Host genetic susceptibility underlying SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Brazilian Children.

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a life-threatening complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which manifests as a hyper inflammatory process with multiorgan involvement in predominantly healthy children in the weeks following mild or asymptomatic coronavirus disease 2019 (COVID-19). However, host monogenic predisposing factors to MIS-C remain elusive. METHODS: Herein, we used whole exome sequencing (WES) on 16 MIS-C Brazilian patients to identify single nucleotide/InDels variants as predisposition factors associated with MIS-C. RESULTS: We identified ten very rare variants in eight genes (FREM1, MPO, POLG, C6, C9, ABCA4, ABCC6, and BSCL2) as the most promising candidates to be related to a higher risk of MIS-C development. These variants may propitiate a less effective immune response to infection or trigger the inflammatory response or yet a delayed hyperimmune response to SARS-CoV-2. Protein-Protein Interactions (PPIs) among the products of the mutated genes revealed an integrated network, enriched for immune and inflammatory response mechanisms with some of the direct partners representing gene products previously associated with MIS-C and Kawasaki disease (KD). In addition, the PPIs direct partners are also enriched for COVID-19-related gene sets. HLA alleles prediction from WES data allowed the identification of at least one risk allele in 100% of the MIS-C patients. CONCLUSIONS: This study is the first to explore host MIS-C-associated variants in a Latin American admixed population. Besides expanding the spectrum of MIS-C-associated variants, our findings highlight the relevance of using WES for characterising the genetic interindividual variability associated with COVID-19 complications and ratify the presence of overlapping/convergent mechanisms among MIS-C, KD and COVID-19, crucial for future therapeutic management.

Pharmacogenetics of HIV therapy: State of the art in Latin American countries.

The use of combined antiretroviral therapy (cART) has resulted in a remarkable reduction in morbidity and mortality of people living with HIV worldwide. Nevertheless, interindividual variations in drug response often impose a challenge to cART effectiveness. Although personalized therapeutic regimens may help overcome incidence of adverse reactions and therapeutic failure attributed to host factors, pharmacogenetic studies are often restricted to a few populations. Latin American countries accounted for 2.1 million people living with HIV and 1.4 million undergoing cART in 2020-21. The present review describes the state of art of HIV pharmacogenetics in this region and highlights that such analyses remain to be given the required relevance. A broad analysis of pharmacogenetic markers in Latin America could not only provide a better understanding of genetic structure of these populations, but might also be crucial to develop more informative dosing algorithms, applicable to non-European populations.

Pharmacogenetics of HIV therapy: challenges for tailoring treatment in genetically complex populations.

Tweetable abstract Pharmacogenetic tests are a promising strategy to improve safety and effectiveness of HIV therapy. However, implementation can be challenging in populations with complex genetic structure.

Polymorphisms at CYP enzymes, NR1I2 and NR1I3 in association with virologic response to antiretroviral therapy in Brazilian HIV-positive individuals.

Virologic failure of antiretroviral therapy (ART) may be explained by single nucleotide polymorphisms (SNPs) in drug absorption and metabolism genes. Here, we characterized the associations between polymorphisms in cytochrome P450 enzymes' genes CYP2B6 and CYP3A4/A5, nuclear receptor genes NR1I2/3, and initial ART efficacy among 203 HIV-positive individuals from Rio de Janeiro. Association between SNPs and virologic control was evaluated after 6 and 12 months of follow-up using Cox regression models. The SNP rs2307424 (NR1I3) was associated with increased virologic response after 12 months of treatment, while rs1523127 (NR1I2), rs3003596, and rs2502815 (NR1I3) were associated with decreased response. Increased virologic response after 12 months (adjHR = 1.54; p = 0.02) was also observed among carriers of the NR1I3 haplotype rs2502815G-rs3003596A-rs2307424A versus the reference haplotype G-A-G. Our results suggest that NR1I2 and NR1I3 variants are associated with virologic responses to ART among Brazilians.

Congenital Zika Syndrome Is Associated With Interferon Alfa Receptor 1.

Host factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections. Here, we accessed samples from 153 pregnant women (77 without and 76 with CZS) and 143 newborns (77 without and 66 with CZS) exposed to ZIKV conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS outcome, and characterized placenta gene expression profile at term. Newborns carrying CG/CC genotypes of rs2257167 in IFNAR1 presented higher risk of developing CZS (OR=3.41; IC=1.35-8.60; Pcorrected=0.032). No association between IFNL SNPs and CZS was observed. Placenta from CZS cases displayed lower levels of IFNL2 and ISG15 along with higher IFIT5. The rs2257167 CG/CC placentas also demonstrated high levels of IFIT5 and inflammation-related genes. We found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta at term, forming an unbalanced response modulated by the IFNAR1 rs2257167 genotype. Despite of the low sample size se findings shed light on the host-pathogen interaction focusing on the genetically regulated type I/type III IFN axis that could lead to better management of Zika and other TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes) congenital infections.

Association between Maternal Non-Coding Interferon-λ Polymorphisms and Congenital Zika Syndrome in a Cohort from Brazilian Northeast.

Congenital Zika syndrome (CZS) is characterized by a diverse group of congenital malformations induced by ZIKV infection during pregnancy. Type III interferons have been associated with placental immunity against ZIKV and restriction of vertical transmission in mice, and non-coding single-nucleotide polymorphisms (SNPs) on these genes are well known to influence susceptibility to other viral infections. However, their effect on ZIKV pathogenesis has not yet been explored. To investigate whether maternal non-coding SNPs at IFNL genes are associated with CZS, 52 women infected with ZIKV during pregnancy were enrolled in a case-control association study. A total of 28 women were classified as cases and 24 as controls based on the presence or absence of CZS in their infants, and seven Interferon-λ non-coding SNPs (rs12980275, rs8099917, rs4803217, rs4803219, rs8119886, rs368234815, rs12979860) were genotyped. The results of logistic regression analyses show an association between the G allele at rs8099917 and increased susceptibility to CZS under a log-additive model (adjustedOR = 2.80; 95%CI = 1.14-6.91; p = 0.02), after adjustment for trimester of infection and genetic ancestry. These results provide evidence of an association between Interferon-λ SNPs and CZS, suggesting rs8099917 as a promising candidate for further studies on larger cohorts.

Differential Expression of Human MicroRNAs During Dengue Virus Infection in THP-1 Monocytes.

Dengue virus (DENV) is the most widespread arbovirus, responsible for a wide range of clinical manifestations, varying from self-limited illness to severe hemorrhagic fever. Dengue severity is associated with host intense proinflammatory response and monocytes have been considered one of the key cell types involved in the early steps of DENV infection and immunopathogenesis. To better understand cellular mechanisms involved in monocyte infection by DENV, we analyzed the expression levels of 754 human microRNAs in DENV-infected THP-1 cells, a human monocytic cell line. Eleven human microRNAs showed differential expression after DENV infection and gene ontology and enrichment analysis revealed biological processes potentially affected by these molecules. Five downregulated microRNAs were significantly linked to cellular response to stress, four to cell death/apoptosis, two to innate immune responses and one upregulated to vesicle mediated, TGF-ß signaling, phosphatidylinositol mediated signaling, lipid metabolism process and blood coagulation.

CYP2D6 Allele Frequency in Five Malaria Vivax Endemic Areas From Brazilian Amazon Region.

Genetic variability was linked with individual responses to treatment and susceptibility to malaria by Plasmodium vivax. Polymorphisms in the CYP2D6 gene may modulate enzyme level and activity, thereby affecting individual responses to pharmacological treatment. The aim of the study was to investigate whether or not CYP2D6 single nucleotide polymorphisms rs1065852, rs38920-97, rs16947 and rs28371725 are unequally distributed in malaria by Plasmodium vivax individuals from the Brazilian Amazon region. The blood samples were collected from 220 unrelated Plasmodium vivax patients from five different endemic areas. Genotyping was performed using SNaPshot® and real-time polymerase chain reaction methods. In all five areas, the rs1065852 (CYP2D6*10, C.100C > T), rs3892097 (CYP2D6*4, 1846C > T) and rs16947 (CYP2D6*2, C.2850G > A), as a homozygous genotype, showed the lowest frequencies. The rs28371725 (CYP2D6*41, 2988G > A) homozygous genotype was not detected, while the allele A was found in a single patient from Macapá region. No deviations from Hardy-Weinberg equilibrium were found, although a borderline p-value was observed (p = 0.048) for the SNP rs3892097 in Goianésia do Pará, Pará state. No significant associations were detected in these frequencies among the five studied areas. For the SNP rs3892097, a higher frequency was observed for the C/T heterozygous genotype in the Plácido de Castro and Macapá, Acre and Amapá states, respectively. The distribution of the CYP2D6 alleles investigated in the different areas of the Brazilian Amazon is not homogeneous. Further investigations are necessary in order to determine which alleles might be informative to assure optimal drug dosing recommendations based on experimental pharmacogenetics.

Putative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.

Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and with susceptibility to intracellular pathogens in experimental models. In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus-North; Salvador-Northeast; Rondonópolis-Midwest and Rio de Janeiro-Southeast) and with tuberculosis in Mozambique. Haplotype T/G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin levels in serum. Furthermore, we observed genetic signatures of positive selection in the HCN3 gene (xpEHH>2 -recent selection) in Europe but not in Africa, involving 6 SNPs which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other tests (FST, Tajima's D and iHS). Altogether, we provide evidence that a common PKLR locus in Africans contribute to mycobacterial susceptibility in African descent populations and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.

Whole-exome sequencing reveals insights into genetic susceptibility to Congenital Zika Syndrome.

Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn's genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10-5). The IL12RB2 gene (p-value: 2.18x10-11) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future.

Association between ACE2 and TMPRSS2 nasopharyngeal expression and COVID-19 respiratory distress.

ACE2 and TMPRSS2 are key players on SARS-CoV-2 entry into host cells. However, it is still unclear whether expression levels of these factors could reflect disease severity. Here, a case-control study was conducted with 213 SARS-CoV-2 positive individuals where cases were defined as COVID-19 patients with respiratory distress requiring oxygen support (N = 38) and controls were those with mild to moderate symptoms of the disease who did not need oxygen therapy along the entire clinical course (N = 175). ACE2 and TMPRSS2 mRNA levels were evaluated in nasopharyngeal swab samples by RT-qPCR and logistic regression analyzes were applied to estimate associations with respiratory outcomes. ACE2 and TMPRSS2 levels positively correlated with age, which was also strongly associated with respiratory distress. Increased nasopharyngeal ACE2 levels showed a protective effect against this outcome (adjOR = 0.30; 95% CI 0.09-0.91), while TMPRSS2/ACE2 ratio was associated with risk (adjOR = 4.28; 95% CI 1.36-13.48). On stepwise regression, TMPRSS2/ACE2 ratio outperformed ACE2 to model COVID-19 severity. When nasopharyngeal swabs were compared to bronchoalveolar lavages in an independent cohort of COVID-19 patients under mechanical ventilation, similar expression levels of these genes were observed. These data suggest nasopharyngeal TMPRSS2/ACE2 as a promising candidate for further prediction models on COVID-19.

Exome-Wide Search for Genes Associated With Central Nervous System Inflammatory Demyelinating Diseases Following CHIKV Infection: The Tip of the Iceberg.

Chikungunya virus (CHIKV) is a re-emergent arbovirus that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia, although <1% of cases develop severe neurological manifestations such as inflammatory demyelinating diseases (IDD) of the central nervous system (CNS) like acute disseminated encephalomyelitis (ADEM) and extensive transverse myelitis. Genetic factors associated with host response and disease severity are still poorly understood. In this study, we performed whole-exome sequencing (WES) to identify HLA alleles, genes and cellular pathways associated with CNS IDD clinical phenotype outcomes following CHIKV infection. The cohort includes 345 patients of which 160 were confirmed for CHIKV. Six cases presented neurological manifestation mimetizing CNS IDD. WES data analysis was performed for 12 patients, including the CNS IDD cases and 6 CHIKV patients without any neurological manifestation. We identified 29 candidate genes harboring rare, pathogenic, or probably pathogenic variants in all exomes analyzed. HLA alleles were also determined and patients who developed CNS IDD shared a common signature with diseases such as Multiple sclerosis (MS) and Neuromyelitis Optica Spectrum Disorders (NMOSD). When these genes were included in Gene Ontology analyses, pathways associated with CNS IDD syndromes were retrieved, suggesting that CHIKV-induced CNS outcomesmay share a genetic background with other neurological disorders. To our knowledge, this study was the first genome-wide investigation of genetic risk factors for CNS phenotypes in CHIKV infection. Our data suggest that HLA-DRB1 alleles associated with demyelinating diseases may also confer risk of CNS IDD outcomes in patients with CHIKV infection.

Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil.

BACKGROUND: Dengue is an arthropod-borne viral disease with a majority of asymptomatic individuals and clinical manifestations varying from mild fever to severe and potentially lethal forms. An increasing number of genetic studies have outlined the association between host genetic variations and dengue severity. Genes associated to viral recognition and entry, as well as those encoding mediators of the immune response against infection are strong candidates for association studies. OBJECTIVES: The aim of this study was to investigate the association between MBL2, CLEC5A, ITGB3 and CCR5 genes and dengue severity in children. METHODS: A matched case-control study was conducted and 19 single nucleotide polymorphisms (SNPs) were investigated. FINDINGS: No associations were observed in single SNP analysis. However, when MBL2 SNPs were combined in haplotypes, the allele rs7095891G/rs1800450C/ rs1800451C/rs4935047A/rs930509G/rs2120131G/rs2099902C was significantly associated to risk of severe dengue under α = 0.05 (aOR = 4.02; p = 0.02). A second haplotype carrying rs4935047G and rs7095891G alleles was also associated to risk (aOR = 1.91; p = 0.04). MAIN CONCLUSIONS: This is the first study to demonstrate the association between MBL2 haplotypes and dengue severity in Brazilians including adjustment for genetic ancestry. These results reinforce the role of mannose binding lectin in immune response to DENV.

Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil

BACKGROUND Dengue is an arthropod-borne viral disease with a majority of asymptomatic individuals and clinical manifestations varying from mild fever to severe and potentially lethal forms. An increasing number of genetic studies have outlined the association between host genetic variations and dengue severity. Genes associated to viral recognition and entry, as well as those encoding mediators of the immune response against infection are strong candidates for association studies. OBJECTIVES The aim of this study was to investigate the association between MBL2, CLEC5A, ITGB3 and CCR5 genes and dengue severity in children. METHODS A matched case-control study was conducted and 19 single nucleotide polymorphisms (SNPs) were investigated. FINDINGS No associations were observed in single SNP analysis. However, when MBL2 SNPs were combined in haplotypes, the allele rs7095891G/rs1800450C/ rs1800451C/rs4935047A/rs930509G/rs2120131G/rs2099902C was significantly associated to risk of severe dengue under α = 0.05 (aOR = 4.02; p = 0.02). A second haplotype carrying rs4935047G and rs7095891G alleles was also associated to risk (aOR = 1.91; p = 0.04). MAIN CONCLUSIONS This is the first study to demonstrate the association between MBL2 haplotypes and dengue severity in Brazilians including adjustment for genetic ancestry. These results reinforce the role of mannose binding lectin in immune response to DENV.

Hepatitis C Virus-Infected Responders and Relapsers to Treatment Show Similar Genetic Profiles of IL28B and IL10 Single Nucleotide Polymorphisms.

Genotype 1 of hepatitis C virus (HCV) is the most prevalent worldwide. Pegylated-interferon and ribavirin therapy is still used in the developing world but has less efficiency in this genotype. Single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 (IL28B) and rs1800896, rs1800871, and rs1800872 (IL10) are related to treatment outcome, but previous studies clustered nonresponse and relapse patients. The aim of this study is to analyze the frequency of those SNPs in HCV genotype 1 for response, nonresponse, or relapse. Patients were classified according to treatment outcome. Genomic DNA was extracted by blood samples and SNPs were defined by PCR and sequencing. Data analysis was performed with R project. The frequency of rs12979860 CC was similar among responders (0.48) and relapsers (0.46) and lower among nonresponders (0.18). The same trend was observed for rs8099917 TT. rs12979860 CC showed a protective effect for relapsers compared to nonresponders (OR = 0.25) as it occurs with responders (OR = 0.17). Haplotypes 12979860/C rs8099917/T were associated with protection against the nonresponder phenotype compared to responders (OR = 0.27) or relapsers (OR = 0.37). Frequency of rs12979860 and rs8099917 is different between relapsers and nonresponders, but similar between relapsers and responders.

Polymorphism of IL10, IL4, CTLA4, and DAO Genes in Cross-Reactive Nonsteroidal Anti-inflammatory Drug Hypersensitivity.

Our aim was to evaluate genetic polymorphism of molecules involved in immunoregulatory/allergic processes in patients who presented with cutaneous hypersensitivity caused by chemically unrelated nonsteroidal anti-inflammatory drugs. Polymorphisms at IL10 (-1082 G>A), IL4 (-589 C>T), CTLA4 (+49A>G), and DAO (+8956 C>G) genes were studied in 55 cases and 97 controls by the polymerase chain reaction-restriction fragment length polymorphism technique. With regard to the polymorphism at IL10 -1082, higher frequencies of the AG genotype (57% vs 39%) and G allele carriers (70% vs 48%) were found among the patients, indicating a risk effect (odds ratio [OR] = 2.56 and P = .01 for AG genotype and OR = 2.52; P = .01 for AG/GG). For the CTLA4 +49 A/G single-nucleotide polymorphism (SNP), AG genotype (31.0%) (P = .02) and G carrier (54.0%) (P = .05) frequencies were found to be significantly lower in the patient group compared with the control group (51.0% and 69.0%, respectively). The SNP DAO +8956 C>G was associated with a strong protective effect, with OR values of 0.83 for CG and 0.11 for GG genotype (P = .04 for the codominant model), suggesting an allele dose effect. The combination of IL10 and DAO SNPs in a multivariate model did not alter the OR values, suggesting independent effects for both SNPs. The results are striking. In conclusion, these results suggest that polymorphisms in regulatory targets of the immune response and in DAO gene could modulate an individual's susceptibility to nonsteroidal anti-inflammatory drug hypersensitivity reactions. Further studies will be necessary to complement our results.

Host genetics and dengue fever.

Dengue is a major worldwide problem in tropical and subtropical areas; it is caused by four different viral serotypes, and it can manifest as asymptomatic, mild, or severe. Many factors interact to determine the severity of the disease, including the genetic profile of the infected patient. However, the mechanisms that lead to severe disease and eventually death have not been determined, and a great challenge is the early identification of patients who are more likely to progress to a worse health condition. Studies performed in regions with cyclic outbreaks such as Cuba, Brazil, and Colombia have demonstrated that African ancestry confers protection against severe dengue. Highlighting the host genetics as an important factor in infectious diseases, a large number of association studies between genetic polymorphisms and dengue outcomes have been published in the last two decades. The most widely used approach involves case-control studies with candidate genes, such as the HLA locus and genes for receptors, cytokines, and other immune mediators. Additionally, a Genome-Wide Association Study (GWAS) identified SNPs associated with African ethnicity that had not previously been identified in case-control studies. Despite the increasing number of publications in America, Africa, and Asia, the results are quite controversial, and a meta-analysis is needed to assess the consensus among the studies. SNPs in the MICB, TNF, CD209, FcγRIIA, TPSAB1, CLEC5A, IL10 and PLCE1 genes are associated with the risk or protection of severe dengue, and the findings have been replicated in different populations. A thorough understanding of the viral, human genetic, and immunological mechanisms of dengue and how they interact is essential for effectively preventing dengue, but also managing and treating patients.

Genetic polymorphisms of the IL6 and NOD2 genes are risk factors for inflammatory reactions in leprosy.

The pathways that trigger exacerbated immune reactions in leprosy could be determined by genetic variations. Here, in a prospective approach, both genetic and non-genetic variables influencing the amount of time before the development of reactional episodes were studied using Kaplan-Meier survival curves, and the genetic effect was estimated by the Cox proportional-hazards regression model. In a sample including 447 leprosy patients, we confirmed that gender (male), and high bacillary clinical forms are risk factors for leprosy reactions. From the 15 single nucleotide polymorphisms (SNPs) at the 8 candidate genes genotyped (TNF/LTA, IFNG, IL10, TLR1, NOD2, SOD2, and IL6) we observed statistically different survival curves for rs751271 at the NOD2 and rs2069845 at the IL6 genes (log-rank p-values = 0.002 and 0.023, respectively), suggesting an influence on the amount of time before developing leprosy reactions. Cox models showed associations between the SNPs rs751271 at NOD2 and rs2069845 at IL6 with leprosy reactions (HRGT = 0.45, p = 0.002; HRAG = 1.88, p = 0.0008, respectively). Finally, IL-6 and IFN-γ levels were confirmed as high, while IL-10 titers were low in the sera of reactional patients. Rs751271-GT genotype-bearing individuals correlated (p = 0.05) with lower levels of IL-6 in sera samples, corroborating the genetic results. Although the experimental size may be considered a limitation of the study, the findings confirm the association of classical variables such as sex and clinical forms with leprosy, demonstrating the consistency of the results. From the results, we conclude that SNPs at the NOD2 and IL6 genes are associated with leprosy reactions as an outcome. NOD2 also has a clear functional pro-inflammatory link that is coherent with the exacerbated responses observed in these patients.

Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals.

Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.