👤 Javier Delgado-Lista

Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases. Show less

rs964184 variant in the ZPR1 gene has been associated with blood lipids levels both in fasting and postprandial state and with the risk of myocardial infarction in high-risk cardiovascular patients. However, whether this association is modulated by diet has not been studied. To investigate whether the type of diet (low-fat or Mediterranean diets) interacts with genetic variability at this loci to modulate fasting and postprandial lipids in coronary patients. The genotype of the rs964184 polymorphism was determined in the Cordioprev Study population (NCT00924937). Fasting and Postprandial triglycerides were assessed before and after 3 years of dietary intervention with either a Mediterranean or a low-fat diet. Postprandial lipid assessment was done by a 4-h oral fat tolerance test (OFTT). Differences in triglycerides levels were identified using repeated-measures ANCOVA. From 523 patients (85% males, mean age 59 years) that completed the OFTT at baseline and after 3 years of intervention and had complete genotype information, 125 of them were carriers of the risk allele G. At the start of the study, these patients showed a higher fasting and postprandial triglycerides (TG) plasma levels. After 3 years of dietary intervention, G-carriers following a Mediterranean Diet maintained higher fasting and postprandial triglycerides, while those on the low-fat diet reduced their postprandial triglycerides to similar values to the population without the G-allele. After 3 years of dietary intervention, the altered postprandial triglyceride response induced by genetic variability in the rs964184 polymorphism of the ZPR1 gene can be modulated by a low-fat diet, better than by a Mediterranean diet, in patients with coronary artery disease. Show less

The cholesteryl ester transfer protein (CETP) gene has been implicated in high-density lipoprotein (HDL-C) metabolism. However, little is known about the impact of this gene on metabolic syndrome (MetS) patients and its interaction with diet. Here, we evaluate whether the consumption of a Mediterranean diet, compared with a Low-fat diet, interacts with the rs3764261 SNP at the CETP locus to modify lipid metabolism in MetS patients. Plasma lipid concentrations and rs3764261 genotypes were determined in 424 MetS subjects participating in the CORDIOPREV clinical trial (NCT00924937). Gene-diet interactions were analyzed after a year of dietary intervention (Mediterranean diet (35% fat, 22% MUFA) vs Low-fat diet (28% fat, 12% MUFA)). We found significant gene-diet interactions between rs3764261 SNP and the dietary pattern for HDL-C (P = 0.006) and triglyceride concentrations (P = 0.040). Specifically, after 12 months of Mediterranean diet intervention, subjects who were carriers of the minor T allele (TT + TG) displayed higher plasma HDL-C concentrations (P = 0.021) and lower triglycerides (P = 0.020) compared with those who were homozygous for the major allele (GG). In contrast, in the Low-fat intervention group, no significant differences were found between CETP genotypes after 12 months of dietary treatment. Our data support the notion that the consumption of a Mediterranean diet may play a contributing role in triggering lipid metabolism by interacting with the rs3764261 SNP at CETP gene locus in MetS patients. Due to the complex nature of gene-environment interactions, dietary adjustment in MetS patients may require a personalized approach. Show less

To determine whether the insulin resistance that exists in metabolic syndrome (MetS) patients is modulated by dietary fat composition. Seventy-five patients were randomly assigned to one of four diets for 12 wk: high-saturated fatty acids (HSFAs), high-MUFA (HMUFA), and two low-fat, high-complex carbohydrate (LFHCC) diets supplemented with long-chain n-3 (LFHCC n-3) PUFA or placebo. At the end of intervention, the LFHCC n-3 diet reduced plasma insulin, homeostasis model assessment of insulin resistance, and nonsterified fatty acid concentration (p < 0.05) as compared to baseline Spanish habitual (BSH) diet. Subcutaneous white adipose tissue (WAT) analysis revealed decreased EH-domain containing-2 mRNA levels and increased cbl-associated protein gene expression with the LFHCC n-3 compared to HSFA and HMUFA diets, respectively (p < 0.05). Moreover, the LFHCC n-3 decreased gene expression of glyceraldehyde-3-phosphate dehydrogenase with respect to HMUFA and BSH diets (p < 0.05). Finally, proteomic characterization of subcutaneous WAT identified three proteins of glucose metabolism downregulated by the LFHCC n-3 diet, including annexin A2. RT-PCR analysis confirmed the decrease of annexin A2 (p = 0.027) after this diet. Our data suggest that the LFHCC n-3 diet reduces systemic insulin resistance and improves insulin signaling in subcutaneous WAT of MetS patients compared to HSFA and BSH diets consumption. Show less

Accumulating evidence suggests that elevated plasma triglycerides concentrations, in both the fasting and the postprandial states, may pose a significant independent risk for cardiovascular disease (CVD). Both fasting and postprandial lipoprotein concentrations vary substantially among individuals, and this inter individual variability is driven by a combination of non-genetic and genetic factors. Regarding the genetic component, the efforts to elucidate the variability in postprandial response have resulted in the identification of associations with multiple lipid candidate genes. However, most reported associations are based on very simple models including one single-nucleotide polymorphism (SNP) or haplotype at a time and small sample sizes. Progress in this promising area of research requires more comprehensive experimental models, including larger sample sizes that will allow investigating gene-gene interactions. Reviews of the literature in the area of ApoA5, GCKR, and PLIN genes and postprandial lipemia are used to demonstrate the complexities of genotype-phenotype associations. Knowledge of how these and other genes influence postprandial response should increase the understanding of personalised nutrition. Show less

We investigated whether APOA1 and APOA4 genotypes interact with diet to determine changes in LDL size and their susceptibility to oxidative modifications. A total of 97 healthy volunteers each consumed 3 diets for 4 wk: a SFA diet (38% fat, 20% SFA) followed by a low-fat and high-carbohydrate (CHO) diet (30% fat, 55% carbohydrate) or a monounsaturated fatty acid (MUFA) diet (38% fat, 22% MUFA) following a randomized crossover design. For each diet, we determined susceptibility to oxidative modifications and LDL size. To investigate the combined effects of the APOA1 G-76A and APOA4 Thr347Ser single nucleotide polymorphisms (SNP), we defined 4 combined genotype groups: GG/ThrThr, GG/ThrSer, GA/ThrThr, and GA/ThrSer. After participants consumed the CHO diet, there was a significant decrease in LDL size with respect to high-fat diets in GG homozygotes for the APOA1 G-76A SNP. However, LDL size did not differ in GA carriers among participants consuming the 3 diets. Carriers of the A allele for this polymorphism had smaller LDL size as well as increased susceptibility to oxidation after the SFA diet than the GG homozygous. Moreover, the interaction between the APO A1 and APOA4 genotypes revealed that individuals with the GA/ThrSer genotype had larger LDL particle size during consumption of the MUFA diet than when they consumed the CHO diet. No differences in LDL oxidation were found in this analysis. Our study supports the concept that SNP in APOA1and APOA4 genes influences atherogenic characteristics of LDL particles in response to diet. Show less

The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092), and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 h after the meal. Total cholesterol and fractions [HDL-cholesterol, LDL-cholesterol, trifacylglycerols (TGs) in plasma, TG-rich lipoproteins (TRLs) (large TRLs and small TRLs), apolipoprotein A-I and apolipoprotein B] were determined. APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics but not its magnitude. We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism. Show less

Apolipoprotein A5 (APOA5) plays an important role in plasma triacylglycerol (TG) homeostasis. Five polymorphisms (1131T>C, c.-3A>G, c.56C>G, IVS3+476G>A, and c.1259T>C) in the APOA5 gene define three common haplotypes (APOA5*1, APOA5*2, and APOA5*3) in Caucasian individuals. Our aim was to determine whether these haplotypes could modulate the postprandial response in young healthy males. Eighty-eight APO E3/3 volunteers [67 with (-1131T and 56C) APOA5*1 haplotype, 12 with (-1131C and 56C) APOA5*2 haplotype, and nine with (-1131T and 56G) APOA5*3 haplotype] underwent a fat load test consisting of the consumption of 1 g of fat per kilogram body weight and 60,000 IU vitamin A. Blood samples were taken at time 0, at every hour until the sixth hour, and at every 2.5 h until the 11th hour. Total plasma cholesterol (C) and TG, and C, TG, apolipoprotein B-100, apolipoprotein B-48, and retinyl palmitate in lipoprotein fractions were determined. Subjects with the APOA5*2 and APOA5*3 haplotypes had a higher area under the curve of total plasma TG (P = 0.03), large TG-rich lipoprotein (TRL)-TG (P = 0.02), small TRL-TG (P = 0.04), small TRL-C (P = 0.04), large TRL-C (P = 0.03), and small apolipoprotein B100 (P = 0.04) than subjects with the APOA5*1 haplotype. Our findings show that the presence of the APOA5*2 and APOA5*3 haplotypes in the APOA5 gene is associated with a higher postprandial response that could be involved in the higher risk of coronary heart disease associated with the 56G and -1131C alleles. Show less