RESUMO
Introducción: Los triglicéridos se consideran un factor independiente de riesgo vascular. La influencia, por separado, de polimorfismos en genes como APOE, APOA5, LPL, LIPC y CETP sobre dichos niveles está descrita, por lo que resulta de interés su análisis conjunto y el estudio de interacciones con factores ambientales. Métodos: Se han genotipado en 1.825 sujetos (80% varones, edad media 36 años) procedentes del estudio ICARIA, el polimorfismo de APOE, 2 variantes de APOA5 (S19W y -1131 T/C), 5 deLPL (D9N, N291S, PvuII, HindIII y S447X), 1 de LIPC (-250G/A) y 1 de CETP (TaqI ) mediante PCR-restricción y ensayos TaqMan. El efecto conjunto de las variantes se ha analizado mediante regresión lineal con la variable triglicéridos transformada logarítmicamente y corrigiendo porcovariables. Las interacciones se han explorado mediante contrastes múltiples. Resultados: El alelo 4 de APOE, los polimorfismos de APOA5 S19W y -1131T/C y las variantes de LPL, D9N y N291S mostraron un efecto elevador de triglicéridos significativo e independiente. Los polimorfismos HindIII y S447X de LPL se asociaron significativamente con una reducción de los niveles de TG. Las variantes PvuII (LPL), -250G/A (LIPC) y TaqI (CETP) no mostraron asociaciones significativas. Se encontró una tendencia estadística (p=0,048) para la interacción entre obesidad abdominal (perímetro de cintura >102 cm en hombres; >88 cm en mujeres) y elalelo APOE- 4 (AU)
Introduction: Triglyceride levels are considered to be an independent vascular risk factor. The influence of polymorphisms in genes such as APOE, APOA5, LPL, LIPC and CETP on these levels has been separately described. The aim of the present study was to analyze the combined effects of these polymorphisms and their interaction with environmental factors. Methods: We genotyped the APOE polymorphism, two variants of APOA5 (S19W and -1131 T/C),five of LPL (D9N, N291S, PvuII, HindIII and S447X), one of LIPC (-250G/A) and one of CETP (TaqI )by polymerase chain reaction-restriction and TaqMan assays in 1825 subjects (80% male, meanage 36 years) from the ICARIA study. The combined effect of the variants was analyzed by linear regression with the log-transformed triglyceride variable and adjustment for covariates. The interactions were explored by multiple comparisons. Results: The 4 allele of APOE, the APOA5 polymorphisms S19W and -1131T/C and the LPL variants D9N and N291S independently and significantly increased triglyceride levels. The HindIII and S447X LPL polymorphisms were significantly associated with lower triglyceride levels. The PvuII (LPL), -250G/A (LIPC) and TaqI (CETP) variants showed no significant associations. There was a statistical trend (p = 0.048) for an interaction between abdominal obesity (waist circumference >102 cm in men and >88 cm in women) and the APOE- 4 allele. Conclusions: Our study shows the influence of the APOE- 4 allele, the S19W and -1131T/Cpolymorphisms of APOA5 and the LPL-D9N, N291S, HindIII and S447X variants on triglyceride levels and suggests that the effect of the 4 allele could by modulated by interaction with abdominal obesity (AU)
Assuntos
Humanos , Triglicerídeos , Obesidade Mórbida/genética , Variação Genética , Alelos , GenótipoRESUMO
BACKGROUND: Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. METHODS: A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG > or = 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. RESULTS: We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-epsilon4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; p < 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; p < 0.001) were associated with HTG. CONCLUSION: Our results showed a significant independent additive effect on TG levels of the LPL polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of APOA5, and the epsilon4 allele of APOE in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.