Influence of vitamin D-related gene polymorphisms (CYP27B and VDR) on the response to interferon/ribavirin therapy in chronic hepatitis C.

BACKGROUND AND AIMS: Vitamin D exerts immunomodulatory effects on the host response against infection with hepatitis C virus (HCV). This study was performed to assess the putative influence of polymorphisms in vitamin D-related genes on the response to antiviral therapy in patients with chronic hepatitis C (CHC). METHODS: Single nucleotide polymorphisms (SNPs) in CYP27B-1260 gene promoter (rs10877012AC) and in vitamin D receptor (VDR) gene rs2228570TC, rs1544410CT, rs7975232AC and rs731236AT were analyzed in a cohort of 238 Caucasian CHC patients treated with pegylated interferon (Peg-IFN) plus ribavirin (RBV). Multivariate analyses were performed to exclude confounding effects of well-known baseline predictors of response to therapy (HCV genotype and load, IL28B genotype, age, and GGT and serum cholesterol). RESULTS: Three SNPs at the VDR gene (rs1544410, rs7975232 and rs731236) were in strong linkage disequilibrium, with the CCA haplotype predicting therapeutic failure [Odds ratio 2.743; (95% C.I. 1.313-5.731), p = 0.007]. The carrier state of the VDR rs2228570 T allele was inversely related to the probability of therapeutic failure [Odds ratio 0.438; 95 C.I. (0.204-0.882), p = 0.021]. No relation existed between CYP27B-1260 rs10877012 polymorphism and response to therapy. The area under the operating curve (AUROC) based on the model including all variables significantly related to the response to therapy was 0.846 (95% confidence interval = 0.793-0.899). CONCLUSION: VDR gene polymorphisms are independently related to the response to Peg-IFN+RBV therapy in chronic hepatitis C and could be used as complementary biomarkers of response when included in a prediction algorithm in association with demographic, virologic, biochemical and genetic traits.

Serum level of fibroblast growth factor 23 in maintenance renal transplant patients.

BACKGROUND: The discovery of fibroblast growth factor 23 (FGF23) provides a new conceptual framework that improves our understanding of the pathogenesis of post-transplant bone disease. Excess FGF23 is produced in the early post-transplant period; levels return to normal in the months following transplant. However, few manuscripts discuss FGF23 levels in stable long-term renal transplant recipients. METHODS: We performed a cross-sectional observational study of 279 maintenance kidney recipients with chronic kidney disease (CKD) Stages 1-4 and stable allograft function who had received their transplant at least 12 months previously. We calculated the estimated GFR (eGFR) using the MDRD4 equation. RESULTS: FGF23, parathyroid hormone (PTH) and phosphorus values were higher in more advanced stages, while the serum calcitriol levels and the phosphate reabsorption rate were lower. A significant inverse correlation was found between eGFR and FGF23 (r = -0.487; P < 0.001), PTH (r = -0.444; P < 0.001), serum phosphate levels (r = -0.315; P < 0.001) and fractional excretion of magnesium (r = -0.503; P < 0.001). Multivariable analysis showed that increased time on corticosteroids (P < 0.001), PTH (P < 0.001), serum phosphate (P = 0.003), decreased serum calcitriol (P = 0.049) and estimated glomerular filtration (P = 0.003) rate were associated with high FGF23 levels. In contrast with pre-transplant patients and first year post-transplant patients, higher FGF23 values were not correlated with increased phosphate excretion. An elevated phosphate reabsorption rate was associated with decreased PTH (P < 0.001) and calciuria (P = 0.028) and increased serum calcitriol (P = 0.009), plasma bicarbonate (P = 0.024) and estimated glomerular filtration (P = 0.003). CONCLUSIONS: Serum FGF23 concentrations remain increased in long-term kidney graft recipients, even in the early stages of CKD. It remains to be seen whether measures aimed at reducing serum levels of PTH and phosphate and/or corticosteroid doses might help to lower serum FGF23 and whether this will improve kidney recipient outcomes.

La inestabilidad de microsatélites predice un mejor pronóstico en los pacientes intervenidos de carcinoma colorrectal / Microsatellite instability predicts better outcome in colorectal cancer patients

FUNDAMENTO Y OBJETIVO: En el carcinoma colorrectal se describen 2 vías genéticas diferentes implicadas en la génesis del tumor: la inestabilidad cromosómica, debida a la alteración de genes supresores o protooncogenes, y la inestabilidad de microsatélites, originada por alteraciones en los genes reparadores del ADN. PACIENTES Y MÉTODO: En este estudio se determina la frecuencia y el significado clínico de la vía de la inestabilidad de microsatélites en una cohorte prospectiva consecutiva de 106 pacientes intervenidos por carcinoma colorrectal por un mismo cirujano. Para la determinación de la inestabilidad de microsatélites se han seguido los criterios propuestos por el National Cancer Instituteen 1998. RESULTADOS: El 9,4% de los pacientes muestra una alta inestabilidad y el 11,3% una inestabilidad baja. Ambos grupos presentan diferentes características clínico patológicas (edad, sexo, localización del tumor y tipo histológico). En el análisis multivariante de la supervivencia global y de la supervivencia libre de enfermedad, la alta inestabilidad presenta un valor pronóstico independiente del resto de las variables clínico patológicas analizadas (p < 0,0001). CONCLUSIONES: La alteración genética que supone la alta inestabilidad de microsatélites confierea los pacientes con cáncer colorrectal un mejor pronóstico

BACKGROUND AND OBJECTIVE: Two different pathways for the development of tumor have been described in colorectal carcinoma: the chromosomic instability, raised by suppressor genes and protooncogene alterations, and the microsatellite instability (MSI), caused by alterations in DNA repairing genes. PATIENTS AND METHOD: The frequency and the clinical meaning of the Microsatellites instability pathway were determined in a consecutive prospective cohort of 106 patients who underwent surgical resection of colorectal carcinoma by a single surgeon. Microsatellite instability determination was established according to the criteria proposed by the National Cancer Institute in1998. RESULTS: 9.4% of patients had a high instability and it was low in 11.3%; both groups displayed different clinico-pathological characteristics (age, sex, tumor site and histologic type). In the multivariant analysis of overall survival and disease free survival, high instability exhibited prognostic value independent of the rest of variables evaluated (p < 0.0001). CONCLUSIONS: The genetic alterations giving rise to microsatellite instability lead to a better prognosis in patients with colorectal cancer