The APOB polymorphism rs1801701 A/G (p.R3638Q) is an independent risk factor for early-onset coronary artery disease: Data from a Spanish cohort.

BACKGROUND AND AIMS: Apoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed. METHODS AND RESULTS: The study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression. The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05-1.99) and female (OR = 2.22, 95%CI = 1.58-3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression). CONCLUSION: A common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male.

[Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology]. / Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología.

The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease.

Impact of a soy drink on climacteric symptoms: an open-label, crossover, randomized clinical trial.

OBJECTIVES: The objective of this study is to evaluate the effects of a soy drink with a high concentration of isoflavones (ViveSoy®) on climacteric symptoms. METHODS: An open-label, controlled, crossover clinical trial was conducted in 147 peri- and postmenopausal women. Eligible women were recruited from 13 Spanish health centers and randomly assigned to one of the two sequence groups (control or ViveSoy®, 500 mL per day, 15 g of protein and 50 mg of isoflavones). Each intervention phase lasted for 12 weeks with a 6-week washout period. Changes on the Menopause Rating Scale and quality of life questionnaires, as well as lipid profile, cardiovascular risk and carbohydrate and bone metabolism were assessed. Statistical analysis was performed using a mixed-effects model. RESULTS: A sample of 147 female volunteers was recruited of which 90 were evaluable. In both sequence groups, adherence to the intervention was high. Regular consumption of ViveSoy® reduced climacteric symptoms by 20.4% (p = 0.001) and symptoms in the urogenital domain by 21.3% (p < 0.05). It also improved health-related quality life by 18.1%, as per the MRS questionnaire (p <0.05). CONCLUSION: Regular consumption of ViveSoy® improves both the somatic and urogenital domain symptoms of menopause, as well as health-related quality of life in peri- and postmenopausal women.

Next generation sequencing search for uromodulin gene variants related with impaired renal function.

Uromodulin gene (UMOD) mutations have been linked to rare forms of mendelian dominant medullary cystic kidney disease and familial hyperuricemia. In addition, common single nucleotide polymorphisms in the UMOD promoter have been associated with the risk for impaired renal function and chronic kidney disease. Our main purpose was to identify UMOD variants related with impaired renal function in an elderly population. The UMOD gene was next generation sequenced in a total of 100 healthy individuals with normal or reduced renal function [measured as the rate of estimated glomerular filtration (eGFR)]. The identified missense changes and the common promoter rs12917707 polymorphism were determined in individuals with reduced (n = 88) and normal (n = 442) eGFR values. Allele and genotype frequencies were compared between the groups. We only identified a rare UMOD misense change, p.V458L, and the rare leu allele was significantly more frequent in a cohort of individuals with reduced (eGFR < 60) compared to normal eGFR (P = 0.02). The common rs12917707 polymorphism previously linked to renal function and kidney disease was not associated with impaired filtration rate in our cohort. We found a significant effect of the rare p.V458L variant on the value of estimated glomerular filtration. This finding deserves further validation in larger cohorts.

[Consensus document for the detection and management of chronic kidney disease]. / Documento de consenso para la detección y manejo de la enfermedad renal crónica.

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations.

Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity.

The chemokine receptor CCR5 has been implicated in COVID-19. CCR5 and its ligands are overexpressed in patients. The pharmacological targeting of CCR5 would improve the COVID-19 severity. We sought to investigate the role of the CCR5-Δ32 variant (rs333) in COVID-19. The CCR5-Δ32 was genotyped in 801 patients (353 in the intensive care unit, ICU) and 660 healthy controls, and the deletion was significantly less frequent in hospitalysed COVID-19 than in healthy controls (p = 0.01, OR = 0.66, 95%CI = 0.49-0.88). Of note, we did not find homozygotes among the patients, compared to 1% of the controls. The CCR5 transcript was measured in leukocytes from 85 patients and 40 controls. We found a significantly higher expression of the CCR5 transcript among the patients, with significant difference when comparing the non-deletion carriers (controls = 35; patients = 81; p = 0.01). ICU-patients showed non-significantly higher expression than no-ICU cases. Our study points to CCR5 as a genetic marker for COVID-19. The pharmacological targeting of CCR5 should be a promising treatment for COVID-19.

[Development and validation of a generic questionnaire for evaluating satisfaction in patients with chronic disease: the SAT-Q Questionnaire]. / Desarrollo y validación de un cuestionario genérico para la evaluación de la satisfacción de los pacientes crónicos: Cuestionario SAT-Q.

OBJECTIVES: To develop and validate a brief general questionnaire to assess satisfaction in patients with chronic disease. DESIGN: epidemiological, observational, multicentre cross-sectional study. LOCATION: 4 Primary Health Care Centers from the IV Health Area in the Principality of Asturias. SUBJECTS: A total of 202 patients diagnosed with chronic illness who were following a pharmacological regimen for at least one year. METHODS: An extensive literature review was conducted to create an initial item pool of 61 questions regarding patient satisfaction. Then, a forward-backward translation into Spanish was carried out. Next, both the expert (n=8) and patient (n=30) panels led to a new version of 34 items (concerning satisfaction with medication and satisfaction with health service). Finally, scale item reduction (item-total correlation and exploratory factorial analysis -EFA-) and psychometrical validation (feasibility, reliability and criterion validity) of the SAT-Q- were evaluated. Both the SAT-Q and the SF-12 (to assess patient health related quality of life) were applied. RESULTS: Item reduction analysis resulted in 18 items: general satisfaction with medication (3), adverse-events (3), oversights (2), effectiveness (3), convenience (4) and Health services (3). Internal consistency (Cronbach α) and Intraclass Correlation Coefficients were moderate-high. Moreover, significant positive correlations between SAT-Q scores and SF-12 Physical and Mental Summary Components were found (with the exception of oversights). CONCLUSIONS: A brief questionnaire for measuring satisfaction in chronic patients has been developed and preliminary validated.

Factors associated with the discontinuation of evidence-based cardiovascular therapies in patients with stable coronary artery disease: a primary care perspective.

BACKGROUND: To identify factors associated with the discontinuation of evidence-based cardiovascular therapies after hospital discharge for a coronary event. DESIGN: Cross-sectional study carried out between June and October 2004 in 1799 primary care centers throughout Spain. PATIENTS AND METHODS: Eight thousand eight hundred and seventeen patients (73.7% males; 65.4 years) admitted for coronary disease causes in the past 6 months to 10 years and attending primary care postdischarge from hospital. Current medications, those prescribed at hospital discharge, and the development of adverse events, new risk factors, and comorbidities during follow-up, were collected from clinical records. RESULTS: After a median follow-up of 37.4 months, discontinuation rate of lipid-lowering agents, angiotensin renin system blockers, antiplatelet drugs, and beta-blockers were 7.2, 9.1, 10, and 20%, respectively. Of these, 10.8, 16.5, 9.9, and 20.1%, respectively, were because of adverse events. Factors associated with the discontinuation of lipid-lowering agents were the development of hypertension and diabetes during the follow-up. Discontinuation of antiplatelet drug was associated with an earlier history, or with de-novo occurrence, of atrial fibrillation. Discontinuation of angiotensin renin system blockers was associated with the development of atrial fibrillation, diabetes and hypercholesterolemia, and discontinuation of beta-blockers with de-novo appearance of peripheral artery disease, cerebrovascular disease, and heart failure. CONCLUSION: In patients followed-up in primary care, the discontinuation rate of cardiovascular disease medications was low and was mainly related to the development of adverse events together with new risk factors and comorbidities arising after hospital discharge.

Achievement of therapeutic goals and utilization of evidence-based cardiovascular therapies in coronary heart disease patients with chronic kidney disease.

To evaluate whether the presence of chronic kidney disease (CKD) influenced the rate of prescription of evidence-based cardiovascular preventive therapies and attainment of therapeutic goals in patients with stable coronary heart disease, 7,884 patients (mean age 65.4 years; 81.7% men; 22.4% with CKD) attended to in 1,799 primary-care centers and who had had a coronary event requiring hospitalization in the previous 6 months to 10 years were recruited. Glomerular filtration rate (GFR) was estimated using the MDRD Study equation. Results indicated that patients with CKD received more diuretics (47.6% vs 32.8%; p = 0.034), calcium channel blockers (29.3% vs 23.2%, p = 0.027); and blockers of the angiotensin-renin system (76.4% vs 65.3%; p <0.001). The lower prescription rate of antiaggregants, beta blockers, and statins in subjects with CKD did not reach statistical significance in multivariate analysis. A lower percentage of subjects with CKD achieved good control of blood pressure (39.2% vs 65.4%; p <0.001) and glycosylated hemoglobin (43.9% vs 53.4%; p <0.001) relative to patients without CKD. Only 11.8% of patients with CKD had optimum control of all risk factors. Using multivariate analysis, the presence of CKD was inversely related to the degree of risk-factor control, especially in groups with low GFR. In conclusion, patients with stable coronary heart disease and CKD attended to in primary-care centers had poorer control of coronary heart disease risk factors than those with normal GFR despite receiving a similar rate of prescription of evidence-based cardiovascular disease preventive therapies.

[Occult chronic kidney disease in patients with stable coronary heart disease]. / Insuficiencia renal crónica oculta en pacientes con enfermedad coronaria estable.

BACKGROUND AND OBJECTIVE: Chronic kidney disease (CKD) increases cardiovascular risk mainly in subjects with coronary heart disease. The aim of this study was to evaluate the prevalence of occult CKD (OCKD) in stable coronary heart disease patients and to study the factors associated in order to improve its detection. PATIENTS AND METHOD: Cross sectional study of 7,884 patients who had had a coronary event requiring hospitalization in the previous 6 months to 10 years. Glomerular filtration rate was estimated by means of the Modification of Diet in Renal Disease (MDRD) study equation. CKD was defined as a glomerular filtration rate lower than 60 ml/min/1.73 m(2), and OCKD when, in addition, serum creatinine was < 133 mmol/l in men and < 124 mmol/l in women. RESULTS: The mean age was 65.3 years, 73.7% male and 22.4% had CKD, 68.3% of them with normal serum creatinine. In subjects with OCKD the prevalence of risk factors and cardiovascular diseases associated was intermediate between subjects without CKD and subjects with CKD and high serum creatinine. Age, female sex, hypertension, diabetes, heart failure, cerebrovascular disease and peripheral artery disease were significantly and independently associated with OCKD in the multivariate analysis. CONCLUSIONS: Almost one in 4 subjects with stable coronary heart disease had CKD, most of them with normal serum creatinine, mainly women and older patients.

Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology. / Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología.

The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease.

Genetic Variation in the H19-IGF2 Cluster Might Confer Risk of Developing Impaired Renal Function.

The H19-IGF2 imprinted gene region could be implicated in the risk of developing impaired renal function (IRF). Our aim was to determine the association of several common H19-IGF2 variants and IRF in a cohort of elderly healthy individuals. The study involved 675 individuals >65 years of age, 184 with type 2 diabetes mellitus (T2DM), and 105 with IRF (estimated glomerular filtration rate [eGFR] <60). They were genotyped for two common H19 single nucleotide polymorphisms (SNPs) (rs2839698 and rs10732516), one H19-IGF2 intergenic indel (rs201858505), and one indel in the 3'UTR of the IGF2. For the H19 SNPs, we also determined the allele present in the methylated chromosome through genotyping the DNA digested with a methylation-sensitive endonuclease. None of the four H19-IGF2 variants was associated with IRF in our cohort. We found a significantly higher frequency of the 3'UTR IGF2 deletion (D) in the eGFR <60 group (p = 0.01; odds ratio = 1.16, 95% confidence interval = 1.10-2.51). This association was independent of age and T2DM, two strong predictors of IRF. In conclusion, a common indel variant in the 3'UTR of the IGF2 gene was associated with the risk of IRF. This association could be explained by the role of IGF2 in podocyte survival, through regulation of IGF2 expression by differential binding of miRNAs to the indel sequences. Functional studies should be necessary to clarify this issue.

Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and their association with type 2 diabetes and impaired renal function.

The NF-kappaB pathway might play a role in the pathogenesis of renal disease and type 2 diabetes (T2DM). Our aim was to determine whether common polymorphisms in NF-kappaB genes were associated with impaired renal function and T2DM in a cohort of healthy elderly individuals. We studied 487 individuals, all Caucasian and aged 65-85 years. A total of 104 (21%) had impaired renal function (estimated glomerular filtration rate, eGFR < 60) and 146 (30%) were classified as diabetics. The genotypes of 4 common variants were determined through PCR-RFLP or fluorescent capillary electrophoresis. The NFKB1 variants were significantly associated with T2DM: rs7667496 p = 0.01, OR = 1.68; and rs28362491 p = 0.02, OR = 1.67. They remained significantly associated in a multiple logistic regression with age, gender, hypertension, body mass index, and cholesterol. There was a trend toward the association of these variants with eGFR < 60. The two NFKB1 variants were in linkage disequilibrium (D' = -0.86), and homozygous for the two non-risk alleles (rs7667496 CC + rs28362491 II), were significantly more common in the non-diabetics (p = 0.02). In our cohort the NFKB1 variation was an independent risk factor for developing T2DM. Additional studies to confirm this association are of special interest, as well as studies to give a functional explanation to the genetic association.

Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.

BACKGROUND: Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. METHODS AND RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (P=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign. CONCLUSIONS: We provide a compelling evidence of the involvement of FLNC in the development of HCM. Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.

Evidence-based cardiovascular therapies and achievement of therapeutic goals in diabetic patients with coronary heart disease attended in primary care.

BACKGROUND: Diabetic patients have a higher rate of recurrent cardiovascular events and death than nondiabetic individuals. Although partially attributable to lower use of evidence-based preventive therapies, studies are lacking on the prescription rate during the stable phase of the disease. METHODS: Between June 1 and October 19, 2004, we obtained, from 1799 primary care centers throughout Spain, data on 8817 subjects (mean age 65.4 years, 73.7% male, 32.7% with diabetes) who had had a coronary event requiring hospitalization in the previous 6 months to 10 years. RESULTS: After adjustment for confounding variables, the diabetic patients received more frequent treatment with angiotensin-renin system blockers (73.5% vs 61%, P < .001), calcium channel blockers (29.8% vs 21.9%, P < .001), nitrates (58% vs 47.5%, P < .001), digoxin (6.6% vs 3.9%, P < .001), and diuretics (46.2% vs 32.2%, P < .001), but it is similar with respect to lipid-lowering drugs (81.1% vs 80.3%), antiplatelet drugs (80.2% vs 80.2%), or beta-blockers (45.4% vs 47.7%). The percentage of diabetic subjects attaining objectives for smoking habit, low-density lipoprotein cholesterol, blood pressure, and glycated hemoglobin were 90.7%, 29%, 38.2%, and 49.7%, respectively. Only 7% had optimum control of all their risk factors. The parameters most closely related to optimum treatment and risk-factor control were the specialist follow-up and the attending physician's awareness of appropriate treatment objectives. CONCLUSIONS: A significant percentage of diabetic patients with stable coronary disease receive evidence-based preventive medications in primary care. However, the percentage achieving adequate control of their risk factors is low and is related to the level of physician awareness of appropriate therapeutic targets.

KCNQ1 gene variants in the risk for type 2 diabetes and impaired renal function in the Spanish Renastur cohort.

Several common KCNQ1 gene polymorphisms have been associated with the risk of type 2 diabetes (T2DM) and diabetic nephropathy. This effect is explained by the role of the kcnq1 protein as a potassium channel that in the pancreatic beta-cells drives an electrical signal that facilitates glucose-stimulated insulin secretion. The KCNQ1 gene is also expressed in the kidney, and could thus be implicated in the risk of developing impaired renal function. To test this hypothesis, we genotyped six common KCNQ1 gene variants (three single nucleotide polymorphisms, rs2237892, rs2237895, and rs231362, and three intronic indels) in 681 healthy elderly individuals (>65 years old) from the Spanish Renastur cohort. None of the six variants was associated with T2DM (180 diabetics vs. 581 non-diabetics). The intron 12 insertion allele was associated with a reduced estimated glomerular filtration rate (eGFR<60, n = 90 vs. eGFR≥60, n = 591; II vs ID + DD genotypes, p = 0.031, OR = 2.06, 95%CI = 1.12-4.14). We also performed a next generation sequencing search of variants in the coding regions of the KCNQ1 gene in 100 individuals with the extreme eGFR values. We found two rare amino acid changes (p.K393N and p.P408A) and the 393 Asn variant was found only among diabetics (n = 4; p = 0.05). The two rare alleles were present in the two eGFR groups. Our results suggest that a common KCNQ1 intron 12 indel polymorphism is a risk factor for impaired renal function independent of T2DM. If this association is confirmed by others, further research to determine the mechanism that drives this association would be warranted.

Cardiovascular risk factors in type 2 diabetic patients: multifactorial intervention in primary care.

BACKGROUND: Cardiovascular disease is the main cause of morbidity and mortality in patients with type 2 diabetes mellitus (DM). Intervention on cardiovascular risk factors (CVRF) is essential to obtain clinical results reducing the excess of cardiovascular risk (CVR) in these patients. METHODS: The objective of this study was to describe the association of type 2 DM with modifiable cardiovascular risk factors and the degree of control of these in a population of type 2 diabetics in attendance in primary care clinics, and also to establish prospectively whether an integral and multifactorial intervention on uncontrolled cardiovascular risk factors, carried out in conditions of routine clinical practice by applying an open protocol, could significantly reduce the estimated CVR according to the Framingham scale. The proposed intervention included both actions aimed at modifying habits, and pharmacologic intervention to achieve an optimum level of control in accordance with international recommendations for the objectives and treatment for type 2 diabetes. RESULTS: A total of 3466 patients with a mean age of 58 +/- 7.5 years were studied and followed-up for 1 year. Of these, 90.4% of patients had high blood pressure; 60.1% of men and 32.7% of women presented CVR >20% in 10 years according to the Framingham scale by categories. Intervention at 1 year of follow-up had achieved statistically significant reductions in blood pressure, glycated hemoglobin, and lipid levels, but not of patients' body weight. After 1 year of follow-up, 29% of males and 24% of women with a high CVR (>20%) at the start of the study presented reduced risk levels. CONCLUSION: The results of the study demonstrate that an integrated and multifactorial intervention in type 2 diabetic patients can achieve clinically significant reductions in CVR. However, conducted in effective conditions, it is not able to achieve optimum levels of control in spite of the initial proposal, possibly due to some degree of inertia in routine clinical practice.

Association between the IL17RA rs4819554 polymorphism and reduced renal filtration rate in the Spanish RENASTUR cohort.

DNA variants at the genes that encode components of the IL17-pathway may contribute to the risk of impaired renal function/chronic kidney disease. Our aim was to determine whether common IL17RA single nucleotide polymorphisms (SNPs) were associated with a reduced estimated glomerular filtration rate (eGFR) in a cohort of healthy elderly individuals (n=650). We found a significantly higher frequency of SNP rs4819554 AA homozygotes among individuals with eGFR<60 ml/min/1.73 m(2) (n=90) (p=0.005, OR=2.11; 1.26-3.54), an effect that was independent of the presence of type 2 diabetes. Allele rs4819554 A had been associated to the risk of developing end stage renal disease, and was also linked to an increased expression of the IL17RA protein and higher levels of Th17 cell subsets. A scenario in which the pro-inflammatory role of the IL17-pathway contributes to kidney damage might explain the association between Il17RA polymorphisms and an impaired renal function.