RESUMEN

Genetic variants of the POMC and PCSK1 genes cause severe obesity among patients in the early stages of childhood. This family-based study analyzed the links between single nucleotide polymorphisms (SNPs) in either the POMC or PCSK1 genes and obesity, as well as obesity-related traits among obese Thai children and their families. The variants rs1042571 and rs6713532 in the POMC gene in a sample of 83 obese children and their family members were investigated using polymerase chain reaction (PCR)-restriction fragment length polymorphism. In addition, the SNPs rs6232, rs155971, rs3762986, rs3811942, and rs371897784 of PCSK1 were analyzed in all samples using PCR and gene sequencing methods. Participants with the homozygous variant genotype in rs155971 had significantly elevated cholesterol and low-density lipoprotein cholesterol (LDL-C) levels (P = 0.011, OR = 1.025, 95%CI = 1.006-1.045; and P = 0.006, OR = 1.030, 95%CI = 1.009-1.053, respectively) after adjustment for age, gender, and body mass index (BMI). In addition, patients with the heterozygous variant genotype in rs371897784 of PCSK1 had a 1.249- fold higher risk (95%CI = 1.081-1.444, P = 0.027) of increased waist circumference than patients with the normal genotype, after adjustment for age, gender, and BMI. However, this analysis did not find any correlation between obesity and SNPs in PCSK1 and POMC. Therefore, these common variants in PCSK1 and POMC were not the major cause of obesity in the Thai subjects sampled. However, variants in PCSK1 did affect cholesterol level, LDL-C level, and waist circumference.

Asunto(s)

Estudios de Asociación Genética , Obesidad/genética , Proopiomelanocortina/genética , Proproteína Convertasa 1/genética , Pueblo Asiatico/genética , Índice de Masa Corporal , Niño , LDL-Colesterol/sangre , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Obesidad/sangre , Obesidad/patología , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Circunferencia de la Cintura

RESUMEN

BACKGROUND: Bariatric surgery is the most effective therapeutic option for obesity and its complications, especially in type 2 diabetes. The aim of this study was to investigate the messenger RNA (mRNA) gene expression of proglucagon, glucose-dependent insulinotropic peptide (GIP), prohormone convertase 1/3 (PC1/3), and dipeptidyl peptidase-IV (DPP-IV) in jejunum cells of the morbidly obese (OB) non type 2 diabetes mellitus (NDM2) and type 2 diabetes mellitus (T2DM), to determine the molecular basis of incretin secretion after bariatric surgery. METHODS: Samples of jejunal mucosa were obtained from 20 NDM2 patients: removal of a section of the jejunum about 60 cm distal to the ligament of Treitz and 18 T2DM patients: removal of a section of the jejunum about 100 cm distal to the ligament of Treitz. Total RNA was extracted using TRIzol. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was carried out. Samples were sequenced to PC1/3 by ACTGene Análises Moleculares Ltd. Immuno content was quantified with a fluorescence microscope. RESULTS: T2DM showed decreased PC1/3 mRNA expression in the primers tested (primer a, p=0.014; primer b, p=0.048). Many patients (36.5 %) did not express PC1/3 mRNA. NDM2 and T2DM subjects showed nonsignificantly different proglucagon, GIP, and DPP-IV mRNA expression. The immuno contents of glucagon-like peptide-1 and GIP decreased in T2DM jejunum, but incubation with high glucose stimulated the immuno contents. CONCLUSIONS: The results suggest that bioactivation of pro-GIP and proglucagon could be impaired by the lower expression of PC1/3 mRNA in jejunum cells of obese patients with T2DM. However, after surgery, food could activate this system and improve glucose levels in these patients.

Asunto(s)

Diabetes Mellitus Tipo 2/metabolismo , Yeyuno/metabolismo , Obesidad Mórbida/metabolismo , Proproteína Convertasa 1/metabolismo , Adulto , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/complicaciones , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Femenino , Polipéptido Inhibidor Gástrico/genética , Polipéptido Inhibidor Gástrico/metabolismo , Regulación de la Expresión Génica , Péptido 1 Similar al Glucagón/genética , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/complicaciones , Proproteína Convertasa 1/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa

RESUMEN

BACKGROUND: Common variants rs6232 and rs6235 in the PCSK1 gene have been associated with obesity in European populations. We aimed to evaluate the contribution of these variants to obesity and related traits in Mexican children and adults. METHODOLOGY/PRINCIPAL FINDINGS: Rs6232 and rs6235 were genotyped in 2382 individuals, 1206 children and 1176 adults. Minor allele frequencies were 0.78% for rs6232 and 19.99% for rs6235. Rs6232 was significantly associated with childhood obesity and adult class III obesity (OR = 3.01 95%CI 1.64-5.53; P = 4 × 10⁻4 in the combined analysis). In addition, this SNP was significantly associated with lower fasting glucose levels (P = 0.01) and with increased insulin levels and HOMA-B (P = 0.05 and 0.01, respectively) only in non-obese children. In contrast, rs6235 showed no significant association with obesity or with glucose homeostasis parameters in any group. CONCLUSION/SIGNIFICANCE: Although rs6232 is rare in the Mexican population, it should be considered as an important risk factor for extreme forms of obesity.

Asunto(s)

Genotipo , Obesidad/genética , Polimorfismo de Nucleótido Simple , Proproteína Convertasa 1/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Niño , Preescolar , Femenino , Frecuencia de los Genes , Glucosa/metabolismo , Homeostasis , Humanos , México , Persona de Mediana Edad , Prevalencia , Factores de Riesgo