Genetic Determinants of Cardiovascular-Kidney-Metabolic Syndrome - ABSTRACT Cardiac, kidney, and metabolic conditions, including cardiovascular disease, chronic kidney disease, and type 2 diabetes, are leading causes of morbidity and mortality in the United States and affect individuals from all backgrounds. These interconnected conditions, recently recognized as cardiovascular-kidney-metabolic (CKM) syndrome, share pathophysiology and risk factors, including dysfunctional adiposity, dysglycemia, dyslipidemia, ectopic lipid deposition, and hypertension. Native Hawaiians and Pacific Islanders (NHPI), who have among the world's highest burden of metabolic disease, are at disproportionally higher risk for other associated comorbidities, including CKD and CVD, and also have among the world's highest burden of CKM syndrome. The Utah Pacific Islander Study (UPIS) was implemented to better understand the basis of CKM syndrome in NHPI. With community support, more than 800 participants with extensive phenotypic information were enrolled into the UPIS within a 20-month period. Ongoing genetic and multi-omics analyses have already identified a population-specific variant in the ASAH2 gene that is associated with diabetes and kidney disease risk in NHPI. In addition, we have observed a recently identified NHPI population-specific variant in ACADVL that is associated with CKM risk factors. Leveraging long-read whole-genome sequences (WGS) from UPIS participants from 8 islands across the Pacific, we created the first NHPI Pangenome Reference to vastly improve genetic analyses in this population, including the identification of novel structural variation. The overall goal of this proposal is to leverage these experiences and resources to further advance understanding of the genetic basis of CKM syndrome. Specific Aim 1 will expand the already existing biorepository of deeply phenotyped NHPI individuals across the CKM syndrome spectrum to >1,800 NHPI individuals, archive biospecimens (plasma, serum, urine, DNA, RNA, and peripheral blood mononuclear cells (PBMCs)) from participants of the UPIS and perform WGS in 1,000 newly recruited UPIS participants. Specific Aim 2 will assess the contribution of genetic factors to CKM syndrome risk by conducting genotype-based discovery and replication analyses using state-of-the-art methodologies, including pangenome-based variant discovery using our Pacific Ancestry Pangenome Reference and an NHPI imputation reference panel, and cohorts totaling >20,000 NHPI. Specific Aim 3 will advance the functional and mechanistic assessment of genetic variants in NHPI with CKM syndrome using variant gene editing in differentiated human induced pluripotent stem cells derived from PBMCs from ASAH2 and ACADVL variant carriers and functionally characterize the consequence of the observed alleles. This project will advance our understanding of the basis of CKM syndrome. This research will provide a solid foundation for future efforts aimed at elucidating the mechanisms behind the disparity of CKM syndrome in NHPI, facilitate translation of these findings to improved diagnostics and therapeutics, and facilitate additional studies on risk factors, both genetic and non-genetic, that contribute to the burden of CKM syndrome for all at risk individuals in the US.
