TY - JOUR
T1 - Genome-Wide Association Study Identifies a Functional SIDT2 Variant Associated with HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease
AU - León-Mimila, Paola
AU - Villamil-Ramírez, Hugo
AU - MacÍas-Kauffer, Luis R.
AU - Jacobo-Albavera, Leonor
AU - López-Contreras, Blanca E.
AU - Posadas-Sánchez, Rosalinda
AU - Posadas-Romero, Carlos
AU - Romero-Hidalgo, Sandra
AU - Morán-Ramos, Sofía
AU - Domínguez-Pérez, Mayra
AU - Olivares-Arevalo, Marisol
AU - López-Montoya, Priscilla
AU - Nieto-Guerra, Roberto
AU - Acuña-Alonzo, Víctor
AU - MacÍn-Pérez, Gastón
AU - Barquera-Lozano, Rodrigo
AU - Del-Río-Navarro, Blanca E.
AU - González-González, Israel
AU - Campos-Pérez, Francisco
AU - Gómez-Pérez, Francisco
AU - Valdés, Victor J.
AU - Sampieri, Alicia
AU - Reyes-García, Juan G.
AU - Carrasco-Portugal, Miriam Del C.
AU - Flores-Murrieta, Francisco J.
AU - Aguilar-Salinas, Carlos A.
AU - Vargas-Alarcón, Gilberto
AU - Shih, DIana
AU - Meikle, Peter J.
AU - Calkin, Anna C.
AU - Drew, Brian G.
AU - Vaca, Luis
AU - Lusis, Aldons J.
AU - Huertas-Vazquez, Adriana
AU - Villarreal-Molina, Teresa
AU - Canizales-Quinteros, Samuel
N1 - Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Objective: Low 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 Results: A 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=5.9×10-18in 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. Conclusions: This 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.
AB - Objective: Low 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 Results: A 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=5.9×10-18in 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. Conclusions: This 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.
KW - cholesterol
KW - coronary artery disease
KW - dyslipidemias
KW - genetics
KW - genome
UR - http://www.scopus.com/inward/record.url?scp=85113784969&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.120.315391
DO - 10.1161/ATVBAHA.120.315391
M3 - Artículo
C2 - 34233476
AN - SCOPUS:85113784969
SN - 1079-5642
VL - 41
SP - 2494
EP - 2508
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 9
ER -