Search

Background: Genetic risk scores (GRSs) have partially improved the understanding of the etiology of moderate hypertriglyceridemia (HTG), which until recently was mainly assessed by secondary predisposing causes. The main objective of this study was to assess whether this variability is due to the interaction between clinical variables and GRS. Methods: We analyzed 276 patients with suspected polygenic HTG. An unweighted GRS was developed with the following variants: c.724C > G (ZPR1 gene), c.56C > G (APOA5 gene), c.1337T > C (GCKR gene), g.19986711A > G (LPL gene), c.107 + 1647T > C (BAZ1B gene) and g.125478730A > T (TRIB gene). Interactions between the GRS and clinical variables (body mass index (BMI), diabetes mellitus, diet, physical activity, alcohol consumption, age and gender) were evaluated. Results: The GRS was associated with triglyceride (TG) concentrations. There was a significant interaction between BMI and GRS, with the intensity of the relationship between the number of alleles and the TG concentration being greater in individuals with a higher BMI. Conclusions: GRS is associated with plasma TG concentrations and is markedly influenced by BMI. This finding could improve the stratification of patients with a high genetic risk for HTG who could benefit from more intensive healthcare interventions.

ObjectiveSLE is associated with increased cardiovascular risk (CVR). High serum concentrations of triglyceride-rich lipoproteins and apolipoprotein B-rich particles constitute the characteristic dyslipidaemia of SLE.MethodsA cross-sectional study was conducted to study the relationship between genetic variants involved in polygenic hypertriglyceridaemia, subclinical atherosclerosis and lipoprotein abnormalities. 73 women with SLE and 73 control women age-matched with the case group were recruited (age range 30–75 years). Serum analysis, subclinical atherosclerosis screening studies for the detection of plaque, and genetic analysis of the APOE, ZPR1, APOA5 and GCKR genes were performed.ResultsTriglyceride concentrations and the prevalence of hypertension, dyslipidaemia and carotid atherosclerosis were higher in women with SLE than in the control group. Multivariate logistic regression showed that CC homozygosity for the GCKR rs1260326 gene (OR=0.111, 95% CI 0.015 to 0.804, p=0.030) and an increase of 1 mmol/L in triglyceride concentrations were associated with a greater risk of carotid plaque in women with SLE (OR=7.576, 95% CI 2.415 to 23.767, p=0.001).ConclusionsGCKR CC homozygosity (rs1260326) and serum triglyceride concentrations are independently associated with subclinical carotid atherosclerosis in women with SLE. Subclinical carotid atherosclerosis is also more prevalent in these women compared with the control group. The study of GCKR rs1260326 gene variants may contribute to more precise assessment of CVR and modulation of the intensity of lipid-lowering treatment in patients with SLE.

Diagnosis and treatment of triglyceride metabolism disorders: from pathophysiology to clinical practice. Hypertriglyceridaemia (HTG) affects 15%-20% of the world's population, and is frequently discovered as an incidental finding in a laboratory test. Disorders of triglyceride (TG) metabolism have a complex genetic basis. New genetic tools that allow a more precise approach to the disorders have made it possible to redefine and classify HTG into two groups: monogenic HTG (TG10 mmol/L) and polygenic HTG (2 mmol/LTG10 mmol/L) with a milder phenotype, but with a clear genetic influence. In approximately 50% of patients with severe HTG a genetic cause has not yet been found. In addition to the inclusion of ever more genes in studies, statistical models are now also being examined that consider complex gene-environment interactions that could explain why the presence of a set of apparently benign variants may cause HTG in the presence of a triggering factor such as adiposity. Knowledge of the genetic nature of HTG has also helped identify targets for pharmacological treatments, thus avoiding a strict diet with a fat content of less than 20%, which is difficult to maintain. Accurate diagnosis of these disorders is essential for correct treatment according to the inherent risk of each HTG, since, as has been shown in multiple studies, high fasting and postprandial TG concentrations are an independent risk factor for cardiovascular disease.

Background: Lipid metabolism disorders, especially hypertriglyceridemia (HTG), are risk factors for non-alcoholic fatty liver disease (NAFLD). However, the association between genetic factors related to HTG and the risk of NAFLD has been scarcely studied. Methods: A total of 185 subjects with moderate HTG were prospectively included. We investigated the association between genetic factors’ (five allelic variants with polygenic hypertriglyceridemia) clinical and biochemical biomarkers with NAFLD severity. The five allelic variants’ related clinical and biochemical data of HTG were studied in all the subjects. NAFLD was assessed by abdominal ultrasound and patients were divided into two groups, one with no or mild NAFLD and another with moderate/severe NAFLD. Results: Patients with moderate/severe NAFLD had higher weight and waist values and a higher prevalence of insulin resistance than patients with no or mild NAFLD. Moderate/severe NAFLD was independently associated with APOA5 rs3134406 and ZPR1 rs964184 variants, and also showed a significant inverse relationship with lipoprotein(a) [Lp(a)] concentrations. Conclusions: APOA5 rs3135506 and ZPR1 rs964184 variants and lipoprotein(a) are associated with moderate/severe NAFLD. This association was independent of body weight, insulin resistance, and other factors related to NAFLD. info:eu-repo/semantics/publishedVersion

This document describes the application of the syntax, semantic rules, and format of the Nomenclature for Properties and Units (NPU) terminology for coded dedicated kinds-of-property in the subject field of clinical molecular genetics. A vocabulary for NPU definitions in this field, based on international terminology and nomenclature, is introduced; examples of actual NPU definitions for different types of investigations are given and explained.

International audience; Background LDL-C lowering is the main measure in cardiovascular disease prevention but a residual risk of ischemic events still remains. Alterations of lipoproteins, specially, increase in small dense LDL (sdLDL) particles are related to this risk.Objective To investigate the potential use of sdLDL cholesterol concentration (sdLDL-C) isolated by an easy precipitation method and to assess the impact of a set of clinical and biochemical variables determined by NMR on sdLDL concentration.Methods sdLDL-C and NMR lipid profile were performed in 85 men samples. Association among them was evaluated using Pearson coefficients (r(xy)). A multivariate regression was performed to identify the influence of NMR variables on sdLDL-C.Results A strong association between sdLDL-C and LDLLDL-P (r(xy) = 0.687) and with LDL-Z (r(xy) = -0.603) was found. The multivariate regression explained a 56.8% in sdLDL-C variation (P = 8.77.10-12). BMI, ApoB, triglycerides, FFA, and LDL-Z showed a significant contribution. The most important ones were ApoB and LDL-Z; a 1nm increase (LDL-Z) leads to decrease 126 nmol/L in sdLDL-C.Conclusion The association between sdLDL-C, LDL-Z, and LDL-P is clear. From a large number of variables, especially LDL-Z and apoB influence on sdLDL-C. Results show that the smaller the LDL size, the higher their cholesterol concentration. Therefore, sdLDL-C determination by using this easy method would be useful to risk stratification and to uncover cardiovascular residual risk.Background LDL-C lowering is the main measure in cardiovascular disease prevention but a residual risk of ischemic events still remains. Alterations of lipoproteins, specially, increase in small dense LDL (sdLDL) particles are related to this risk.Objective To investigate the potential use of sdLDL cholesterol concentration (sdLDL-C) isolated by an easy precipitation method and to assess the impact of a set of clinical and biochemical variables determined by NMR on sdLDL concentration.Methods sdLDL-C and NMR lipid profile were performed in 85 men samples. Association among them was evaluated using Pearson coefficients (r(xy)). A multivariate regression was performed to identify the influence of NMR variables on sdLDL-C.Results A strong association between sdLDL-C and LDLLDL-P (r(xy) = 0.687) and with LDL-Z (r(xy) = -0.603) was found. The multivariate regression explained a 56.8% in sdLDL-C variation (P = 8.77.10-12). BMI, ApoB, triglycerides, FFA, and LDL-Z showed a significant contribution. The most important ones were ApoB and LDL-Z; a 1nm increase (LDL-Z) leads to decrease 126 nmol/L in sdLDL-C.Conclusion The association between sdLDL-C, LDL-Z, and LDL-P is clear. From a large number of variables, especially LDL-Z and apoB influence on sdLDL-C. Results show that the smaller the LDL size, the higher their cholesterol concentration. Therefore, sdLDL-C determination by using this easy method would be useful to risk stratification and to uncover cardiovascular residual risk.

Statin therapy response is highly variable. Variants of lipid metabolism genes and statin pharmacokinetic modulators could play a role, however, the impact of most of these variants remains unconfirmed. A prospective and multicenter study included 252 patients was carried out in order to assess, according to achievement of LDL-C or non-HDL-C therapeutic targets and quantitative changes in lipid profiles, the impact of CETP, ABCA1, CYP2D6, and CYP2C9 gene candidate variants on the simvastatin, atorvastatin, and rosuvastatin response. Patients carrier ABCA1 rs2230806 and CYP2D6*3 variants are less likely to achieve therapeutic lipid targets (p = 0.020, OR = 0.59 [0.37, 0.93]; p = 0.040, OR = 0.23 [0.05, 0.93], respectively). Among CETP variants, rs708272 was linked to a 10.56% smaller reduction in LDL-C with rosuvastatin (95% CI = [1.27, 19.86] %; p = 0.028). In contrast, carriers of rs5882 had a 13.33% greater reduction in LDL-C (95% CI = [25.38, 1.28]; p = 0.032). If these findings are confirmed, ABCA1, CYP2D6, and CETP genotyping could be used to help predict which statin and dosage is appropriate in order to improve personalized medicine.

INTRODUCTION Most of the cost-effectiveness analyses are based on estimations to make decisions on the future implementation of a test. However, the model should be verified with real data to prove that previous estimations have been successfully fulfilled. OBJECTIVE To study the economic impact of the systematic HLA-B*57:01 genotyping in preventing hypersensitivity reactions (HSRs) in the patient population of a tertiary-care hospital treated with abacavir (ABC) using retrospective data of 5 years of experience. METHODS A retrospective study was carried out with two cohorts including 780 and 473 patients before and after the implementation of the systematic HLA-B*57:01 genotyping before ABC treatment. Cost-effectiveness analysis was carried out by the parameter 'cost per HSR avoided'. The clinical utility of the test was verified by evaluating the differences in HSR incidence between both cohorts. Finally, a sensitivity analysis including all variables was carried out. RESULTS In the population studied, systematic genotyping represents an additional cost of O306 per HSR avoided. In the sensitivity analysis, pharmacological therapy cost is the major influencing factor found in the estimation of the 'cost per HSR avoided'. In terms of clinical utility, the incidence ratio was 0.040 (95% confidence interval 0.0009-0.2399) and statistically significant differences were found between both groups (P=1.40×10). CONCLUSION Retrospective data from 5 years of experience have confirmed the cost-effectiveness of the systematic genotyping in candidate patients for ABC therapy, and have shown that cost-effectiveness is a dynamic parameter closely linked to allele prevalence and pharmacological therapy costs.

Background Patients with dyslipidemia are often treated with statins to reduce lipids and hence cardiovascular risk, but treatment response is variable, partly due to genetic factors. Methods We studied the influence of 6 gene variants (APOE c.526C > T (APOE2), APOE c.388T > C (APOE4), SLCO1B1 c.521T > C, CYP3A4 c.-392G > A, HMGCR c.1564-106A > G, and LPA c.3947 + 467T > C) on statin efficacy assessing 2 indicators: the percent reduction in total cholesterol (TC) and non-HDL cholesterol (non-HDL), as well as the achievement of therapeutic goals. The study was performed in a group of patients (n = 100) without previous pharmacological treatment. Multiple regression models were used to calculate the percentage of explanation in response variability added by every variant to a basal model constructed with significant nongenetic control variables. Results The most influential variant was HMGCR c.1564-106A > G (rs3846662), and carriers showed a significantly lower reduction in TC and non-HDL. This variant is related to an alternative splicing involving exon 13, which is also regulated by lipid concentrations in patients without the variant. Concerning therapeutic goals, HMGCR c.1564-106A > G hindered the achievement of TC targets on patients. Conclusions The HMGCR c.1564-106A > G variant was associated with less statin efficacy to decrease cholesterol.

Bárbara Fernández-Cidón,1–3 Ariadna Padró-Miquel,1 Pedro Alía-Ramos,1 María José Castro-Castro,1 Marta Fanlo-Maresma,4 Dolors Dot-Bach,1 José Valero-Politi,1 Xavier Pintó-Sala,4 Beatriz Candás-Estébanez1 1Clinical Laboratory, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain; 2Department of Biochemistry, Molecular Biology and Biomedicine, Autonomous University of Barcelona (UAB), Barcelona, Spain; 3Department of Pharmacotherapy, Pharmacogenetics and Pharmaceutical Technology, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Spain; 4Cardiovascular Risk Unit, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Spain Background: High serum concentrations of small dense low-density lipoprotein cholesterol (sd-LDL-c) particles are associated with risk of cardiovascular disease (CVD). Their clinical application has been hindered as a consequence of the laborious current method used for their quantification. Objective: Optimize a simple and fast precipitation method to isolate sd-LDL particles and establish a reference interval in a Mediterranean population. Materials and methods: Forty-five serum samples were collected, and sd-LDL particles were isolated using a modified heparin-Mg2+ precipitation method. sd-LDL-c concentration was calculated by subtracting high-density lipoprotein cholesterol (HDL-c) from the total cholesterol measured in the supernatant. This method was compared with the reference method (ultracentrifugation). Reference values were estimated according to the Clinical and Laboratory Standards Institute and The International Federation of Clinical Chemistry and Laboratory Medicine recommendations. sd-LDL-c concentration was measured in serums from 79 subjects with no lipid metabolism abnormalities. Results: The Passing–Bablok regression equation is y = 1.52 (0.72 to 1.73) + 0.07x (−0.1 to 0.13), demonstrating no significant statistical differences between the modified precipitation method and the ultracentrifugation reference method. Similarly, no differences were detected when considering only sd-LDL-c from dyslipidemic patients, since the modifications added to the precipitation method facilitated the proper sedimentation of triglycerides and other lipoproteins. The reference interval for sd-LDL-c concentration estimated in a Mediterranean population was 0.04–0.47mmol/L. Conclusion: An optimization of the heparin-Mg2+ precipitation method for sd-LDL particle isolation was performed, and reference intervals were established in a Spanish Mediterranean population. Measured values were equivalent to those obtained with the reference method, assuring its clinical application when tested in both normolipidemic and dyslipidemic subjects. Keywords: sd-LDL-c, small dense lipoprotein, sd-LDL reference values

Background Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). Single nucleotide polymorphisms (SNPs) in ANRIL gene have been associated with higher cardiovascular morbidity and mortality in general population. The main objective was to ascertain whether ANRIL polymorphisms could identify risk of major adverse cardiovascular event (MACE) in patients starting on hemodialysis (HD). Methods This was a prospective observational cohort study. 284 CKD patients starting on HD were included in the study and followed until achievement of the primary end-point (MACE) or end of the study. All patients were genotyped for four ANRIL SNPs (rs10757278, rs4977574, rs10757274 and rs6475606). Kaplan-Meier curves and multivariate Cox survival analyses, together with multiple logistic regression were used to analyze the association between ANRIL SNPs and MACE. Results We found that ANRIL SNP rs10757278 was a representative SNP of a strong linkage disequilibrium block and showed significant genotypic associations with MACE in hemodialysis patients. Homozygous patients for the risk allele (GG) showed 2.17 (1.05–4.49) fold increased risk of MACE during hemodialysis than carriers of the protective allele (AA or AG). Diabetes mellitus was a strong enhancer of this effect. Conclusions Our results indicate that ANRIL polymorphisms may confer risk to development of MACE in incident patients on hemodialysis.

Background The APOE Christchurch (APOECh) is a rare variant (c.543C>A) in codon 154. It was first described in an E2 patient with type III dyslipidemia, and thus initially called E2Ch. Its prevalence and the lipid profile of carriers remain unclear. Methods E2, E3, and E4 screening for the APOE gene was performed by PCR-RFLP. The rare APOECh variant was firstly found after detecting an unexpected 109 base-pair band in the high-resolution agarose gel electrophoresis leading to a genotype misinterpretation: the presence of APOECh alters the restriction-bands pattern. To confirm the Ch variant, a second PCR-RFLP method was specifically designed to detect this variant and Sanger sequencing was also performed for all positive samples. Results We identified 12 unrelated subjects for the APOECh among a cohort of 2,560 patients: nine E3/E3Ch, two E3Ch/E4, and one E2/E3Ch or E2Ch/E3. The frequency of the variant is 0.4% in our study population, which represents the highest percentage published so far. If there is a 109 bp band, it is easy to recognize the presence of the variant. However, in APOE routine genotyping, an E4Ch allele is indistinguishable from a standard E3. Therefore, E4Ch alleles might be underrepresented in the results. Conclusion We recommend APOE exon 4 sequencing to unequivocally detect the common three variants E2, E3, and E4 and the rare variants as well, to find out the real role they play in atherosclerosis and to estimate its real frequency which is nowadays unclear, in part by the small number of cases identified.

The interpretation of a change between two consecutive measured values of a given quantity in the same patient is still controversial and it is not commonly found in clinical laboratory reports. We present here a manageable and affordable approach for all clinical laboratories to help physicians to interpret these differences.We selected all pairs of two consecutive measured values of serum albumin concentration and serum thyrotropin concentration, both within the biological reference interval, delivered by our clinical laboratory in a 2-year period (2008-2009). We calculated the relative difference between pairs from which we estimated percentiles 2.5 and 97.5 in order to set an interval defining the significance of a change. We verified these intervals with data from the year 2010.During the 2-year period, we found 122,626 consecutive pairs of serum albumin concentration and 9 374 pairs of serum thyrotropin concentration, with both measured values within our biological reference interval. The intervals defining the significance of a change between two consecutive measured values were: (-14.0 to 17.6)% for the relative differences of albumin concentration, and (-61.4 to 177.8)% for the differences of thyrotropin concentration, which determined 12.7% and 18.4% of significant relative differences, respectively. Similar results were obtained from data for the year 2010.The interval that defines the significance of a change could easily be estimated with the patients' measured values obtained daily in the laboratory. Our proposal is more appropriate to each specific population than the conventional intra-individual biological variation approach.

HLA-B*51, a class I human leukocyte antigen (HLA) molecule, is the strongest known genetic risk factor for Behçet disease. However, there are only few articles reporting methods to determine the presence or absence of HLA-B51. For this reason, we designed and developed an easy, fast, and inexpensive real-time high-resolution melting (HRM) assay to detect HLA-B*51. We genotyped 61 samples by our HRM assay and by conventional polymerase chain reaction, and no discrepancies were found between results. Besides, a subgroup of 25 samples was also genotyped in a different laboratory, and another subgroup of 16 samples was obtained from the International Histocompatibility Working Group DNA Bank, and a full concordance of results was observed with those obtained by HRM. Regarding the identifying system evaluated, we obtained 100% of specificity, sensibility, and repeatability, and 0% of false positive and false negative rates. Therefore, this HRM analysis is easily applicable to the rapid detection of HLA-B*51, exhibits a high speed, and requires a very low budget.

Progressive loss of bone mineral density weakens the bones and increases the probability of osteoporotic fractures. It is well known that sex steroids play a role in the maintenance of bone density. This fact makes us think there might be a correlation between sex steroid levels and osteoporotic hip fractures.A case-control study was performed. The cases were 54 men who suffered from hip fracture. They were compared with 54 age-matched male control subjects. Levels of total testosterone, sex hormone binding globuline, albumin and oestradiol were measured in all subjects in order to calculate free testosterone and bio-testosterone levels.Men who suffered from hip fracture had lower serum total testosterone (8.74 nmol/L versus 11.16 nmol/L; p=0.116) and lower free testostenone (155.1pmol/L versus 204.4pmol/L; p=0.02) than control subjects. Bio-testosterone levels were lower in patients with hip fracture (2.69 nmol/L versus 3.89 nmol/L; p=0.002), being the latter the best fracture predictor (OR: 1.58).In our study population, men with hip fractures had significantly lower levels of calculated free testosterone and bio-testosterone. These findings suggest that free testosterone and bio-testosterone levels are independent predictors for osteoporotic hip fracture in eldery men.

Background: It is customary to assume that pre-analytical variation is negligible if all pre-analytical sources of variation have been standardised. The aim of this study was to quantify the pre-analytical variation of some haematological quantities frequently measured in clinical laboratories. Methods: The experimental design considers different sources of pre-analytical variation that usually occur day-to-day for samples from patients. Results: The results demonstrate that for concentrations of erythrocytes, haemoglobin, leukocytes, neutrophilocytes (segmented) and lymphocytes, and for the volume fraction of erythrocytes ("packed cell volume") in blood, the pre-analytical variance is not negligible. Conclusions: We suggest that these variances should be taken into account when estimating the uncertainty of measurement for patient results.

Objectives To study the combined effect of polymorphisms in genes of the renin-angiotensin system on mortality in type 2 diabetic patients in dialysis. Design and methods From 1993 to 2007, we followed 89 patients from the start of dialysis until the end point, which was all-cause mortality. All patients were genotyped for the following polymorphisms: ACE (I/D), AGT (p.235M>T) and AGTR1 (g.1166A>C). The relative risks of death were examined by Cox-proportional hazard analysis after adjusting for age, sex, modality of dialysis, baseline and residual filtration rate, cardiovascular comorbidity, anemia, glycemic control, hypertension, nutritional status, risk of infection and dyslipidemia. Results We first assigned and quantified the number of risk alleles – D (I/D), M (p.235 M>T) and A (g.1166A>C) – each patient carried. The Cox-proportional hazard analysis showed that every single additional risk allele multiplied the mortality hazard ratio by 1.58 (95% CI: 1.16–2.15, P = 0.003). Conclusions Our data suggest a combined effect among the polymorphisms of the Renin-Angiotensin-System genes on mortality in type 2 diabetic patients undergoing dialysis.

Introduction The therapeutic response to statins has a high interindividual variability with respect to reductions in plasma LDL-cholesterol (c-LDL) and increases in HDL cholesterol (c-HDL). Many studies suggest that there is a relationship between the rs20455 KIF6 gene variant (c.2155T> C, Trp719Arg) and a lower risk of cardiovascular disease in patients being treated with statins. Aim The aim of this study was to investigate whether or not the c.2155T> C KIF6 gene variant modulates the hypercholesteremic effects of treatment with simvastatin, atorvastatin, or rosuvastatin. Materials and methods This was a prospective, observational and multicenter study. Three hundred and forty-four patients who had not undergone prior lipid-lowering treatment were recruited. Simvastatin, atorvastatin or rosuvastatin were administered. Lipid profiles and multiple clinical and biochemical variables were assessed before and after treatment. Results The c.2155T> C variant of the KIF6 gene was shown to influence physiological responses to treatment with simvastatin and atorvastatin. Patients who were homozygous for the c.2155T> C variant (CC genotype, ArgArg) had a 7.0% smaller reduction of LDL cholesterol levels (p = 0.015) in response to hypolipidemic treatment compared to patients with the TT (TrpTrp) or CT (TrpArg) genotype. After pharmacological treatment with rosuvastatin, patients carrying the genetic variant had an increase in c-HDL that was 21.9% lower compared to patients who did not carry the variant (p = 0.008). Conclusion Being a carrier of the c.2155T> C variant of the KIF6 gene negatively impacts patient responses to simvastatin, atorvastatin or rosuvastatin in terms of lipid lowering effect. Increasing the intensity of hypolipidemic therapy may be advisable for patients who are positive for the c.2155T> C variant.