Study of common hypertriglyceridaemia genetic variants and subclinical atherosclerosis in a group of women with SLE and a control group

Objective SLE 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. Methods A 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. Results Triglyceride 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). Conclusions GCKR 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

Implication between Genetic Variants from APOA5 and ZPR1 and NAFLD Severity in Patients with Hypertriglyceridemia

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

Properties and units in the clinical laboratory sciences part XXIV. Properties and units in clinical molecular genetics (IUPAC Technical Report)

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 and examples of actual NPU definitions for different types of investigations are given and explained

Precipitated sdLDL: An easy method to estimate LDL particle size

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 (rxy ). 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 (rxy = 0.687) and with LDL-Z (rxy = -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

Asymptomatic carotid atherosclerosis cardiovascular risk factors and common hypertriglyceridemia genetic variants in patients with systemic erythematosus lupus

SLE is associated with increased cardiovascular risk. The objective of this study was to determine the prevalence of asymptomatic carotid atherosclerosis to analyze its relationship with dyslipidemia and related genetic factors in a population of patients with SLE. Seventy-one SLE female patients were recruited. Carotid ultrasound, laboratory profiles, and genetic analysis of the ZPR1, APOA5, and GCKR genes were performed. SLE patients were divided into two groups according to the presence or absence of carotid plaques. Patients with carotid plaque had higher plasma TG (1.5 vs. 0.9 mmol/L, p = 0.001), Non-HDL-C (3.5 vs. 3.1 mmol/L, p = 0.025), and apoB concentrations (1.0 vs. 0.9 g/L, p = 0.010) and a higher prevalence of hypertension (80 vs. 37.5%, p = 0.003) than patients without carotid plaque. The GCKR C-allele was present in 83.3% and 16.7% (p = 0.047) of patients with and without carotid plaque, respectively. The GCKR CC genotype (OR = 0.026; 95% CI: 0.001 to 0.473, p = 0.014), an increase of 1 mmol/L in TG concentrations (OR = 12.550; 95% CI: 1.703 to 92.475, p = 0.013) and to be hypertensive (OR = 9.691; 95% CI: 1.703 to 84.874, p = 0.040) were independently associated with carotid atherosclerosis. In summary, plasma TG concentrations, CGKR CC homozygosity, and hypertension are independent predictors of carotid atherosclerosis in women with SLE

Data on genotypic distribution and linkage disequilibrium of several ANRIL polymorphisms in hemodialysis patients

A long non-coding RNA called ANRIL located on chromosome 9p21.3 has been identified as a novel genetic factor associated with cardiovascular disease. Investigation of several single nucleotide polymorphisms (SNPs) of Noncoding Antisense RNA in the INK4 Locus (ANRIL) gene are of particular interest. This article reports data related to the research article entitled: "Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients" (Arbiol-Roca et al. [1]). Data presented show the genotypic distribution of four selected ANRIL SNPs: rs10757278, rs4977574, rs10757274 and rs6475606 in a cohort constituted by 284 hemodialysis patients. This article analyzes the Hardy-Weinberg disequilibrium of each studied SNP, and the linkage disequilibrium between them

Reference values assessment in a Mediterranean population for small dense low-density lipoprotein concentration isolated by an optimized precipitation method

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 0.04-0.47 mmol/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

Physicochemical Properties of Lipoproteins Assessed by Nuclear Magnetic Resonance as a Predictor of Premature Cardiovascular Disease. PRESARV-SEA Study

Some lipoprotein disorders related to the residual risk of premature cardiovascular disease (PCVD) are not detected by the conventional lipid profile. In this case-control study, the predictive power of PCVD of serum sdLDL-C, measured using a lipoprotein precipitation method, and of the physicochemical properties of serum lipoproteins, analyzed by nuclear magnetic resonance (NMR) techniques, were evaluated. We studied a group of patients with a first PCVD event (n = 125) and a group of control subjects (n = 190). Conventional lipid profile, the size and number of Very Low Density Lipoproteins (VLDL), Low Density Lipoproteins (LDL), High Density Lipoproteins (HDL) particles, and the number of particles of their subclasses (large, medium, and small) were measured. Compared to controls, PCVD patients had lower concentrations of all LDL particles, and smaller and larger diameter of LDL and HDL particles, respectively. PCVD patients also showed higher concentrations of small dense LDL-cholesterol (sdLDL), and triglycerides (Tg) in LDL and HDL particles (HDL-Tg), and higher concentrations of large VLDL particles. Multivariate logistic regression showed that sdLDL-C, HDL-Tg, and large concentrations of LDL particles were the most powerful predictors of PCVD. A strong relationship was observed between increased HDL-Tg concentrations and PCVD. This study demonstrates that beyond the conventional lipid profile, PCVD patients have other atherogenic lipoprotein alterations that are detected by magnetic resonance imaging (MRI) analysis

Influència de gens del sistema renina-angiotensina sobre la instauració i progressió de la nefropatia i la mortalitat en diàlisi de pacients diabètics de tipus 2

La nefropatia diabètica és una complicació secundària greu de la diabetis i es desenvolupa en el 35% d'aquests pacients. Estudis d'agrupació familiar han suggerit que aquesta malaltia podria estar subjecta a un component genètic.Aquesta tesi s'ha centrat en l'estudi de la influència de 6 polimorfismes de gens del sistema renina-angiotensina amb la progressió de la nefropatia, i amb la mortalitat en diàlisi de pacients diabètics de tipus 2. També s'ha inclòs un estudi preliminar que explora la relació entre els polimorfismes i la instauració de la nefropatia.La classificació genotípica dels pacients s'ha dut a terme mitjançant la tècnica de PCR-RFLP o bé PCR a temps real. S'han genotipat els següents polimorfismes: I/D del gen que codifica per l'enzim convertidor d'angiotensina I (ACE1), p.M235T del gen que codifica per l'angiotensinogen (AGT), g.1166A>C del gen que codifica pel receptor d'angiotensina II de tipus 1 (AGTR1), c.186+2053G>A, c.439+4C>T i c.1542-361C>G del gen que codifica per l'enzim convertidor d'angiotensina I de tipus 2 (ACE2).La influència dels polimorfismes sobre la mortalitat en diàlisi s'ha estudiat mitjançant una anàlisi de la supervivència amb models de regressió de Cox multivariant amb 100 pacients diabètics de tipus 2 que havien iniciat tractament amb diàlisi al nostre centre hospitalari. A la regressió de Cox individual de cada polimorfisme, l'I/D de l'ACE1 i el p.M235T de l'AGT van presentar efectes significatius sobre la mortalitat. Concretament el genotip DD va explicar un augment del risc de mortalitat de 3,5 (1,3 - 9,9) vegades el dels pacients II, i el genotip MM al seu torn va explicar un augment del risc de mortalitat de 3,8 (1,2 - 12,4) vegades el dels pacients TT. En l'estudi conjunt dels polimorfismes es va observar que el nombre d'al·lels D (I/D), M (p.M235T) i G (c.186+2053G>A) que tenia un pacient determinava de forma estadísticament significativa un increment del risc de morir (p=0,002) de tal forma que els pacients amb els sis al·lels de risc tenien una probabilitat de morir 11 vegades superior als que no en tenien cap. La influència dels polimorfismes sobre la progressió de la nefropatia una vegada ja establerta es va estudiar mitjançant models de Cox i de regressió lineal multivariant amb 320 pacients diabètics de tipus 2 diagnosticats d'insuficiència renal crònica d'estadis 1-3. Pel que fa a l'estudi individual dels polimorfismes, es va observar una relació estadísticament significativa entre el pendent de disminució d'MDRD i els polimorfismes p.M235T de l'AGT, c.186+2053G>A i c.1542-361C>G de l'ACE2 -els dos darrers únicament en els homes-. Aquesta relació va ser encara més intensa amb els pacients amb velocitat de filtració glomerular encara conservada (> 60 mL/min/1,73 m2) a la primera visita. L'estudi conjunt dels polimorfismes va mostrar que la combinació d'al·lels que millor estimava la progressió de la nefropatia (p=0,0005) era la formada per D (I/D), M (p.M235T) i A (c.186+2053G>A). El fet de tenir els 6 al·lels de risc respecte no tenir-ne cap, explicava una pèrdua anual de la velocitat de filtració glomerular de -5,2 mL/min/1,73 m2.Finalment, la influència dels polimorfismes sobre l'establiment de la nefropatia es va estudiar mitjançant models de regressió logística multivariant amb 227 casos i 69 controls. No es va poder evidenciar cap efecte genètic en la instauració de la nefropatia.Els resultats presentats en aquesta tesi posen de manifest que els polimorfismes I/D, p.M235T, c.186+2053G>A i en menor importància c.1542-361C>G actuen conjuntament influint en la mortalitat dels pacients diabètics de tipus 2 en diàlisi i en la progressió de la nefropatia. Per contra, no hem pogut demostrar que estiguin relacionats en la susceptibilitat a desenvolupar la nefropatia.Diabetic nephropathy is a severe secondary complication of diabetes that is developed in 35% of these patients. Studies of family association have suggested that this illness could be subject to a genetic component.This thesis studies the influence of 6 polymorphisms of the renin-angiotensin system genes on the progression of the nephropathy, and mortality in dialysis of type 2 diabetic patients. It has also been included a preliminary study that explores the relationship between these polymorphisms and the development of nephropathy.The genotypic classification of the patients has been carried out through PCR-RFLP or real time PCR. The following polymorphisms have been genotyped: I/D of the angiotensin-converting enzyme gene (ACE1), p.M235T of the angiotensinogen gene (AGT), g.1166A>C of the type1 angiotensin II receptor type 1 gene (AGTR1) and c.186+2053G>A, c.439+4C>T and c.1542-361C>G of the angiotensin-converting enzyme 2 gene (ACE2).The influence of these polymorphisms on mortality in dialysis has been studied through Cox regression analysis with 100 type 2 diabetic patients that began dialysis in our Hospital. The individual Cox regressions of each polymorphism, I/D (ACE1) and p.M235T (AGT) showed significant effects on mortality. Specifically, DD genotype explained an increased mortality risk of 3,5 (1,3 - 9,9) times that of II patients, and MM genotype explained an increased mortality risk of 3,8 (1,2 - 12,4) times that of TT patients. In the combined study of polymorphisms it was observed that the number of D (I/D), M (p.M235T) and G (c.186+2053G>A) alleles that a patient carries determined the mortality risk (p=0,002): patients with the six risk-alleles had a probability of death 11 times that of those patients without any risk-allele.The influence of the polymorphisms on nephropathy progression was studied through Cox and linear regression multivariate analysis with 320 type 2 diabetic patients diagnosed of chronic kidney disease from stages 1 to 3. Regarding the individual study of polymorphisms, a statistically significant relationship was observed between the glomerular filtration rate slope decrease and p.M235T (AGT), c.186+2053G>A and c.1542-361C>G (ACE 2). This relationship was still more intense with patients that presented with a preserved glomerular filtration rate (> 60 mL/min/1,73 m2) in their first visit. The combined study of polymorphisms showed that the combination of D (I/D), M (p.M235T) and T (c.186+2053G>A) alleles best predicted progression (p=0,0005): patients with the six risk alleles had an annual loss of glomerular filtration rate of -5,2 mL/min/1,73 m2 with respect to those patients without any risk-allele.Finally, the influence of the polymorphism on the development of nephropathy was studied through multivariate logistical regression analysis with 227 cases and 69 controls. No genetic effect was found.The results presented in this thesis bring to light that I/D, p.M235T, c.186+2053G>A and c.1542-361C>G polymorphisms act together influencing on the mortality of type 2 diabetic patients in dialysis and in nephropathy progression. In return, we have not been able to prove their relationship with the development of nephropathy

Influència de gens del sistema renina-angiotensina sobre la instauració i progressió de la nefropatia i la mortatlitat en diàlisi de pacients diabètics de tipus 2

Descripció del recurs: el 11 d'agost de 2010La nefropatia diabètica és una complicació secundària greu de la diabetis i es desenvolupa en el 35% d'aquests pacients. Estudis d'agrupació familiar han suggerit que aquesta malaltia podria estar subjecta a un component genètic. Aquesta tesi s'ha centrat en l'estudi de la influència de 6 polimorfismes de gens del sistema renina-angiotensina amb la progressió de la nefropatia, i amb la mortalitat en diàlisi de pacients diabètics de tipus 2. També s'ha inclòs un estudi preliminar que explora la relació entre els polimorfismes i la instauració de la nefropatia. La classificació genotípica dels pacients s'ha dut a terme mitjançant la tècnica de PCR-RFLP o bé PCR a temps real. S'han genotipat els següents polimorfismes: I/D del gen que codifica per l'enzim convertidor d'angiotensina I (ACE1), p.M235T del gen que codifica per l'angiotensinogen (AGT), g.1166A>C del gen que codifica pel receptor d'angiotensina II de tipus 1 (AGTR1), c.186+2053G>A, c.439+4C>T i c.1542-361C>G del gen que codifica per l'enzim convertidor d'angiotensina I de tipus 2 (ACE2). La influència dels polimorfismes sobre la mortalitat en diàlisi s'ha estudiat mitjançant una anàlisi de la supervivència amb models de regressió de Cox multivariant amb 100 pacients diabètics de tipus 2 que havien iniciat tractament amb diàlisi al nostre centre hospitalari. A la regressió de Cox individual de cada polimorfisme, l'I/D de l'ACE1 i el p.M235T de l'AGT van presentar efectes significatius sobre la mortalitat. Concretament el genotip DD va explicar un augment del risc de mortalitat de 3,5 (1,3 - 9,9) vegades el dels pacients II, i el genotip MM al seu torn va explicar un augment del risc de mortalitat de 3,8 (1,2 - 12,4) vegades el dels pacients TT. En l'estudi conjunt dels polimorfismes es va observar que el nombre d'al·lels D (I/D), M (p.M235T) i G (c.186+2053G>A) que tenia un pacient determinava de forma estadísticament significativa un increment del risc de morir (p=0,002) de tal forma que els pacients amb els sis al·lels de risc tenien una probabilitat de morir 11 vegades superior als que no en tenien cap. La influència dels polimorfismes sobre la progressió de la nefropatia una vegada ja establerta es va estudiar mitjançant models de Cox i de regressió lineal multivariant amb 320 pacients diabètics de tipus 2 diagnosticats d'insuficiència renal crònica d'estadis 1-3. Pel que fa a l'estudi individual dels polimorfismes, es va observar una relació estadísticament significativa entre el pendent de disminució d'MDRD i els polimorfismes p.M235T de l'AGT, c.186+2053G>A i c.1542-361C>G de l'ACE2 -els dos darrers únicament en els homes-. Aquesta relació va ser encara més intensa amb els pacients amb velocitat de filtració glomerular encara conservada (> 60 mL/min/1,73 m2) a la primera visita. L'estudi conjunt dels polimorfismes va mostrar que la combinació d'al·lels que millor estimava la progressió de la nefropatia (p=0,0005) era la formada per D (I/D), M (p.M235T) i A (c.186+2053G>A). El fet de tenir els 6 al·lels de risc respecte no tenir-ne cap, explicava una pèrdua anual de la velocitat de filtració glomerular de -5,2 mL/min/1,73 m2. Finalment, la influència dels polimorfismes sobre l'establiment de la nefropatia es va estudiar mitjançant models de regressió logística multivariant amb 227 casos i 69 controls. No es va poder evidenciar cap efecte genètic en la instauració de la nefropatia. Els resultats presentats en aquesta tesi posen de manifest que els polimorfismes I/D, p.M235T, c.186+2053G>A i en menor importància c.1542-361C>G actuen conjuntament influint en la mortalitat dels pacients diabètics de tipus 2 en diàlisi i en la progressió de la nefropatia. Per contra, no hem pogut demostrar que estiguin relacionats en la susceptibilitat a desenvolupar la nefropatia.Diabetic nephropathy is a severe secondary complication of diabetes that is developed in 35% of these patients. Studies of family association have suggested that this illness could be subject to a genetic component. This thesis studies the influence of 6 polymorphisms of the renin-angiotensin system genes on the progression of the nephropathy, and mortality in dialysis of type 2 diabetic patients. It has also been included a preliminary study that explores the relationship between these polymorphisms and the development of nephropathy. The genotypic classification of the patients has been carried out through PCR-RFLP or real time PCR. The following polymorphisms have been genotyped: I/D of the angiotensin-converting enzyme gene (ACE1), p.M235T of the angiotensinogen gene (AGT), g.1166A>C of the type1 angiotensin II receptor type 1 gene (AGTR1) and c.186+2053G>A, c.439+4C>T and c.1542-361C>G of the angiotensin-converting enzyme 2 gene (ACE2). The influence of these polymorphisms on mortality in dialysis has been studied through Cox regression analysis with 100 type 2 diabetic patients that began dialysis in our Hospital. The individual Cox regressions of each polymorphism, I/D (ACE1) and p.M235T (AGT) showed significant effects on mortality. Specifically, DD genotype explained an increased mortality risk of 3,5 (1,3 - 9,9) times that of II patients, and MM genotype explained an increased mortality risk of 3,8 (1,2 - 12,4) times that of TT patients. In the combined study of polymorphisms it was observed that the number of D (I/D), M (p.M235T) and G (c.186+2053G>A) alleles that a patient carries determined the mortality risk (p=0,002): patients with the six risk-alleles had a probability of death 11 times that of those patients without any risk-allele. The influence of the polymorphisms on nephropathy progression was studied through Cox and linear regression multivariate analysis with 320 type 2 diabetic patients diagnosed of chronic kidney disease from stages 1 to 3. Regarding the individual study of polymorphisms, a statistically significant relationship was observed between the glomerular filtration rate slope decrease and p.M235T (AGT), c.186+2053G>A and c.1542-361C>G (ACE 2). This relationship was still more intense with patients that presented with a preserved glomerular filtration rate (> 60 mL/min/1,73 m2) in their first visit. The combined study of polymorphisms showed that the combination of D (I/D), M (p.M235T) and T (c.186+2053G>A) alleles best predicted progression (p=0,0005): patients with the six risk alleles had an annual loss of glomerular filtration rate of -5,2 mL/min/1,73 m2 with respect to those patients without any risk-allele. Finally, the influence of the polymorphism on the development of nephropathy was studied through multivariate logistical regression analysis with 227 cases and 69 controls. No genetic effect was found. The results presented in this thesis bring to light that I/D, p.M235T, c.186+2053G>A and c.1542-361C>G polymorphisms act together influencing on the mortality of type 2 diabetic patients in dialysis and in nephropathy progression. In return, we have not been able to prove their relationship with the development of nephropathy