Lone and secondary nonvalvular atrial fibrillation: role of a genetic susceptibility

Background: An involvement of the renin angiotensin system in atrial fibrillation (AF) has been hypothesized, and ACE DD genotype has been suggested to influence the predisposition to AF. The aim of this study was to investigate the role of the ACE I/D polymorphism in relation to the different clinical forms of AF, lone and secondary nonvalvular atrial fibrillation (NVAF). Methods: 510 consecutive patients with documented NVAF (106 patients had lone, and 404 secondary NVAF), and 520 controls with a negative history of cardiovascular disease have been studied. Results: A significant difference in allele frequency between lone and secondary NVAF (p= 0.002) has been found. The ACE D allele was associated with the predisposition to lone NVAF under a dominant, recessive and additive model, both at univariate and multivariate analysis, after adjustment for age and gender (multivariate analysis: dominant OR= 2.87, p= 0.02; recessive OR= 2.01, p= 0.003; additive OR= 4.47, p < 0.0001). ACE D allele was significantly associated with secondary NVAF at both univariate and multivariate analysis under a recessive and additive, but not dominant, model (multivariate analysis: recessive OR= 1.89, p= 0.001; additive OR= 2.50, p < 0.0001). Conclusions: This study highlights the role of ACE gene in predisposing to both lone and secondary NVAF, further contributing to penetrate the genetic mechanisms responsible for this complex disease. The clinical relevance of our results may be related to the possible characterization of subjects predisposed to NVAF in the absence of traditional risk factors, and to the use of ACE-inhibitors therapy able to improve the arrhythmogenic substrate. (C) 2006 Elsevier Ireland Ltd. All rights reserved

Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil

BACKGROUND AND OBJECTIVES: Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) within the 3R allele and a 6bp deletion in the 3' UTR. To evaluate the influence of TS expression and polymorphisms on clinical outcome of 5-FU-treated patients we performed a comprehensive genetic analysis on 63 CRC patients. METHODS: TS expression levels were analyzed in normal and tumor tissues. TS coding sequence and UTR polymorphisms were investigated on DNA from normal tissue. LOH analysis was performed to determine tumor genotype. RESULTS: A difference in disease-free survival (DFS), although not statistically significant, was observed between high and low mRNA expression levels: patients with low levels showed longer DFS. The 2R2R genotype showed significantly lower expression than the 3R3R and 2R3R genotypes in normal tissue. No other TS polymorphism was associated with mRNA expression or clinical outcome. CONCLUSIONS: The results obtained in this pilot study indicate that the number of 5' UTR repeats is the major genetic determinant of TS expression. The lack of association with other polymorphisms might be partially explained by the existence of linkage disequilibrium in the TS gene. Our data support the growing evidence that TS control may require multiple mechanisms acting in close coordination with one another and suggest that TS genotyping alone in tumor samples is not sufficient to accurately predict response to 5-FU

A founder MLH1 mutation in families from the districts of Modena and Reggio-Emilia in northern Italy with hereditary non-polyposis colorectal cancer associated with protein elongation and instability.

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The chromosome analysis of the miscarriage tissue. Miscarried embryo/fetal crown rump length (CRL) measurement: A practical use

Objective To investigate whether miscarried embryo/fetal crown rump length (CRL) measurement may yield a practical application for predicting a conclusive result at the cytogenetic analysis of miscarriage tissue. Our study might help in improving the cytogenetic method, the results of which may be affected by maternal cell contamination (MCC). In particular, we aimed at establishing whether the miscarried embryo/fetal CRL measurement shows accuracy in predicting the possibility of MCC and the scan cut-off value useful to this purpose and, as a result, suggest a multi-step procedure for the genetic ascertainment. Methods Women experiencing at least two miscarriages of less than 20 weeks size at the Pregnancy Loss Unit at Fondazione Policlinico A. Gemelli underwent a scan before surgery. The CRL value was recorded. After the dilatation and courettage (D&C) procedure, miscarriage tissue was processed through the proposed multi-step procedure before performing oligo-nucleotide- based and SNP (single nucleotide polymorphisms)-based comparative genomic hybridization (CGH+SNP) microarray analysis. Results 63 women and 63 miscarriages met the criteria. By using the Receiving Operator Characteristic (ROC) curves, CRL showed an AUC of 0.816 (95%CI:0.703\ub10.928,p<0.001). A CRL24.5 mm cut-off value showed a higher positive likelihood ratio (5.27) but, conversely, a higher negative likelihood ratio (0.64) in predicting the possibility of MCC. Microarray analysis was successful in the totality of cases in which the embryo/fetal origin of miscarriage tissues was proven

Workload measurement for molecular genetics laboratory: A survey study

Genetic testing availability in the health care system is rapidly increasing, along with the diffusion of next-generation sequencing (NGS) into diagnostics. These issues make imperative the knowledge-drive optimization of testing in the clinical setting. Time estimations of wet laboratory procedure in Italian molecular laboratories offering genetic diagnosis were evaluated to provide data suitable to adjust efficiency and optimize health policies and costs. A survey was undertaken by the Italian Society of Human Genetics (SIGU). Forty-two laboratories participated. For most molecular techniques, the most time-consuming steps are those requiring an intensive manual intervention or in which the human bias can affect the global process time-performances. For NGS, for which the study surveyed also the interpretation time, the latter represented the step that requiring longer times. We report the first survey describing the hands-on times requested for different molecular diagnostics procedures, including NGS. The analysis of this survey suggests the need of some improvements to optimize some analytical processes, such as the implementation of laboratory information management systems to minimize manual procedures in pre-analytical steps which may affect accuracy that represents the major challenge to be faced in the future setting of molecular genetics laboratory