RESUMEN
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=5.9×10−18 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. 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.
Asunto(s)
HDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/genética , Hiperlipoproteinemia Tipo II/genética , Proteínas de Transporte de Nucleótidos/genética , Polimorfismo de Nucleótido Simple , Adulto , Edad de Inicio , Animales , Biomarcadores/sangre , Estudios de Casos y Controles , Niño , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Células HEK293 , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Masculino , Análisis de la Aleatorización Mendeliana , México/epidemiología , Ratones , Persona de Mediana Edad , Proteínas de Transporte de Nucleótidos/metabolismo , Fenotipo , Medición de RiesgoRESUMEN
Obesity is a risk factor for the development of anterior abdominal wall hernias. Incisional hernias develop in up to 13% of laparotomies: the most difficult to repair are complex and multiple recurrent hernias with significant loss of control. The best approach to treating obese patients who concomitantly have hernias of the anterior abdominal wall is still a matter of debate. We present a clinical case of a patient with morbid obesity and abdominal hernia with loss of residence, who underwent bariatric surgery before ventral plasty.
La obesidad es un factor de riesgo para el desarrollo de hernias de la pared abdominal anterior. Las hernias incisionales se desarrollan hasta en el 13% de las laparotomías. Las más difíciles de reparar son las hernias recurrentes complejas y múltiples con pérdida significativa de domicilio. El mejor enfoque en el tratamiento de pacientes obesos y que concomitantemente tienen hernias de la pared abdominal anterior es aún un tema de debate. Presentamos el caso clínico de un paciente con obesidad mórbida y hernia abdominal con pérdida de domicilio, intervenido de cirugía bariatrica antes de la plastia ventral.