Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.

Bayesian Machine Learning Techniques for revealing complex interactions among genetic and clinical factors in association with extra-intestinal Manifestations in IBD patients.

The objective of the study is to assess the predictive performance of three different techniques as classifiers for extra-intestinal manifestations in 152 patients with Crohn's disease. Naïve Bayes, Bayesian Additive Regression Trees and Bayesian Networks implemented using a Greedy Thick Thinning algorithm for learning dependencies among variables and EM algorithm for learning conditional probabilities associated to each variable are taken into account. Three sets of variables were considered: (i) disease characteristics: presentation, behavior and location (ii) risk factors: age, gender, smoke and familiarity and (iii) genetic polymorphisms of the NOD2, CD14, TNFA, IL12B, and IL1RN genes, whose involvement in Crohn's disease is known or suspected. Extra-intestinal manifestations occurred in 75 patients. Bayesian Networks achieved accuracy of 82% when considering only clinical factors and 89% when considering also genetic information, outperforming the other techniques. CD14 has a small predicting capability. Adding TNFA, IL12B to the 3020insC NOD2 variant improved the accuracy.

Modeling the role of genetic factors in characterizing extra-intestinal manifestations in Crohn's disease patients: does this improve outcome predictions?

OBJECTIVE: To evaluate to what extent an inefficient statistical model affects the study of genetic factors in extra-intestinal manifestations of Crohn's disease (CD) and how clinical predictions can be improved using more adequate techniques. MATERIALS: Extra-intestinal manifestations were studied in 152 CD patients. Three sets of variables were considered: (1) disease characteristics--presentation, behavior, location; (2) generic risk factors--age, gender, smoke and familiarity; and (3) genetic polymorphisms of the NOD2, CD14, TNF, IL12B, and IL1RN genes, whose involvement in CD is known or suspected. METHODS: Six statistical classifiers and data mining models were applied: (1) logistic regression as a benchmark; (2) generalized additive model; (3) projection pursuit regression; (4) linear discriminant analysis, (5) quadratic discriminant analysis; (6) artificial neural networks one-layer feed forward. Models were selected using the Akaike Information criterion and their accuracy was compared with several indexes. RESULTS: Extra-intestinal manifestations occurred in 75 patients. The model with clinical variables only selected familiarity, gender, presentation, and behavior as significantly associated with extra-intestinal manifestations, whereas when the genetic factors were also included familiarity was no longer significant, being replaced by the NOD2, TNF, and IL12B single nucleotide polymorphisms. The projection pursuit regression performed best in predicting individual outcomes (Kappa statistics 0.078 [SE 0.09] without and 0.108 [SE 0.075] with genetic information). One-layer artificial neural networks did not show any particular improvement in terms of model accuracy over nonlinear techniques. CONCLUSIONS: The correct identification of factors associated with extra-intestinal symptoms in CD, in particular the genetic ones, is highly dependent on the model chosen for the analysis. By using the most sophisticated statistical models, the accuracy of prediction can be strengthened by 10-64%, compared with linear regression.

Prospective assessment of XPD Lys751Gln and XRCC1 Arg399Gln single nucleotide polymorphisms in lung cancer.

PURPOSE: XRCC1 and XPD play key roles in the repair of DNA lesions and adducts. Contrasting findings have been reported on the effect of polymorphisms of these genes on the response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). This study aimed to investigate the relationship between the XPD Lys751Gln and XRCC1 Arg399Gln genotypes and outcome in lung cancer patients. EXPERIMENTAL DESIGN: We genotyped 203 NSCLC and 45 small-cell lung carcinoma (SCLC) patients for the two polymorphisms. Most of the patients (81%) received a platinum-based chemotherapy. RESULTS: The patients' genotype frequencies did not significantly differ from controls and both groups were in Hardy-Weinberg equilibrium for the two polymorphisms. The XRCC1399 Gln/Gln variant genotype was associated with a higher median survival time (80 weeks versus 54.6 weeks for the Arg/Gln heterozygous and 55.6 weeks for the wild-type Arg/Arg genotype; P=0.09). At the multivariable analysis adjusted for histology, stage of the disease, performance status, age, and gender, the Gln/Gln genotype was associated with a better survival of borderline significance in the subgroup of patients treated with cisplatin (hazard ratio, 0.55; 95% CI, 0.30-1.00); this association became significant for those with grade 3-4 clinical toxicity (hazard ratio, 0.46; 95% CI, 0.22-0.98). No association between XPD Lys751Gln genotype and clinical outcome was found. CONCLUSION: This prospective investigation provides suggestive evidence of a favorable effect of the XRCC1399 Gln/Gln genotype on survival in platinum-treated NSCLC and, for the first time, in SCLC patients also. This contrasts with other authors who did not include non-platinum-treated patients, but it does fit the expectation for a suboptimal ability to remove DNA adducts.