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Principal Investigator: JOANNE E. CURRAN
Organization: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
Fiscal Year: 2024
Award: $500,383
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Type 2 diabetes is a major public health concern. Diabetes currently affects 25.8 million people in the US alone
and 90-95% of all cases are type 2. There are many complications related to diabetes, including a significantly
increased risk of heart disease and stroke, blindness, kidney failure and kidney disease, nonalcoholic fatty liver
disease, neuropathy, hearing loss and lower-limb amputations. There are several risk factors predisposing
individuals to the development of this disease including demographic characteristics like sex, age and ethnicity;
and behavioral and lifestyle-related modifications. In addition, metabolic determinants such as impaired glucose
tolerance and insulin resistance increase the risk of an individual progressing to type 2 diabetes. Significant
diabetes health disparities exist in minority populations, including Hispanics and African Americans, where
prevalence of diabetes is increased. Evidence from both epidemiological and lipidomic studies have shown that
specific lipoproteins and their constituent lipids are important factors in the development of type 2 diabetes,
where, like many other metabolic diseases, lipid metabolism is disrupted. The classical lipid parameters most
commonly examined in relation to disease risk are themselves complex entities composed of multiple lipid
species. We hypothesize that these basic lipid species represent intermediate phenotypes that lie closer to the
genomic level in the interplay between phenotype and disease, and therefore may be better predictors of disease
risk and increase the pace of discovery of genes causally involved in lipid variation and type 2 diabetes.
In this project, we will exploit whole genome sequence (WGS) information in powerful extended pedigrees of
Mexican American individuals in combination with comprehensive measures of the human lipidome, to identify
novel genes and functional variants influencing lipid variation and type 2 diabetes, in an effort to reduce the
diabetes health disparities evident in Hispanic populations. The combination of these precise biological lipid
phenotypes and WGS gives us an unprecedented opportunity to identify novel genes and functional variants
influencing human lipid variation and risk of diabetes. To achieve these objectives, we will (I) measure T2D risk
phenotypes including targeted lipid profiling of more than 800 lipid species; and multiple measures of metabolic
function, and perform quantitative genetic analyses; (II) identify sequence variation influencing lipid variation and
diabetes in all individuals using WGS; (Ill) perform hypothesis based replication in an independent Mexican
American population; and (IV) perform functional assessments of variants of interest in relevant iPSC-derived
cells and analyze free and total fatty acid content in a subset of the cohort.
The estimated economic burden of diabetes in the United States alone is approximately $245 billion per year,
making this disease of major public health importance. The ability to identify genes that are causally involved in
disease risk provides an unparalleled opportunity to quickly determine biological pathways that are involved in
disease pathology. A better understanding of the genetic contribution to lipid variation and diabetes development
will provide novel approaches for the characterization, treatment and potential prevention of this costly disease.
Terms: <Adult-Onset Diabetes Mellitus><Affect><African American group><African American individual><African American people><African American population><African Americans><Age><Apo-B><ApoB><Apolipoproteins B><Apoplexy><Behavioral><Biological><Blindness><Blood Plasma><Body Tissues><Brain Vascular Accident><C-Peptide><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Characteristics><Chicanas><Chicanos><Cholesterol><Chromosome Mapping><Complex><Cost of Illness><Data><Developing Countries><Developing Nations><Development><Diabetes Mellitus><Diathesis><Disease><Disease Costs><Disease susceptibility><Disorder><Drug Targeting><Economic Burden><Epidemic><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology><Epidemiology Research><Ethnic Origin><Ethnicity><Family Study><Fatty Acids><Gene Localization><Gene Mapping><Gene Mapping Genetics><Gene variant><Genes><Genetic><Genetic Diversity><Genetic Markers><Genetic Variation><Genetic analyses><Genomics><Genotype><Groups at risk><HDL><HDL Lipoproteins><Hearing Loss><Heavy Lipoproteins><Heritability><Heterozygote><High Density Lipoproteins><High density lipoprotein><Hispanic Americans><Hispanic Populations><Hispanic group><Hispanic individual><Hispanic people><Hispanics><Human><Humulin R><Hypoacuses><Hypoacusis><Impairment><Individual><Individuals from minority><Individuals of minority><Insulin><Insulin Resistance><Ketosis-Resistant Diabetes Mellitus><Kidney Diseases><Kidney Failure><Kidney Insufficiency><LDL><LDL Lipoproteins><Less-Developed Countries><Less-Developed Nations><Life Style><Lifestyle><Linkage Mapping><Lipids><Lipoproteins><Low-Density Lipoproteins><Lower Extremity><Lower Limb><Maturity-Onset Diabetes Mellitus><Measures><Membrum inferius><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic syndrome><Methods><Mexican Americans><Minority Groups><Minority People><Minority Population><Minority individual><Modern Man><Modification><NAFLD><NIDDM><Nephropathy><Neuropathy><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Pathogenesis><Pathology><Pathway interactions><Pedigree><People at risk><Persons><Persons at risk><Phenotype><Phosphatides><Phospholipids><Plasma><Plasma Serum><Population><Populations at Risk><Predisposing Factor><Predisposition><Prevalence><Prevention><Proinsulin><Proteins><Public Health><QTL><Quantitative Genetics><Quantitative Trait Loci><Regular Insulin><Renal Disease><Renal Failure><Renal Insufficiency><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><SEQ-AN><Sampling><Sequence Analyses><Sequence Analysis><Sickness Cost><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stroke><Susceptibility><T2 DM><T2D><T2DM><Testing><Thesaurismosis><Third-World Countries><Third-World Nations><Tissues><Total Human and Non-Human Gene Mapping><Triacylglycerol><Triglycerides><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Under-Developed Countries><Under-Developed Nations><United States><Variant><Variation><Visit><adult onset diabetes><ages><allele variant><allelic variant><alpha-Lipoproteins><amputated limb><beta-Lipoproteins><biologic><brain attack><cardiac disease risk><cardiac disorder risk><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cerebral vascular accident><cerebrovascular accident><cohort><connecting peptide><design><designing><developing country><developing nation><developmental><diabetes><diabetes risk><discover genes><disease phenotype><disease risk><disorder risk><disparity in health><dysfunctional hearing><endophenotype><entire genome><epidemiologic><epidemiologic investigation><epidemiological><epidemiology study><ethnic minority group><ethnic minority individual><ethnic minority people><ethnic minority population><fasting glucose><fat metabolism><full genome><gene biomarker><gene discovery><gene expression biomarker><gene marker><gene signature biomarker><genetic analysis><genetic biomarker><genetic mapping><genetic pedigree><genetic variant><genome sequencing><genomic variant><health disparity><hearing challenged><hearing defect><hearing deficient><hearing deficit><hearing difficulty><hearing dysfunction><hearing impairment><heart disease risk><heart disorder risk><heterozygosity><iPS><iPSC><iPSCs><impaired glucose tolerance><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><insulin resistant><insulin secretion><insulin tolerance><ketosis resistant diabetes><kidney disorder><liability to disease><limb amputation><lipid metabolism><lipidome><lipidomics><maturity onset diabetes><metabolism disorder><neuropathic><new approaches><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel><novel approaches><novel strategies><novel strategy><particle><pathway><pedigree structure><renal disorder><sex><stroked><strokes><success><trait><type 2 DM><type II DM><type two diabetes><validation studies><variant of interest><vision loss><visual loss><whole genome>