Sodium-lithium Countertransport Research Articles

Computational analysis of sodium-dependent phosphate transporter SLC20A1/PiT1 gene identifies missense variations C573F, and T58A as high-risk deleterious SNPs

SLC20A1/PiT1 is a sodium-dependent inorganic phosphate transporter, initially recognized as the retroviral receptor for Gibbon Ape Leukemia Virus in humans. SNPs in SLC20A1 is associated with Combined Pituitary Hormone Deficiency and Sodium Lithium Counter transport. Using in silico techniques, we have screened the nsSNPs for their deleterious effect on the structure and function of SLC20A1. Screening with sequence and structure-based tools on 430 nsSNPs, filtered 17 nsSNPs which are deleterious. To evaluate the role of these SNPs, protein modeling and MD simulations were performed. A comparative analysis of model generated with SWISS-MODEL and AlphaFold shows that many residues are in the disallowed region of Ramachandran plot. Since SWISS-MODEL structure has a 25-residue deletion, the AlphaFold structure was used to perform MD simulation for equilibration and structure refinement. Further, to understand perturbation of energetics, we performed in silico mutagenesis and ΔΔG calculation using FoldX on MD refined structures, which yielded SNPs that are neutral (3), destabilizing (12) and stabilizing (2) on protein structure. Furthermore, to elucidate the impact of SNPs on structure, we performed MD simulations to discern the changes in RMSD, Rg, RMSF and LigPlot of interacting residues. RMSF profiles of representative SNPs revealed that A114V (neutral) and T58A (positive) were more flexible & C573F (negative) was more rigid compared to wild type, which is also reflected in the changes in number of local interacting residues in LigPlot and ΔΔG. Taken together, our results show that SNPs can lead to structural perturbations and impact the function of SLC20A1 with potential implications for disease. Communicated by Ramaswamy H. Sarma

Abstract TP319: Risk Factors of Post-stroke Epilepsy

Purpose: The aim of the study was to identify the risk factors for seizures in patients with ischemic stroke using clinical, functional, neuroimaging research methods. Materials and methods: The results of the complex survey of 468 patients suffering from ischemic stroke (256 patients experienced epileptic seizures and 203 experienced no epileptic seizures) are presented. The diagnostic procedures included clinical evaluation, magnetic resonance imaging, electroencephalography, extracranial and transcranial Doppler sonography. In addition the assessment of the rate of sodium lithium countertransport (the marker of genetically determined on transport mechanisms of cell membranes) in patients with c ischemic stroke with the development of epileptic seizures and no seizures was carried out. Results: The focal seizures are the most common (92,5%). Cortical ischemic brain lesions prevailed in patients with seizures (81,1%), whereas in the control group cortex was affected in 38,9% patients (χ2=89.2, <0,001). Stenosis of cerebral arteries was more common in patients with epilepsy (82.3%) compared to patients without seizures (74.4%, <0.05). Reduced cerebrovascular reactivity (CVR) in vertebro-basilar basin was more frequently detected in patients with seizures (85.9%, p<0.001) compared to controls (71.6%). CVR < 10% was registered in 33.8% patients with seizures versus 13.4% controls (p<0.001). Patients with epileptic seizures showed cerebral perfusion reduction mostly in vertebro-basilar basin (85.9%) rather than in carotid basin (61.2%, p<0.001). Patients experienced epileptic seizures had high rates of sodium-lithium antitransport (> 346 μmol/liter cells x hour) more often than patients without epileptic seizures (52,6% and 35,5%, respectively, <0,05). Patients experienced epileptic seizures with high rates of sodium-lithium antitransport had a higher seizure frequency than patients with low rates of sodium-lithium antitransport. Conclusion: Thus, cortical ischemic brain lesions, significant stenosis of cerebral arteries, predominant perfusion reserve reduction in the posterior cerebral circulation, as well as a high rate of sodium lithium countertransport may be considered as risk factors for post-stroke epilepsy.

To the issue of the use of sodium-lithium countertransport rate in red cell membrane as a prognostic marker of artherial hypertension mordbidity and mortality: an experience of 25-year follow up cohort study

Aim. The article discusses the results of a long-term cohort study devoted to the search for the possible relationship of arterial hypertension morbidity and mortality with the rate of sodium-lithium countertransport (Na+-Li+-СT) in red cell membrane which is a marker of the structural and functional state of the cell membrane.
 Methods. The study of the functional state of cell membranes by determining the maximal rate of Na+-Li+-CT in red cell membrane with quintiles analysis of the rate of Na+-Li+-CT. Screening clinical examination, including registration of blood pressure (BP), ECG study, the study of eyeground vessels, one- and two-dimensional echocardiography (EchoCG), the study of the lipid spectrum of the blood. Analysis of medical records.
 Results. Based on the results of long-term follow up of the aging cohort total mortality is not associated with Na+-Li+-СT rate in red cell membrane. At the average age of 50 bimodality is detected in the development of new cases of primary arterial hypertension associated with the values of Na+-Li+-СT rate of the 1st quartile (36-206 micromoles of Li per liter of cells per hour) and 3d quartile (276-347 micromoles of Li per liter of cells per hour). At the average age of cohort of 55.6±6.7 years the distribution of patients with arterial hypertension by quartiles of Na+-Li+-СT rate becomes almost identical with the statistically non-significant prevalence of 4th quartile of Na+-Li+-СT rate.
 Conclusion. The expected correlation between mortality among persons with hypertension and membrane disorders determined by the high rate of Na+-Li+-СT was not revealed. However, the tendency to the predominance of mortality at high Na+-Li+-СT rate suggests that with a much larger sample size a significant relationship may be confirmed. The necessity of studying the relationship between mortality from arterial hypertension and high rate of Na+-Li+-СT in female cohorts remains actual. Increasing difference of mortality rate among patients with and without arterial hypertension with high rate of Na+-Li+-СT can indicate the relationship between mortality from arterial hypertension and membrane disorders.

Indicative role of membranolysis markers in the prognosis of uncomplicated community-acquired pneumonia in children of school age

Aim. To evaluate the indicative role of membranolysis markers in the prognosis of uncomplicated community-acquired pneumonia in school children and to establish its relation with zinc status indices.
 Methods. The study included 229 children aged 7 to 17 years with community-acquired pneumonia. The patients were divided into three groups based on morphological form of lung involvement: focal (103 children - group 1), segmental (64 patients - group 2), and lobar pneumonia (62 subjects - group 3). The state of cell membranes was evaluated by the activity of 5’-nucleotidase and rate of sodium-lithium countertransport in erythrocyte membrane. Intensity of peroxidation processes was evaluated by the level of end toxic products and total antioxidative activity, and additionally the blood concentration of zinc was measured by atomic absorption spectrophotometry.
 Results. Significant effect of membranolysis processes on the clinical course of pneumonia was revealed. The most prominent pathological changes of the studied indices were registered in patients with focal form of the disease (group 1): increase of the concentration of lipid peroxidation products in average to 5.4±0.06 umol/L and the level of 5’-nucleotidase to 233.90±9.15 nkat, decrease of serum level of zinc to 9.73±0.09 mmol/L and total antioxidative activity to 23.22±0.29%. It was associated with prolonged course and tendency to slow reversal of physical findings in the lungs compared to patients from groups 2 and 3 (p 0.05, respectively).
 Conclusion. Damage of cytoplasmic membrane in the focus of inflammation can be an objective marker of the course of community-acquired pneumonia in children and a sensitive prognostic sign and can allow identifying children into groups of high risk of prolonged course.

Primate response to angiotensin infusion and high sodium intake differ by sodium lithium countertransport phenotype

An increased level of sodium-lithium countertransport (SLC) activity has been associated with salt-sensitive hypertension. Previous findings have suggested that dysregulation of the renin-angiotensin-aldosterone system (RAAS) may be involved in the mechanism linking elevated SLC activity and hypertension. Therefore, baboons with different levels of SLC activity were given two diets differing in sodium content, with and without an angiotensin II (ANG II) infusion, to investigate the relationship between SLC activity, the RAAS, and physiological regulation by sodium. Although we anticipated that high SLC activity would be associated with inappropriate function of the RAAS and greater arterial pressure sensitivity to dietary sodium and ANG II and that low SLC activity would be associated with the least BP sensitivity, we found that the low SLC phenotype correlated with BP sensitivity similar to the high SLC phenotype, and the normal SLC phenotype showed the least BP sensitivity to dietary sodium and ANG II.

Erythrocyte Na +–Li + counter-transport activity and digoxin-like substances in insulin dependent diabetic women with preexisting preeclampsia

Aim of the study To determine whether there is pathogenetic link between red cells sodium–lithium counter-transport activity and digoxin-like immunoreactive substances (DLIS) in plasma of insulin-dependent diabetic (IDDM) and non-diabetic women with preexisting preeclampsia (PE). Subjects and methods We studied Na +/Li + CT activity in red cells and plasma levels of DLIS in 11 IDDM women with preexisting PE (Group 1), 13 IDDM without preexisting PE (Group 2) 23 non-diabetic women with preexisting PE (Group 3) and 12 non-diabetic women with normal pregnancy (Group 4) at least 4 months after delivery. Results Na +/Li + CT activity was higher in Group 1 compared to Group 2 (mean ± SEM 0.316 ± 0.05 vs 0.190 ± 0.02 mmol/LRBC/hr p < 0.05) and in Group 3 compared to Group 4 (0.365 ± 0.004 vs 0.168 ± 0.01 mmol/LRBC/hr, p < 0.01). Plasma levels of DLIS were higher in Group 3 compared to Group 4 (0.727 ± 0.189 vs 0.295 ± 0.066 ng/ml; p < 0.05); there was no statistically significant difference between the two diabetic groups. In Groups 1 and 3, Na +/Li + CT activity was correlated to the plasma levels of DLIS ( r = 0.927; p < 0.001 and r = 0.485; p < 0.05 respectively). Conclusion Increased Na +/Li + CT activity and increased plasma levels of DLIS may contribute to PE in IDDM and non-diabetic women.

Association Between SLC20A1 and Sodium-Lithium Countertransport

Sodium-lithium countertransport (SLC) is a premorbidity marker of essential hypertension. Evidence from linkage analysis and kinetic studies in humans have suggested that SLC20A1 variations may affect SLC activity as measured in erythrocytes and leukocytes. SLC20A1 encodes a sodium-dependent phosphate cotransporter, and is widely expressed on the mammalian plasma membrane. In this study, we investigated the relationship between SLC20A1 and SLC activity. By means of gene expression profiling, we studied the expressions of SLC20A1 in individuals with high SLC activity as compared to those with low SLC activity. In order to investigate the allelic association of SLC20A1 with SLC, we genotyped six tag single-nucleotide polymorphisms (tSNPs) in SLC20A1 in subjects from the Rochester Family Heart Study (RFHS) involving 1,815 individuals from 252 pedigrees of mixed European ancestry. The genetic association of SLC20A1 with SLC was assessed by Sequential Oligogenic Linkage Analysis Routines (SOLAR). Expression levels of SLC20A1 were higher in individuals with high SLC activity than in those with low SLC activity. Four SNPs in SLC20A1 were associated with SLC activity after adjusting for age, sex, body mass index, triglycerides, and antihypertensive drug treatment (P ≤ 0.05). The strongest evidence of association was in respect of rs4849091 (P = 0.001), and this association remained significant even after correction for multiple tests. Allelic variations in SLC20A1 were associated with the levels of SLC activity, thereby supporting the hypothesis that SLC20A1 is involved in determining SLC activity.

Association Between NEDD4L Gene and Sodium Lithium Countertransport

Sodium lithium countertransport (SLC) is an intermediate phenotype of essential hypertension. The aim of this study was to identify candidate genes for SLC by a strategy of combining gene expression profiling and linkage analysis, and to examine the association between the candidate gene and SLC as well as hypertension. In order to identify SLC-related genes, the top 1% of the genes that were differentially expressed between high- and low-SLC groups in a gene expression microarray were compared with published SLC/hypertension gene linkage maps so as to identify regions of overlap. The association between the genetic variation in the candidate gene and the SLC and blood pressure phenotypes were further assessed in the Rochester Family Heart Study (RFHS) involving 1,815 individuals of European ancestry, belonging to 252 pedigrees. Based on gene expression profiling and evidence from genome-wide linkage analysis, and in the light of its potential biochemical function, E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) was identified as being both a positional and a functional candidate gene for SLC. The difference in expressions of NEDD4L between the high- and low-SLC groups was confirmed by reverse transcription-PCR (RT-PCR) analysis. After adjusting for age, sex, and body mass index (BMI), four single-nucleotide polymorphisms (SNPs) in NEDD4L were found to be associated with SLC (P ≤ 0.05). Further, haplotype analysis revealed that, after correction for multiple testing, one of the haplotypes (H2) was still significantly (P = 0.006) associated with SLC. The strategy of combining gene expression profiling and linkage analysis successfully guided us in identifying NEDD4L as a candidate gene involved in regulating SLC activity. Variations in the NEDD4L gene are associated with SLC activity.

Erythrocyte sodium-lithium countertransport activity is inversely correlated to adiponectin, retinol binding protein 4 and body height

Background. We have previously described that the sodium/lithium countertransport (SLC) in the erythrocyte cell membrane is closely linked to obesity and insulin resistance. Adiponectin and retinol-binding protein 4 (RBP-4) are believed to affect obesity and insulin resistance. In the present study, we aimed to further characterize the relationship between SLC, inflammatory markers, adiponectin and RBP-4. Methods. We included 93 clinically healthy 58-year-old men selected to display variations in insulin sensitivity. High sensitivity C-reactive protein (hs-CRP), TNF-alpha, soluble TNF-alpha-receptors (sTNFR) 1 and 2, IL-6 and RBP-4 were measured using antibody-based techniques. Adiponectin was determined by a radioimmunoassay kit. The lithium concentration in the special flux medium was measured by atomic absorption spectrophotometry. Results. In univariate analyses, SLC correlated negatively with RBP-4 (rs = −0.256, p = −0.017) and to adiponectin (rs = −0.316, p = 0.003) and positively with TNF-alpha (rs = 0.346, p = 0.001) and hs-CRP (rs = 0.288, p = 0.005). There were no statistically significant correlations with sTNFR 1 or 2 or IL-6. SLC was negatively associated to body height (rs = −0.256, p = 0.013). Conclusions. We are the first to report that SLC correlates negatively with adiponectin and RBP-4. This finding is intriguing, as adiponectin is anti-inflammatory and anti-diabetic whereas RBP-4 supposedly decreases insulin sensitivity. We also observed a negative association between SLC activity and body height indicating that SLC activity is not primarily influenced by fat mass. The positive association of SLC with markers of inflammatory activity such as TNF-alpha and hs-CRP is in line with the proposed link between inflammation and insulin resistance.

Lack of association of sodium-lithium counter transport with microalbuminuria in young diabetics of Bangladesh

Background: Raised sodium-lithium counter transport activity (SLCT) in red blood cells (RBC) is claimed to be an early marker of nephropathy in type 1 and type 2 diabetic patients. This study aimed to investigate whether SLCT changes parallel with early nephropathy in young diabetics of Bangladesh. Materials and Methods: Thirty-five newly diagnosed, untreated, young and normotensive Bangladeshi diabetics without ketoacidosis, family history of hypertension and renal disease, and 19 age and body mass index (BMI) matched healthy controls without family history of hypertension and diabetes were studied to investigate whether their blood glucose, C-peptide, lipids and microalbuminuria were related with abnormality of SLCT activity. Results: Diabetic subjects had extremely variable degree of serum glucose (mmol/L) (mean ± SD) (fasting 16.6 5.8; postprandial 29.7 ± 7.5) and C-peptide (pmol/L) [median (range) (fasting 0.289 (0.028–0.994); postprandial 0.379 (0.053–2.424)], significantly higher (P 2.6 (mean + 2SD of control) was found in seven (20%) diabetics with no difference of SLCT between normoalbuminuric and microalbuminuric diabetics. Conclusions: SLCT activity in RBC is not a predictor of nephropathy in young diabetics of Bangladesh and the development of nephropathy is mainly related to glycemic and insulin status. SLCT may be elevated by marked hypoinsulinemia even without hypertension or family history of hypertension.

Association of SLC34A2 Variation and Sodium–Lithium Countertransport Activity in Humans and Baboons

Sodium-lithium countertransport (SLC) activity, an intermediate phenotype of essential hypertension, has been linked to a region of baboon chromosome 5, homologous to human chromosome 4p. Human SLC34A2, located at chromosome 4p15.1-p15.3, is a positional candidate gene for SLC. The specific aim of this study was to identify genetic variants of the SLC34A2 gene in both baboon and human, and to examine the relationship of these polymorphisms with SLC activity and blood pressure. Single-nucleotide polymorphism (SNP) was identified by sequencing the SLC34A2 gene in 24 baboon founders and 94 unrelated individuals. All tag SNPs in SLC34A2 were genotyped in 1,856 individuals from 252 pedigrees of mixed European ancestry. Three SNPs in baboon were genotyped in 634 baboons comprising 11 pedigrees. In human, one SNP (rs12501856) was found to be significantly associated with SLC individually, though it did not pass multiple testing correction; however, haplotype 2 containing allele C of SNP rs12501856 showed strong evidence of association with SLC (P = 0.0037) after multiple comparison adjustment. This haplotype was also marginally associated with diastolic blood pressure and systolic blood pressure. This finding was confirmed in baboons, where a highly significant association was detected between SLC and baboon SNP Asn136Asn (P = 0.0001). However, the associated SNP did not account for the linkage signal on baboon chromosome 5. Consistent results in two different species imply that SLC34A2 is associated with SLC activity and blood pressure.

ПОКАЗАТЕЛИ АКТИВНОСТИ НАТРИЙ-ЛИТИЕВОГО ПРОТИВОТРАНСПОРТА И ЛИПИДНОГО СПЕКТРА У ПОДРОСТКОВ С ЧАСТЫМИ РЕСПИРАТОРНЫМИ ЗАБОЛЕВАНИЯМИ

Abstract. 115 children at the age of 15—18 years were examined for the purpose of determined the degree of in fl uense of the friquent respiratory desease on the level of the activity of the sodium-lithium countertransport (SLC) end lipid spectrum. Among them 67 children had the friquent relapses of the acute respiratory desease — the 1-st group, 48 — were sick rarely — the 2-d group. Also some indices of the lipidic exchange were analyzed. During the statistical processing the method of the qartile analysis was used. It was established that according to the average the more, high velocityof the (SLC) is peculiar to the children which are in poor health. The maximum importances of all the examined indices, except of the cholesterol and the malonic dialdehyde, happened to the second quartile of the fi rst group; whereas in the second group of the second qartile the more high were the levels of the cholesterol of the lipoproteins of the low and the lowest thickness. On the basis of the preceding we can suppose that the children have the velocity of the SLC which us in the limits of 166-217 mkmol/L/RBC/h. i.e. The children of the second qartile have a greater risk of the development of dislidemios.

An association study between catalase -262C>T gene polymorphism, sodium-lithium countertrasport activity, insulin resistance, blood lipid parameters and their response to atorvastatin, in Greek dyslipidaemic patients and normolipidaemic controls

This study attempted to examine the effect of a functional catalase gene polymorphism, CAT -262C>T, on sodium-lithium countertransport (Na-Li CT) activity, insulin resistance determined as the homeostasis model assessment index (HOMA-IR), blood lipid parameters (cholesterol, triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apolipoprotein B, apolipoprotein A-I) and their response to atorvastatin, in previously characterized Greek dyslipidaemic patients and normolipidaemic controls. Putative associations were examined by running univariate analyses with a general linear model, using age, sex, smoking and hypertension as covariates. While no statistically significant associations were detected between the CAT -262C>T polymorphism and either baseline values or their modulation by atorvastatin in the patient group, HOMA-IR values were significantly (p=0.028) lower among CAT -262CC controls compared to their T allele carrier counterparts. A trend towards higher plasma triglyceride values among CAT -262CC genotypes was also detected, in both dyslipidaemic patients and normolipidaemic controls.

Urinary Stone Disease in Adults With Celiac Disease: Prevalence, Incidence and Urinary Determinants

Intestinal diseases may cause urinary stone disease via hyperoxaluria or diarrhea induced hyperconcentrated acidic urine. Data are missing on urinary stone disease in celiac disease, a common malabsorptive disorder. In this study we analyzed urinary stone disease and urine composition in adults with celiac disease. Study patients were 18 years or older, untreated, and newly diagnosed with celiac disease by serum markers and jejunal biopsy. Clinical presentation of celiac disease was assessed focusing on 5 disorders of diarrhea, and deficiency of calorie (low body mass index or weight loss), lipid (low prothrombin time or low serum lipids), iron (low hemoglobin or low serum ferritin) and calcium (low serum calcium or low bone densitometry). Urinary stone disease history was assessed by questionnaire (imaging, stone excretion, stone disruption/removal). Urinary variables were measured in a 24-hour collection in a subgroup of patients. Under untreated conditions (baseline) urinary stone disease was independent of celiac disease presentation and more prevalent in patients with celiac disease than in a population sample used as a control (608 and 3,540, 7.9% and 5.0%, sex and age adjusted odds ratio 4.0, 95% CI 2.7-5.9). Excluding from analysis individuals with baseline urinary stone disease, the incidence of urinary stone disease history was not significantly different between the treated celiac disease (gluten-free diet) and control population (458 and 3,003, 2.4% vs 3.9%). The urine of untreated patients with celiac disease differed from that of healthy volunteers with 120% higher oxalate and 43% lower calcium (in 45 and 45, p <0.001). A gluten-free diet corrected urinary abnormalities (p <0.01). Urinary stone disease risk is high in untreated patients with celiac disease independent of overt malabsorption. Hyperoxaluria is likely the underlying disorder. A gluten-free diet reduces urinary stone disease risk and oxaluria.

Sodium-Lithium Countertransport Activity in Healthy, Dyslipidemic, and Hypertensive Individuals

The aim of our study was to investigate the role of dyslipidemia on red blood cell sodium-lithium countertransport activity in healthy and hypertensive individuals. A total of 128 Caucasian individuals, aged 20 to 60 years old, were divided into 4 groups: dyslipidemic/ hypertensive, dyslipidemic/normotensive, normolipidemic/hypertensive, and normolipidemic/ normotensive (controls). Sodium-lithium countertransport activity was determined based on the Canessa et al method. Sodium-lithium countertransport activity was significantly higher in all patient groups compared with controls (P < .001) and similar in the 3 patient groups. Sodium-lithium countertransport activity was significantly and positively associated with triglyceride levels (P < .001), body mass index (P < .001), total cholesterol levels (P = .001), and systolic (P = .001) and diastolic blood pressure (P = .001). In multivariate regression analysis, triglycerides made the largest contribution to sodium-lithium countertransport variation among the variables tested (R(2) = 0.273). Our results suggest that dyslipidemia affects sodium-lithium countertransport activity independently of essential hypertension and even to a greater extent than hypertension.

Renal Response to Dietary Salt in High Sodium Lithium Countertransport (SLC) Baboons

Aim: To identify genes and pathways that regulate SLC activity, a marker for essential hypertension, we challenged normal (N) and high (H) SLC baboons with a high salt (HS) diet and compared renal transcriptome profiles.Study design: NSLC (256 ± 9) and HSLC (426 ± 17) baboons (n = 5/group) were fed a low salt diet (20 mmol/day NaCl) for 8 weeks then fed a HS diet (150 mmol/day NaCl) for 6 weeks. Kidney biopsy transcriptome data from each diet were used for pairwise, cluster and pathway analyses.Results: Analysis of HSLC vs NSLC baboons on HS showed differential expression of 8.2% of expressed genes with 148 genes up‐ and 817 genes down‐regulated [including 10 solute carrier family genes]. Eight KEGG pathways were up‐ and 32 KEGG pathways were down‐regulated including oxidative phosphorylation. Cluster analysis of both SLC groups on both diets revealed 5 clusters. One cluster included 396 genes that were salt responsive in NSLC but not HSLC baboons and included protein kinase C, central to calcium‐, PPAR‐, Wnt‐, MAPK‐, and VEGF‐signaling and NADH dehydrogenase, central to oxidative phosphorylation.Conclusions: Baboon kidney showed salt responsiveness in NSLC baboons for signaling pathways central to sensing stress and nutrients; whereas they were down‐regulated or unchanged in HSLC baboons. This suggests that the HSLC blood pressure phenotype is associated with a lack of response to dietary salt for numerous molecular pathways.

Effects of Atorvastatin on Red-blood Cell Na+/Li+ Countertransport in Hyperlipidemic Patients With and Without Hypertension

To explore the effect of short-term cholesterol-lowering treatment with atorvastatin on erythrocyte sodium-lithium countertransport (Na(+)/Li(+) CT) activity. Group A consisted of 30 patients (14 men) with mild essential hypertension (systolic blood pressure (SBP), 140-159 mm Hg and/or diastolic BP, 90-99 mm Hg) and primary hypercholesterolemia low-density lipoprotein (LDL) cholesterol >4.1 mmol/l and triglycerides (TG) <2.8 mmol/l), group B of 30 normotensive patients (16 men) with primary hypercholesterolemia, while 37 (18 men) healthy volunteers comprised the control group. After a 6-week dietary lead-in, all eligible patients were prescribed 20 mg/day of atorvastatin. Anthropometric data, blood-pressure (BP) measurements and determinations of lipid, non-lipid metabolic parameters (including homeostasis model assessment index, (HOMA-IR)) and erythrocyte Na(+)/Li(+) CT activity were collected at baseline and after 12 weeks of treatment. At baseline Na(+)/Li(+) CT activity was significantly higher in group A and B compared with the control group and correlated directly with obesity indices, systolic and diastolic BP, total cholesterol, LDL-cholesterol, TG, apolipoprotein B (apoB), HOMA-IR, uric acid and inversely with high-density lipoprotein (HDL)-cholesterol and apoA1. Systolic and diastolic BP levels, HOMA-IR and Na(+)/Li(+) CT activity were significantly decreased after atorvastatin treatment in both patient groups. The reduction in Na(+)/Li(+) CT activity correlated with baseline Na(+)/Li(+) CT activity and the changes in HOMA-IR values. Short-term treatment with atorvastatin for patients with hypercholesterolemia, and with or without essential hypertension, is associated with a significant reduction in the erythrocyte Na(+)/Li(+) CT activity, BP levels and insulin resistance independent of concomitant changes in lipid parameters.

Regional Association-based Fine-mapping for Sodium-Lithium Countertransport on Chromosome 10

Increased erythrocyte sodium-lithium countertransport (SLC) has been observed in patients with essential hypertension. Consistent evidence of genetic linkage was shown for SLC on chromosome 10, and a region of interest was localized between 26 and 56 Mb. This study surveyed single nucleotide polymorphisms (SNPs) in 54 genes that reside in the region of interest, and investigated their association with SLC and blood pressure. These SNPs were genotyped in 1,133 non-Hispanic white individuals from 255 pedigrees comprising the second phase of the Rochester Family Heart Study. The variance-components-based genetics software package SOLAR was used for evaluating whether an SNP contributed to a significant fraction of the trait heritability. Of the 77 SNPs surveyed in this study across the region of interest, four SNPs were associated with SLC (P < 0.04), five SNPs were associated with blood pressure (P < 0.04), and two SNPs in mannose-binding lectin 2 (MBL2) were associated with both phenotypes. In general, the pairwise linkage disequilibrium among the genotyped SNPs was low. This fine-mapping survey of genetic variation in a linkage region of interest provides overall support for association-mapping for SLC on chromosome 10. Genes significantly associated with systolic blood pressure and/or SLC in these families will be prioritized for future studies.

An association study of sodium-lithium countertransport activity with glutathione S transferase (GST) T1 and GST M1 null polymorphisms in Greek dyslipidaemic patients and controls

Previous genomic linkage studies have produced evidence linking sodium-lithium countertransport activity (Na/Li CT) with various chromosomal regions including loci harbouring glutathione S transferase (GST) genes. The aim of this study was to examine the putative association of erythrocyte Na/Li CT activity with GST T1 and M1 gene null polymorphisms. Na/Li CT activity was determined in erythrocytes isolated from 85 individuals, using a standard assay procedure employing atomic absorption spectroscopy. Genotyping of the GST T1 and GST M1 null polymorphisms was accomplished with a multiplex PCR method. A general linear model using age, sex, smoking, dyslipidaemia and hypertension as covariates was used to examine the association of Na/Li CT activity with the GST T1 and GST M1 genotypes. Individuals with the GST T1 null genotype displayed marginally significantly (p=0.049) lower values of Na/Li CT activity compared to those harbouring at least one copy of the GST T1 gene. The significance of this association was eliminated following adjustment for covariates (p=0.150), but survived as a trend when the sample was limited to normotensive and normolipidaemic individuals (p=0.070). No association was detected between the GST M1 null polymorphism and Na/Li CT activity. The suggestive association of the GST T1 null polymorphism with erythrocyte Na/Li CT activity is in line with previously published data from genetic linkage and biochemical analyses and may be of potential prognostic value as regards the behaviour of the countertransport and the development of related pathologies under conditions of oxidative insult.

Changes in Erythrocyte Sodium-Lithium Countertransport and Plasma Parameters Following Selenium Treatment

Changes in Erythrocyte Sodium-Lithium Countertransport and Plasma Parameters Following Selenium Treatment