ABSTRACT
Background
Chronic kidney disease (CKD) is associated with increased atherosclerotic burden and higher risk for cardiovascular events (CVE). Atherosclerosis has a significant genetic ...component and, in CKD, it is influenced by mineral metabolism alterations. Therefore, genetic modifications of mineral metabolism–related proteins could affect atherosclerosis in CKD patients. In the present study we investigated the role of single nucleotide polymorphisms (SNPs) of the matrix gamma-carboxy glutamic acid protein (MGP) on atherosclerosis progression and CVE in a CKD cohort.
Methods
A total of 2187 CKD patients from the Observatorio Nacional de Aterosclerosis en Nefrologia (NEFRONA) study were genotyped for SNPs present in the matrix gamma-carboxy glutamic acid (Gla) protein (MGP) gene. Atheromatosis was detected by vascular ultrasound. Progression of atheromatosis, defined as an increase in territories with plaque, was assessed after 24 months. Patients were followed for 48 months for CVE. Association of SNPs with plaque progression was assessed by logistic regression and their capacity to predict CVE by Cox regression.
Results
Three SNPs of the MGP gene were analyzed. No association of the rs4236 or the rs1800801 SNPs was detected with any of the outcomes. However, patients homozygotes for the minor allele of the rs1800802 SNP showed higher adjusted risk for plaque progression odds ratio 2.3 (95% confidence interval 1.06–4.9) and higher risk of suffering a CVE hazard ratio 2.16 (95% confidence interval 1.13–4.12) compared with the rest of genotypes. No association of the SNP with total or dp-ucMGP levels was found in a subsample.
Conclusions
The rs1800802 polymorphism of MGP is associated with plaque progression and CVE in CKD patients.
Graphical Abstract
Graphical Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is attributable to a deficiency of mismatch repair. Inactivation of DNA mismatch repair underlies the genesis of microsatellite instability in ...colorectal cancer. Germline mutations in three DNA mismatch repair genes, hMSH2, hMLH1, and hMSH6, have been found to segregate in HNPCC and HNPCC-like families. The two DNA mismatch repair genes hPMS1 and hPMS2 have also been suggested to predispose to HNPCC. In this study, 84 HNPCC and HNPCC-like kindreds without known mutations in the other three known DNA mismatch repair genes were screened for germline mutations in the hPMS1 or hPMS2 gene. No clear-cut pathogenic mutations were identified. Conversion technology was used to detect a large hMSH2 deletion in two affected members of the kindred in which the hPMS1 mutation was originally reported, whereas the hPMS1 mutation was only present in one of these two individuals. Since the hPMS1 and hPMS2 genes were first reported, germline mutations in hPMS2 have been demonstrated primarily in patients with Turcot's syndrome. However, no mutation in any of the two genes has been found to segregate in HNPCC families. Until there is better evidence for an increased colorectal cancer risk associated with germline mutations in these genes, a conservative interpretation of the role of mutations in these genes is advised.
Background
Complications in sleeve gastrectomy (SG) can cast a shadow over the technique’s good results and compromise its safety. The aim of this study is to identify risk factors for complications, ...and especially those that can potentially be modified to improve safety.
Methods
A retrospective multicenter cohort study was carried out, involving the participation of 29 hospitals. Data was collected on demographic variables, associated comorbidities, technical modifications, the surgeon's experience, and postoperative morbimortality. A multivariate logistic regression analysis was carried out on risk factors (RFs) for the complications of leak/fistula, hemoperitoneum, pneumonia, pulmonary embolism, and death.
Results
The following data were collected for 2882 patients: age, 43.85 ± 11.6. 32.9 % male; BMI 47.22 ± 8.79; 46.2 % hypertensive; 29.2 % diabetes2; 18.2 % smokers; bougie calibre ≥40 F 11.1 %; complications 11.7 % (2.8 % leaks, 2.7 % hemoperitoneum, 1.1 % pneumonia, 0.2 % pulmonary embolism); and death 0.6 %. RFs for complications were as follows: surgeon’s experience < 20 patients, OR 1.72 (1.32–2.25); experience > 100 patients, OR 0.78 (0.69–0.87); DM2, OR1.48(1.12–1.95); probe > 40 F, OR 0.613 (0.429–0.876). Leak RFs were the following: smoking, OR1.93 (1.1–3.41); surgeon’s experience < 20 patients, OR 2.4 (1.46–4.16); experience of 20–50 patients, OR 2.5 (1.3–4.86); experience >100 patients, OR 0.265 (0.11–0.63); distance to pylorus > 4 cm, OR 0.510 (0.29–0.91). RFs for death were as follows: smoking, OR 8.64 (2.63–28.34); DM2, OR 3.25 (1.1–9.99); distance to pylorus < 5 cm, OR 6.62 (1.63–27.02).
Conclusions
The safety of SG may be compromised by nonmodifiable factors such as age >65, patient comorbidities (DM2, hypertension), and prior treatment with anticoagulants, as well as by modifiable factors such as smoking, bougie size <40 F, distance to the pylorus <4 cm, and the surgeon’s experience (<50–100 cases).
Summary TNM stage I colorectal cancer is commonly characterized by a good prognosis, with 5-year survival of around 80% to 90%. Nonetheless, disease progression occurs in a percentage of cases, ...although the causes of an adverse clinical course still remain to be clarified. In the present study, we analyzed and compared the immunohistochemical expression of neutrophil gelatinase–associated lipocalin, an iron-binding protein, which is involved in colorectal cancer progression, in series a of 29 surgically resected colorectal carcinomas obtained from patients who died of the disease and in a cohort of 22 colorectal cancers from patients alive 5 years after the initial diagnosis. The prognostic value of neutrophil gelatinase–associated lipocalin expression on the overall survival to colorectal cancer was investigated. Variable neutrophil gelatinase–associated lipocalin immunoexpression was demonstrated in 23 of the 51 analyzed cases, with a significantly higher frequency of positive cases among patients who died of the disease. Moreover, neutrophil gelatinase–associated lipocalin expression appeared to be a significant independent negative prognostic marker related to shorter overall survival in stage I colorectal carcinoma. If our findings are confirmed in further analyses, neutrophil gelatinase–associated lipocalin assessment might be used to select patients with a higher risk of progression and to find adjuvant therapies for the prevention of adverse outcomes.
The DNA glycosylase gene MBD4 safeguards genomic stability at CpG sites and is frequently mutated at coding poly-A tracks in mismatch repair (MMR)-defective colorectal tumors (CRC). Mbd4 biallelic ...inactivation in mice provided conflicting results as to its role in tumorigenesis. Thus, it is unclear whether MBD4 alterations are only secondary to MMR defects without functional consequences or can contribute to the mutator phenotype. We investigated MBD4 variants in a large series of hereditary/familial and sporadic CRC cases. Whereas MBD4 frameshifts were only detected in tumors, missense variants were found in both normal and tumor DNA. In CRC with double-MBD4/MMR and single-MBD4 variants, transition mutation frequency was increased, indicating that MBD4 defects may affect the mutational landscape independently of MMR defect. Mbd4-deficient mice showed reduced survival when combined with Mlh1-/- genotype. Taken together, these data suggest that MBD4 inactivation may contribute to tumorigenesis, acting as a modifier of MMR-deficient cancer phenotype.
Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk ...factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2,445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionization-time of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD.
Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the ...biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with non-cardiovascular death in CKD populations are lacking.
The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (
= 2185 CKD patients).
After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG + rs2283368 CC/CT + rs2320762 GG). Among the patients with the three SNPs genotyped (
= 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA + rs2283368 TT + rs2320762 GT/TT). All the other combinations
= 846 (83.3%) were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher {hazard ratio HR 3.28 confidence interval (CI) 1.51-7.12} and lower HR 6 × 10
(95% CI 3.3 × 10
-1.1 × 10
) risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination.
Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD.
Abstract
Background
Chronic kidney disease (CKD) patients show an increased burden of atherosclerosis and high risk of cardiovascular events (CVEs). There are several biomarkers described as being ...associated with CVEs, but their combined effectiveness in cardiovascular risk stratification in CKD has not been tested. The objective of this work is to analyse the combined ability of 19 biomarkers associated with atheromatous disease in predicting CVEs after 4 years of follow-up in a subcohort of the NEFRONA study in individuals with different stages of CKD without previous CVEs.
Methods
Nineteen putative biomarkers were quantified in 1366 patients (73 CVEs) and their ability to predict CVEs was ranked by random survival forest (RSF) analysis. The factors associated with CVEs were tested in Fine and Gray (FG) regression models, with non-cardiovascular death and kidney transplant as competing events.
Results
RSF analysis detected several biomarkers as relevant for predicting CVEs. Inclusion of those biomarkers in an FG model showed that high levels of osteopontin, osteoprotegerin, matrix metalloproteinase-9 and vascular endothelial growth factor increased the risk for CVEs, but only marginally improved the discrimination obtained with classical clinical parameters: concordance index 0.744 (95% confidence interval 0.609–0.878) versus 0.723 (0.592–0.854), respectively. However, in individuals with diabetes treated with antihypertensives and lipid-lowering drugs, the determination of these biomarkers could help to improve cardiovascular risk estimates.
Conclusions
We conclude that the determination of four biomarkers in the serum of CKD patients could improve cardiovascular risk prediction in high-risk individuals.
The aim of the study was to investigate the clinical features, including survival, of patients with colorectal malignancies developed at a very early age (≤40 years), together with possible factors ...involved in the pathogenesis of these rare neoplasms. The study took advantage of the existence of a specialized colorectal cancer Registry active from 1984. 57 patients met the criteria of early onset cancer; main epidemiological data, morphology, stage, familial aggregation, possible role of inheritance and survival were analyzed. Despite the relevant increase over time of all registered patients, joiningpoint analysis of crude incidence rate of early onset colorectal neoplasms revealed a certain stability of these tumors (EAPC: 2.4, CI 14–22) with a constant prevalence of the male sex. Stage at diagnosis did not show significant variations between early onset and maturity onset colorectal neoplasms. Hereditary as well as familial cases were significantly (
P
< 0.005 and 0.03) more frequent among patients with early onset tumors, although in the majority of them no specific etiological factor could be identified. Survival was more favorable in patients with early onset tumors, though this had to be attributed to the higher presence of some histological types in early onset cases. Survival was significantly more favorable for patients of all ages registered in the last decade. Incidence of early onset colorectal cancer was relatively stable between 1984 and 2008. A male preponderance was evident through the registration period. Hereditary and familial cases were significantly more frequent among early onset case. A well defined etiology could be observed in 16 % of the cases (versus 2–3 % in older individuals). Five-year survival showed a significant improvement over time.
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