1. Genome-Wide Association Study Identifies a Functional SIDT2 Variant Associated With HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease
- Author
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León-Mimila, Paola, Villamil-Ramírez, Hugo, Macías-Kauffer, Luis R, Jacobo-Albavera, Leonor, López-Contreras, Blanca E, Posadas-Sánchez, Rosalinda, Posadas-Romero, Carlos, Romero-Hidalgo, Sandra, Morán-Ramos, Sofía, Domínguez-Pérez, Mayra, Olivares-Arevalo, Marisol, López-Montoya, Priscilla, Nieto-Guerra, Roberto, Acuña-Alonzo, Víctor, Macín-Pérez, Gastón, Barquera-Lozano, Rodrigo, Del-Río-Navarro, Blanca E, González-González, Israel, Campos-Pérez, Francisco, Gómez-Pérez, Francisco, Valdés, Victor J, Sampieri, Alicia, Reyes-García, Juan G, del C. Carrasco-Portugal, Miriam, Flores-Murrieta, Francisco J, Aguilar-Salinas, Carlos A, Vargas-Alarcón, Gilberto, Shih, Diana, Meikle, Peter J, Calkin, Anna C, Drew, Brian G, Vaca, Luis, Lusis, Aldons J, Huertas-Vazquez, Adriana, Villarreal-Molina, Teresa, and Canizales-Quinteros, Samuel
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Heart Disease - Coronary Heart Disease ,Human Genome ,Heart Disease ,Minority Health ,Genetics ,Atherosclerosis ,Biotechnology ,Clinical Research ,Prevention ,Cardiovascular ,2.1 Biological and endogenous factors ,Adult ,Age of Onset ,Animals ,Biomarkers ,Case-Control Studies ,Child ,Cholesterol ,HDL ,Coronary Artery Disease ,Disease Models ,Animal ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,HEK293 Cells ,Heart Disease Risk Factors ,Humans ,Hyperlipoproteinemia Type II ,Male ,Mendelian Randomization Analysis ,Mexico ,Mice ,Middle Aged ,Nucleotide Transport Proteins ,Phenotype ,Polymorphism ,Single Nucleotide ,Risk Assessment ,cholesterol ,coronary artery disease ,dyslipidemias ,genetics ,genome ,Cardiorespiratory Medicine and Haematology ,Cardiovascular System & Hematology ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
ObjectiveLow HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population.Approach and resultsA genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism.ConclusionsThis is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.
- Published
- 2021