调查太平洋岛民代谢性疾病和家族性神经酰胺血症的遗传基础

基本信息

批准号：
10462627
负责人：
Marcus Guy Pezzolesi
金额：
$ 19.06万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-05 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462627
关键词：
Affect Anabolism Apoptosis Arterial Fatty Streak Beta Cell Biological Models Biology Cardiac Myocytes Cardiovascular Diseases Cell Death Ceramidase Ceramides Code Community Networks Complex Complications of Diabetes Mellitus Computerized Medical Record Data Databases Development Diabetes Mellitus Diagnostic Disease End stage renal failure Enrollment Enzymes Family Family member Foundations Functional disorder Future Genealogy Generations Genes Genetic Genetic Screening Genetic Variation Genomics Goals Health Homeostasis Human Hypertension Impairment Individual Insulin Kidney Diseases Kidney Failure Lipids Liquid Chromatography Literature Malignant Neoplasms Metabolic Diseases Metabolism Mexican Americans Modification Mutation Nonesterified Fatty Acids Obesity Pacific Islander Pacific Islands Pathway interactions Pharmacology Population Database Recording of previous events Research Research Design Research Project Grants Resources Risk Role Solid Sphingolipids Sphingosine Testing Therapeutic Translations Universities Utah Variant base cohort comorbidity diabetic patient dihydroceramide exome sequencing genetic linkage analysis genetic pedigree genetic variant genome sequencing human disease improved insight lipidomics member multiple omics mutation carrier non-genetic novel population based rare variant recruit sphinganine tandem mass spectrometry

项目摘要

PROJECT SUMMARY Pacific Islanders (PIs) have among the world’s highest burden of metabolic disease and are at increased risk for other associated comorbidities, such as cardiovascular disease, kidney disease, and cancer. Despite high rates of these complex diseases, PIs have largely been underrepresented in studies designed to identify the underlying factors that contribute to their increased risk. Ceramides are lipotoxic sphingolipids that contribute to cellular dysfunction that cause metabolic disease. While much of the literature implicating ceramides in metabolic disease has centered on genetic modification or pharmacological inhibition of genes involved in ceramide synthesis pathways in various model systems, accumulation of ceramides has also been demonstrated in human disease. The underlying mechanisms leading to increased ceramides in human disease, however, are unknown. As part of our studies leveraging unique resources at the University of Utah, including the Utah Diabetes Database and the Utah Population Database, we recently identified rare mutations that alter ceramide levels in 2 families enriched for obesity, diabetes, and end-stage renal disease, causing familial dysceramidemia, including the first family from the Pacific Islands with a rare genetic variant associated with elevated ceramides. Given this novel and important finding, we hypothesize that aberrant sphingolipid levels and genetic variants that alter their biosynthesis are key contributors to metabolic disease and related comorbidities in PIs. Building on this evidence, the goal of this developmental research project is to expand this research and investigate the role of sphingolipid levels in metabolic disease in PIs using a multi-omics approach that includes lipidomic and genomic analysis of large, multi-generational PI pedigrees. To accomplish this goal, we will 1) determine sphingolipid levels in members of 25 large, multi-generational PI pedigrees with metabolic disease by i) expanding recruitment of PI families currently enrolled in the Utah Diabetes and Diabetic Complications Study to include at least 10-15 members per family and ii) use liquid chromatography with tandem mass spectrometry to establish lipid profiles of sphingolipid species in all recruited PI family members and 2) evaluate the contribution of genetic variation on sphingolipid levels in members of large, multi-generational PI pedigrees by i) screening for genetic variants in members of PI families with aberrant sphingolipid profiles using whole exome sequencing and ii) performing unified linkage analysis and rare variant association testing to identify variants influencing sphingolipid species. We anticipate that this research will build on exciting preliminary data and provide key insights on the role of this pathway in metabolic disease in PIs. This research will provide a solid foundation for future efforts aimed at elucidating the mechanisms behind the disparity of metabolic disease in PIs and facilitate translation of these findings to improved diagnostics and therapeutics.

项目总结