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Transplantation of stem cells derived from donors with CCR5Δ32 homozygous genotype is a potential strategy to achieve both the control of malignant hematological disease as well as sustained remission of the HIV infection, and researchers in different countries are looking for CCR5Δ32 homozygous donors to replicate such a 'double-target' strategy. We determined the frequency of the CCR5Δ32 variant in a sample of 1,398 bone marrow donors from Rio Grande do Sul State, Brazil. This study also evaluated whether HLA-A, HLA-B and HLA-DRB1 genotypes are homogeneously distributed between CCR5Δ32 carriers and non-carriers in a population characterized by a significant genetic admixture. The CCR5Δ32 allele frequency was 7.4% (CI0.95 6.4-8.4%), and the frequency of the Δ32/Δ32 homozygous genotype was 0.72% (CI0.95 0.34-1.31%). In general, HLA genotypes are homogeneously distributed between CCR5Δ32 carriers and non-carriers. Considering the large number of bone marrow donors in Brazil and the high CCR5Δ32 allele frequency observed in our study, our results clearly indicate the existence of a considerable amount of potential CCR5Δ32 homozygous bone marrow donors in southern Brazil, suggesting that an active search for these donors is not only feasible but an attractive and promising strategy towards effective HIV infection control and treatment.

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Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Chronic HCV infection is also an important cause of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). HCV has the capacity to evade immune surveillance by altering the host immune response. Moreover, variations in immune-related genes can lead to differential susceptibility to HCV infection as well as interfere on the susceptibility to the development of hepatic fibrosis, cirrhosis and HCC. The human leucocyte antigen G (HLA-G) gene codes for an immunomodulatory protein known to be expressed in the maternal-foetal interface and in immune-privileged tissues. The HLA-G 3' untranslated region (3'UTR) is important for mRNA stability, and variants in this region are known to impact gene expression. Studies, mainly focusing in a 14 bp insertion/deletion polymorphism, have correlated HLA-G 3'UTR with susceptibility to viral infections, but other polymorphic variants in the HLA-G 3'UTR might also affect HCV infection as they are inherited as haplotypes. The present study evaluated HLA-G 3'UTR polymorphisms and performed linkage disequilibrium test and haplotype assembly in 286 HCV infected patients who have developed fibrosis, cirrhosis or HCC, as well as in 129 healthy control subjects. Haplotypes UTR-1, UTR-2 and UTR-3 were the most observed in HCV+ patients, in the frequencies of 0.276, 0.255 and 0.121, respectively. No statistically significant difference was observed between HCV+ and control subjects, even when patients were grouped according to outcome (HCC, cirrhosis or fibrosis). Despite that, some trends in the results were observed, and therefore, we cannot rule out the possibility that variants associated to high HLA-G expression can be involved in HCV infection susceptibility.

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Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders usually observed in early life, with impacts on behavioral and social skills. Incidence of ASD has been dramatically increasing worldwide, possibly due to increase in awareness/diagnosis as well as to genetic and environmental triggers. Currently, it is estimated that ∼1% of the world population presents ASD symptoms. In addition to its genetic background, environmental and immune-related factors also influence the ASD etiology. In this context, maternal immune activation (MIA) has recently been suggested as a component potentially involved in ASD development. In addition, extracellular vesicles (EVs) are abundant at the maternal-fetal interface and are actively involved in the immunoregulation required for a healthy pregnancy. Considering that alterations in concentration and content of EVs have also been associated with ASD, this article raises a debate about the potential roles of EVs in the processes surrounding MIA. This represents the major differential of the present review compared to other ASD studies. To support the suggested correlations and hypotheses, findings regarding the roles of EVs during pregnancy and potential influences on ASD are discussed, along with a review and update concerning the participation of infections, cytokine unbalances, overweight and obesity, maternal anti-fetal brain antibodies, maternal fever, gestational diabetes, preeclampsia, labor type and microbiota unbalances in MIA and ASD.

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Human Leukocyte Antigen (HLA)-G participates in several biological processes, including reproduction, vascular remodeling, immune tolerance, and hypoxia response. HLA-G is a potential candidate gene for high altitude adaptation since its expression is modulated in both micro and macro environment under hypoxia and constant cellular stress. Besides the promoter region, the HLA-G 3'untranslated region (UTR) influences HLA-G expression patterns through several post-transcriptional mechanisms. Currently, the 3'UTR genetic diversity in terms of altitude adaptation of Native American populations is still unexplored, particularly at high altitude ecoregions. Here, we evaluated 288 Native Americans from 9 communities located in the Andes [highland (HL); ≥2,500 m (range = 2,838-4,433 m)] and 8 populations located in lowland (LL) regions [<2,500 m (range = 80-431 m); Amazonian tropical forest, Brazilian central plateau, and Chaco] of South America. In total, nine polymorphic sites and ten haplotypes were observed. The most frequent haplotypes (UTR-1, UTR-2, and UTR-3) accounted for âˆ¼ 77% of haplotypes found in LL, while in the HL, the same haplotypes reach âˆ¼ 93%. Also, a remarkable high frequency of putative ancestral UTR-5 haplotype was observed in LL (21.5%), while in HL UTR-2 reaches up to 47%. Further, UTR-2 frequency positively correlates with altitude-related variables, while a negative correlation for UTR-5 was observed. From an evolutionary perspective, we observed a tendency towards balancing selection in HL and LL populations thus suggesting that haplotypes of ancient and more derived alleles may have been co-opted for relatively recent adaptations such as those experienced by modern humans in the highland and lowland of South America. We also discuss how long-term balancing selection can be a reservoir of genetic variants that can be positively selected. Finally, our study provides some pieces of evidence that HLA-G 3'UTR haplotypes may have contributed to high altitude adaptation in the Andes.

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The present study aimed to evaluate the influence of the IL1B -31C/T polymorphism on gastric inflammatory response and precancerous lesions development - atrophic gastritis (AG) and intestinal metaplasia (IM) - in patients positive for Helicobacter pylori infection with functional dyspepsia (FD). The diagnosis of FD followed the Rome III criteria, and the H. pylori infection was evaluated by urease test and histological examination of gastric biopsies (corpus, antrum, and incisura). The severity of chronic inflammation and inflammatory activity, as well as the presence of precancerous lesions were evaluated accordingly to the updated Sydney System. Genotyping of the IL1B -31C/T polymorphism (rs1143627) was performed by polymerase chain reaction-restriction fragment length polymorphism. A total of 303 patients positive for H. pylori infection with FD were analyzed (81.8% women; mean age of 46.3 ± 12.3 years). No differences were observed in overall genotype frequencies among outcomes evaluated. However, in the dominant -31C allele model (CC+CT vs. TT), the frequency of the TT genotype was significantly higher among patients with moderate/severe chronic inflammation of the antrum than the frequency of the CC+CT genotypes (80.8% vs. 65.2%; OR = 2.25; 95% CI = 1.23-4.24; P = .005). The presence of AG and IM in the gastric mucosa of patients was of 19.5% and 19.1%, respectively. No significant association was observed concerning the frequencies of the genotypes of IL1B -31C/T polymorphism with development of precancerous lesions. In conclusion, our data suggest that genetic variants of the IL1B -31C/T polymorphism play a role in chronic inflammation of the gastric mucosa in H. pylori-infected FD patients.

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CCR5 is a chemokine receptor that mediates the action of inflammatory cells, besides acting as an HIV co-receptor. CCR5Δ32 states for a genetic variant containing a 32 base pair deletion in the coding region of the CCR5 gene. In homozygosis, CCR5Δ32 results in the lack of CCR5 expression on the cell surface, which was associated with protection against HIV infection. Heterozygous individuals for CCR5Δ32 have a reduced CCR5 expression. Recent evidence demonstrates that CCR5 and CCR5Δ32 are involved in the pathogenesis of other viral infections besides HIV infection. Nevertheless, the role of CCR5 and CCR5Δ32 in HBV infection is not clear and conflicting results have been reported. Thus, the objective of this study was to investigate the role of CCR5Δ32 in HBV mono-infection and HBV/HIV co-infection in a population from southern Brazil. A total of 1113 individuals were evaluated, divided in controls (n = 334), HBV+ (n = 335), HBV+/HIV+ (n = 144), and including an HIV+ group to complement the analyses (n = 300, obtained from a previous study of our research team). The CCR5Δ32 allele frequencies found were 7.5 %, 9.0 %, and 3.1 %, respectively for controls, HBV+, and HBV+/HIV+ patients. The individuals were classified in CCR5Δ32 allele carriers and CCR5Δ32 allele non-carriers and the groups were compared using binary logistic regression adjusted for covariates. No significant effect of the CCR5Δ32 variant was observed on the susceptibility or protection against HBV mono-infection in individuals from southern Brazil. A potential protective effect of CCR5Δ32 on HBV/HIV co-infection was observed. However, it can be due to the effect of CCR5Δ32 in the protection against HIV infection or external factors not covered in the study. Finally, this study contributes to the understanding of the role of CCR5 in HBV infection, suggesting no effect of CCR5Δ32 on susceptibility to HBV mono-infection.

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In this study we investigated the impact of rs2596542A/G single nucleotide polymorphism (SNP) in the major histocompatibility complex class I chain-related sequence A (MICA) gene on HCV-induced hepatocellular carcinoma (HCC) susceptibility in a Brazilian population. In total, 252 HCV-infected patients (98 with HCV-induced HCC and 154 non-malignant HCV-induced liver cirrhosis) were enrolled and 98 healthy control subjects (negative anti-HCV). The MICA rs2596542 SNP genotypes were determined by real-time PCR assay. No differences in MICA genotype frequencies between HCV-induced cirrhosis patients and controls were observed. However, genotype frequencies of rs2596542A/G SNP were statistically different between HCV-induced HCC patients and controls (p = 0.048), and also between HCC and HCV-induced cirrhosis patients (p = 0.039). The highest frequency of the rs2596542AA genotype was observed in HCC patients (31.6%) when compared with HCV-induced cirrhosis patients (18.8%) and healthy controls (19.4%). Also, rs2596542AA genotype carriers have an increased risk for HCC when compared to HCV-induced cirrhosis status [odds ratio (OR) = 1.99; 95% confidence interval (CI) = 1.06-3.74, p = 0.020)] and healthy individuals (OR = 1.92, 95% CI = 1.00-3.70, p = 0.049). Taken together our study suggest that MICA rs2596542 SNP impacts HCV-induced HCC susceptibility suggesting that genetic variants in MICA are of clinical relevance to hepatocarcinogenesis by impacting host immune response in chronic HCV infection.

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PURPOSE: Idiopathic recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder where an impaired control of apoptosis is likely involved. Triggering the cell death mechanism occurs in a spatiotemporal manner and is strongly related to a healthy pregnancy. Single nucleotide polymorphisms (SNPs) at the regulatory regions of genes are known to influence the expression patterns of apoptosis-related molecules. METHODS: A total of 296 unrelated female Brazilian patients were evaluated for clinical-demographic variables and genetic factors: 140 women who had experienced an unexplained RPL (with at least two consecutive abortions) and 156 healthy multiparous women. In all patients, six SNPs were evaluated in genes of apoptosis-related pathways: FAS (rs2234767, rs1800682), FAS-L (rs763110, rs5030772), BAX (rs4645878), and BCL-2 (rs2279115) by PCR followed by a restriction fragment length polymorphism (RFLP)-based analysis. RESULTS: The BAX-248GA genotype is independently associated with idiopathic RPL [adjusted OR = 0.30, 95% CI 0.13-0.70, P = 0.005] susceptibility. In the same multivariate model, the variables ethnicity, smoking, and alcohol consumption were statistically associated with RPL susceptibility (P < 0.05). No association with RPL susceptibility was reported for the remaining SNPs. CONCLUSION: Our study is the first to evaluate the role of the main SNPs from both the extrinsic and intrinsic apoptosis pathways in RPL susceptibility. The association of BAX-248G/A with RPL susceptibility suggests that maternal predisposition for RPL has an essential contribution from genes involved in the delicate balance of endometrium cell turnover (cell death/proliferation). Therefore, apoptotic genes may represent promising targets for future studies on healthy pregnancies and the spectrum of pregnancy disorders.

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ABSTRACT Aim To analyze the influence of the -31 C/T polymorphism of the interleukin-1β gene on Helicobacter pylori eradication therapy success in patients with functional dyspepsia. Methods Functional dyspepsia was diagnosed according to the Rome III criteria. All patients underwent upper gastrointestinal endoscopy, and gastric biopsies were obtained at screening and 12 months after randomization (last follow-up visit). Urease test and histological examination were performed to define the H. pylori status. Patients received twice-daily amoxicillin, clarithromycin and omeprazole for 10 days. Genotyping of the interleukin-1beta -31 C/T polymorphism (rs1143627) was performed using polymerase chain reaction-restriction fragment length polymorphism. Results One hundred forty-nine patients received treatment with triple therapy for H. pylori eradication. Only one patient was lost to follow-up, and adherence to study medication was 94.6%. A total of 148 patients (mean age 46.08 ± 12.24 years; 81.8% women) were evaluated for the influence of the interleukin-1beta -31 C/T polymorphism on the outcome of H. pylori eradication therapy. After treatment, bacteria were eradicated in 87% of patients (129/148). Genotype frequencies of the polymorphism were as follows: CC, 38/148 (25.7%); CT, 71/148 (47.9%); and TT, 39/148 (26.4%). Successful eradication rate was 78.9%, 94.4% and 82.1% for the CC, CT and TT genotypes, respectively. The CT genotype was significantly associated with successful H. pylori eradication (p= 0.039). Conclusion This study suggests that the CT genotype of the interleukin-1beta -31 C/T polymorphism plays a role in the successful eradication of H. pylori among patients with functional dyspepsia.

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AIM: To analyze the influence of the -31 C/T polymorphism of the interleukin-1ß gene on Helicobacter pylori eradication therapy success in patients with functional dyspepsia. METHODS: Functional dyspepsia was diagnosed according to the Rome III criteria. All patients underwent upper gastrointestinal endoscopy, and gastric biopsies were obtained at screening and 12 months after randomization (last follow-up visit). Urease test and histological examination were performed to define the H. pylori status. Patients received twice-daily amoxicillin, clarithromycin and omeprazole for 10 days. Genotyping of the interleukin-1beta -31 C/T polymorphism (rs1143627) was performed using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: One hundred forty-nine patients received treatment with triple therapy for H. pylori eradication. Only one patient was lost to follow-up, and adherence to study medication was 94.6%. A total of 148 patients (mean age 46.08 ± 12.24 years; 81.8% women) were evaluated for the influence of the interleukin-1beta -31 C/T polymorphism on the outcome of H. pylori eradication therapy. After treatment, bacteria were eradicated in 87% of patients (129/148). Genotype frequencies of the polymorphism were as follows: CC, 38/148 (25.7%); CT, 71/148 (47.9%); and TT, 39/148 (26.4%). Successful eradication rate was 78.9%, 94.4% and 82.1% for the CC, CT and TT genotypes, respectively. The CT genotype was significantly associated with successful H. pylori eradication (p = 0.039). CONCLUSION: This study suggests that the CT genotype of the interleukin-1beta -31 C/T polymorphism plays a role in the successful eradication of H. pylori among patients with functional dyspepsia.

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