Autism spectrum disorders (ASD) can be conceptualized as a genetic dysfunction that disrupts development and function of brain circuits mediating social cognition and language. At least some forms of ASD may be associated with high level of excitation in neural circuits, and gamma-aminobutyric acid (GABA) has been implicated in its etiology. Single-nucleotide polymorphisms (SNP) located within the GABA receptor (GABAR) subunit genes GABRA1, GABRG2, GABRB3, and GABRD were screened. A hundred and thirty-six Argentinean ASD patients and 150 controls were studied, and the contribution of the SNPs in the etiology of ASD was evaluated independently and/or through gene-gene interaction using multifactor dimensionality reduction (MDR) method. From the 18 SNP studied, 11 were not present in our Argentinean population (patients and controls) and 1 SNP had minor allele frequency < 0.1%. For the remaining six SNPs, none provided statistical significant association with ASD when considering allelic or genotypic frequencies. Non-significant association with ASD was found for the haplotype analysis. MDR identified evidence for synergy between markers in GABRB3 (chromosome 15) and GABRD (chromosome 1), suggesting potential gene-gene interaction across chromosomes associated with increased risk for autism (testing balanced accuracy: 0.6081 and cross-validation consistency: 10/10, P < 0.001). Considering our Argentinean ASD sample, it can be inferred that GABRB3 would be involved in the etiology of autism through interaction with GABRD. These results support the hypothesis that GABAR subunit genes are involved in autism, most likely via complex gene-gene interactions.

ABSTRACT. CYP2B6 is a highly polymorphic isoenzyme involved in the metabolism of many drugs including cyclophosphamide, bupropion, and efavirenz. A single nucleotide polymorphism (SNP) in CYP2B6 (516G>T) resulted in decreased expression and function associated with the CYP2B6*6 haplotype. Among the clinical implications of this phenotype, decreased activation of cyclophosphamide and increased plasma levels of efavirenz associated with increased central nervous system toxicity have been reported. The frequency of the CYP2B6 (516G>T) SNP has been studied in several different populations, but there is no data regarding distribution among Argentinians. In this study, 102 DNA samples from healthy volunteers were analyzed using a polymerase chain reactionrestriction fragment length polymorphism reaction specific for the CYP2B6 (516G>T) SNP. Our results showed a prevalence of 71.08% for the G allele and 28.92% for the T allele. This was distributed as 52.9% for the GG genotype (reduced dosage required), 36.6% for the GT genotype (normal dosage range), and 10.8% for the TT genotype (high drug toxicity). There was no preferential gender distribution observed. The relatively high 16595©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 16594-16599 (2015) CYP2B6 polymorphisms and the role of genetic testing prevalence of the TT genotype in our population supports the clinical use of genotyping as an additional tool in personalized medicine.

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Microsatellite instability (MSI) is a hallmark tool for Lynch syndrome (LS) screening and a prognostic marker for sporadic colorectal cancer (CRC). In regions with limited resources and scarce CRC molecular characterization as South America, the implementation of universal MSI screening is under debate for both its purposes. We sought to estimate the frequency of BAT26 in colorectal adenocarcinomas and to determine associated clinical and histological features. Consecutive patients from a CRC registry were included. BAT26 determination was performed in all cases; if instability was found, immunohistochemistry (IHC) and BRAF mutation analyses were done, as appropriate. Differences were assessed by chi-squared or Fisher's exact test, or by T test or Mann-Whitney. Multiple logistic regression was used to identify factors independently associated with BAT26-unstable tumors. We included 155 patients; mean age was 65.6 (SD 14.4) and 56.1% were male. The frequency of BAT26-unstable tumors was 22% (95% CI 15.7-29.3). Factors independently associated with BAT26-unstable tumors were right colon localization (OR 3.4, 95% CI 1.3-8.7), histological MSI features (OR 5.1, 95% CI 1.9-13.6) and Amsterdam criteria (OR 23.2, 95% CI 1.9-286.7). IHC was altered in 85.3% BAT26-unstable tumors and 70.6% lacked MLH1 expression; 47.8% of these harbored BRAF V600E mutation. We provide evidence to link the frequency of BAT26 to an increased diagnostic yield (up to 1.4-folds) of suspected LS cases in comparison to the revised Bethesda guidelines alone. In regions with limited resources, clinical and histological features associated with BAT26-unstable status could be useful to direct MSI screening in sporadic CRCs and may help guide clinical care and future research.

Variations in the serotonin transporter gene (SLC6A4) have been implicated in a wide range of neuropsychiatric disorders such as major depression. However, the results are still controversial. A polymorphism in SLC6A4 gene characterized by an insertion/deletion of 44 bp (5-HTTLPR) in the promoter region (alleles L and S) and a variable number of tandem repeats polymorphism (5-HTTVNTR) in intron 2 (common alleles: 10 and 12) (Lesch et al., 1994) would present a differential regulatory effect on gene transcription.The association between these polymorphisms and major depression was analysed in 95 patients and 107 healthy controls in a sample of Argentinean population. This protocol has been approved by an independent Bioethic board. All the genotypes were obtained by standard procedures (Assal et al., 2004).Patients and controls were interviewed based on diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Hamilton depression scale, self-administered Beck scale and MINI structured diagnostic interview. Only patients with Hamilton depression scale greater than 18 points were included.The comparison of frequencies was carried out through logistic regression. A multiple testing correction was applied.The frequencies in patients and controls for both markers were in Hardy-Weingberg equilibrium (cases: L/L = 22%; L/S = 54%; S/S = 24%; controls: L/L = 27.1%; L/S = 52.3%; S/S = 20.6% and cases: 12/12 = 39%; 12/10 = 54%; 10/10 = 7%; controls: 12/12 = 46%; 12/10 = 42%; 10/10 = 12%).The linkage disequilibrium between polymorphisms was evaluated (D 0 = 0.29; r 2 = 0.04). The results indicate an independent distribution of the polymorphic loci; others authors observed the low rate of linkage between the 5-HTTLPR polymorphism and other polymorphisms could be due to recombination events in hot-spots located in the first intron. When a single marker association was evaluated between patients and controls, no significant differences were found. However, considering the findings of Hranilovic et al. 2004, a combinatorial effect of both polymorphisms is considered to be possible. The genotypes were grouped and compared according to their expression levels (no low expression at both loci, 11% vs. 6%; low expression at one locus: 40% vs. 60%; low expression at both loci: 49% vs. 34%, patients vs. controls, respectively). Although genotypes of the low expression group at one locus would confer protection with P = 0.005 [corrected P < 0.03; odds ratio (OR) = 0.45, 95% confidence interval (CI) = (0.25-0.78)], genotypes of the low expression group in both loci would confer risk with a P = 0.02 [corrected P < 0.03; OR = 1.93, 95% CI = (1.1-3.4)]. There are differences between the groups regarding their carrier status (being or not carriers of risk alleles S and 10). Those individuals carrying S and 10 alleles have an increased risk of having the depressive phenotype.We think it is necessary to increase not only the number of local individuals but also the number of markers under analysis. It shou...