Additive effects of LPL, APOA5 and APOEvariant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

Abstract

BackgroundHypertriglyceridemia (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.MethodsA 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 ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption.ResultsWe 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-ε4 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.ConclusionOur 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 ε4 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.

The lipoprotein lipase S447X and cholesteryl ester transfer protein rs5882 polymorphisms and their relationship with lipid profile in human serum of obese individuals

“…These findings are in line with previous studies (Huang et al, 2006;Ariza et al, 2010). Moreover, our data showed that subjects with LPL GG or GC genotypes had ORs of 0.14 (95% CI = 0.01-1.23) or 0.77(95% CI: 0.41-1.42), although this effect was not statistically significant in our population, which is in agreement with previous studies (Smart et al, 2010;Gagne et al, 1999).…”

Synergistic effects of genetic variants of APOA5 and BTN2A1 on dyslipidemia or metabolic syndrome

“…Genetic variants of APOA5 (rs662799) and APOE (rs429358, rs7412) synergistically affected serum concentrations of triglycerides (29). In simultaneous analysis of four polymorphisms of LPL (rs320, rs328, rs1801177, rs268), two polymorphisms of APOA5 (rs662799, rs3135506), and two polymorphisms of APOE (rs429358, rs7412), serum concentrations of triglycerides were significantly increased in individuals with two or three triglycerides-raising alleles among these polymorphisms (30). In addition, environmental factors, including a high-fat and high-calorie diet and physical inactivity, may affect gene-gene interactions as well as the development of dyslipidemia (31,32).…”

“…Previous studies suggested that the effect of rs662799 of APOA5 on the regulation of serum triglycerides was modulated by other genetic and environmental factors (29)(30)(31)(32). Genetic variants of APOA5 (rs662799) and APOE (rs429358, rs7412) synergistically affected serum concentrations of triglycerides (29).…”

Peripheral arterial disease, type 2 diabetes and postprandial lipidaemia: Is there a link?

“…These steps are all modulated by the levels and genetic variants of the apolipoproteins like C-Ⅱ, C-Ⅲ, E, A-5 [82,83] . As persons with arteriosclerosis, particularly those with PAD, have a marked endothelial dysfunction [84] , it is possible to speculate that the action of an enzyme anchored to the endothelium, as is the case of lipoprotein lipase (LPL), is reduced.…”