RESUMEN
BACKGROUND: Antiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. OBJECTIVE: To identify predictive genetic markers of immune response to ART. METHODS: Case-control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. RESULTS: Male patients were overrepresented in non-responder group (p=0.01). Non-responders also started with lower absolute CD4+ T cell counts (p<0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p=0.04), rs1128503 (ABCB1) A allele (p=0.03) and rs707265 (CYP2B6) A allele (p=0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p=0.004) and rs4646437 (CYP3A4) A allele (p=0.04). CONCLUSION: Some significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.
Asunto(s)
Antirretrovirales/farmacología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Sistema Inmunológico/efectos de los fármacos , Polimorfismo de Nucleótido Simple/inmunología , Adolescente , Adulto , Terapia Antirretroviral Altamente Activa , Brasil , Recuento de Linfocito CD4 , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Marcadores Genéticos , Humanos , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/genética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Estadísticas no Paramétricas , Carga Viral , Adulto JovenRESUMEN
ABSTRACT Background: Antiretroviral therapy (ART) saved millions from HIV-1 infection and AIDS, but some patients do not experience adequate CD4+ T cells gain despite achieving viral suppression. The genetic component of this condition is not yet completely elucidated. Objective: To identify predictive genetic markers of immune response to ART. Methods: Case-control study. Out of 176 HIV-infected patients recruited in the city of Recife, Northeast Brazil, 67 patients with no immunologic response were the cases and the remaining 109 patients who responded were the controls. A set of 94 selected single nucleotide polymorphisms (SNPs) involved in antiretroviral drugs pharmacodynamic pathways and immune system homeostasis were genotyped, while the remaining 48 were ancestry informative markers (AIMs) for controlling for eventual hidden population structure. Results: Male patients were overrepresented in non-responder group (p = 0.01). Non-responders also started with lower absolute CD4+ T cell counts (p < 0.001). We found five SNPs significantly associated with the outcome, being three more frequent in non-responders than responders: rs2243250 (IL4) A allele (p = 0.04), rs1128503 (ABCB1) A allele (p = 0.03) and rs707265 (CYP2B6) A allele (p = 0.02), whereas the other two were less frequent in non-responders: rs2069762 (IL2) C allele (p = 0.004) and rs4646437 (CYP3A4) A allele (p = 0.04). Conclusion: Some significant univariate associations remained independently associated at multivariate survival analysis modeling, such as pre-treatment CD4+ T cells counts, IL2 and ABCB1 genotypes, and use of protease inhibitors, yielding a predictive model for the probability for immune response. More studies are needed to unravel the genetic basis of ART immunological non-response.
Asunto(s)
Humanos , Masculino , Femenino , Adolescente , Adulto , Persona de Mediana Edad , Adulto Joven , Infecciones por VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Polimorfismo de Nucleótido Simple/inmunología , Antirretrovirales/farmacología , Sistema Inmunológico/efectos de los fármacos , Brasil , Marcadores Genéticos , Análisis Multivariante , Estudios Retrospectivos , Estadísticas no Paramétricas , Recuento de Linfocito CD4 , Carga Viral , Terapia Antirretroviral Altamente Activa , Fenómenos Inmunogenéticos/efectos de los fármacos , Fenómenos Inmunogenéticos/genética , Estudios de Asociación Genética , Frecuencia de los GenesRESUMEN
The present study aims at evaluating the association between seven single nucleotide polymorphisms (SNPs) in five genes involved on antiretroviral pharmacokinetic pathways and virological failure in first line highly active antiretroviral therapy. Seven candidate polymorphisms (rs3842 and rs1045642 in ABCB1, rs212091 and rs3743527 in ABCC1, rs3745274 in CYP2B6, rs628031 in SLC22A1 and rs1517618 in SLCO3A1) were evaluated if they were associated with virological failure through logistic regression analysis. The study design was a retrospective cohort, analyzing 187 patients from Recife metropolitan region (Pernambuco, Brazil): among these 160 obtained complete suppression of HIV-1 replication (responders) and were compared to 27 non-responders, which underwent virological failure. There was no association between CYP2B6, SLC22A1, and SLCO3A1 SNPs and virological failure. Using logistic regression analysis, a significant association was detected between rs1045642 (3435C>T, ABCB1) and rs212091 (198217T>C; 3'-UTR, ABCC1) with virological failure of first-line antiretroviral regimens containing protease inhibitors, when controlled by clinical factors, such as sex, age and race. The present results could contribute to unravel the influence of genetic background in anti-HIV-1 therapy outcome and help in treatment personalization of Northeast Brazil HIV infected patients.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Adulto , Terapia Antirretroviral Altamente Activa , Brasil , Femenino , Infecciones por VIH/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease resulting from the interplay between environmental, immunological and genetic factors. In our study, we investigated the role of three single nucleotide polymorphisms (SNPs) at 5'-UTR of DEFB1 gene, encoding for the human beta defensin-1, on the susceptibility to develop AD in a group of Brazilian children and adolescents. METHODS: Three SNPs, -20 G/A (rs11362), -44 C/G (rs1800972), and -52 G/A (rs1799946) at 5'-UTR of DEFB1 gene were genotyped in two groups of children and adolescents, one affected by AD (96 subjects), the other healthy (191 individuals), from northeast Brazil. RESULTS: -44 C/G frequencies were comparable between the two groups. The -20 GG genotype was more frequent in AD subjects than in healthy controls; the -52 GG, conversely, was more frequent in healthy controls than in AD. However, both these differences did not reach statistical significance. Also, association between SNPs and AD severity has been shown. The analysis of DEFB1 haplotypes did not highlight any association of the three SNPs with AD development or disease severity. CONCLUSIONS: Our results seem to exclude a role for the -44 C/G DEFB1 SNPs on the pathogenesis and severity of AD, while for the -20 C/G and -52 G/A, even if not statistically significant, we evidenced a slight trend for susceptibility (-20 GG) and protection (-52 GG) for the development of AD. However, as controversial findings have been reported in the literature, the role of DEFB1 in the development of AD and in the severity of the phenotype deserves further investigation.
Asunto(s)
Dermatitis Atópica/epidemiología , Dermatitis Atópica/genética , beta-Defensinas/genética , Adolescente , Brasil/epidemiología , Niño , Preescolar , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/epidemiología , Haplotipos , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Dendritic cells (DCs)-based vaccine was demonstrated to increase HIV specific cellular immune response; however, in some HIV-infected patients, the response to the vaccine resulted to be not effective. In order to understand if the outcome of the vaccination may be influenced by the host's genome and natural immunity, we studied the innate immune genome of HIV-infected patients previously vaccinated with DCs. We identified 15 SNPs potentially associated with the response to the immuno-treatment and two SNPs significantly associated with the modulation of the response to the DC vaccine: MBL2 rs10824792 and NOS1 rs693534. These two SNPs were also studied in different ethnic groups (Brazilians, African and Caucasian) of HIV-infected, exposed uninfected and unexposed uninfected subjects. The HIV positive Caucasian patients were also characterized by different disease progressions. Our findings suggest that, independently and/or in addition to other variables, the host's genome could significantly contribute to the modulation of the response to the DC vaccine.
Asunto(s)
Vacunas contra el SIDA/inmunología , Células Dendríticas/inmunología , Infecciones por VIH/terapia , Inmunidad Innata/genética , Inmunoterapia/métodos , Polimorfismo de Nucleótido Simple , Etnicidad , Frecuencia de los Genes , Genotipo , Humanos , Lectina de Unión a Manosa/genética , Óxido Nítrico Sintasa de Tipo I/genéticaRESUMEN
In our study we investigated the possible role of MBL2 functional single nucleotide polymorphisms (SNPs) in the augmented susceptibility to develop other autoimmune diseases in presence of type 1 diabetes (T1D) in a group of Brazilian patients. Patients were stratified for the presence of autoimmune diseases known to be associated with T1D, such as autoimmune thyroid disease (AITD) and celiac disease (CD), and compared with healthy controls (HC). Our findings suggest that MBL2 functional SNPs are more closely related to AITD than to T1D, being MBL2 SNPs frequencies in T1D patients not affected by AITD comparable to the HC ones, while significantly different between AITD patients and patients not affected by the disease. Thus, the association between MBL2 polymorphisms and T1D that we previously reported, seems to result from the stronger association of MBL2 SNPs with another autoimmune disease, the AITD, frequently associated with T1D.
Asunto(s)
Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/genética , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad , Lectina de Unión a Manosa/genética , Polimorfismo de Nucleótido Simple , Adolescente , Enfermedades Autoinmunes/epidemiología , Brasil/epidemiología , Niño , Preescolar , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Humanos , Lactante , Masculino , Estándares de ReferenciaRESUMEN
Patients with an autoimmune condition are known to be at higher risk of developing other autoimmune disorders. Type 1 diabetes may be associated with additional autoimmune disorders including autoimmune thyroid disease. The aim of this study was to investigate the prevalence of thyroid autoantibodies in a group of children, adolescents, and young adults with type 1 diabetes from northeastern Brazil as well as their significance for the development of thyroid disorders. The study design was cross-sectional and descriptive, analyzing young people with a previous type 1 diabetes diagnosis. Two hundred and fourteen children and adolescents with prior diagnosis of type 1 diabetes were evaluated. Antibodies to thyroperoxidase (anti-TPO) were determined in all patients and thyroid-stimulating hormone (TSH) levels. The anti-TPO antibody test was positive in 54 out of the 214 patients studied, resulting in an overall prevalence of 25.2%. Among the anti-TPO-positive subjects, females were predominant (72%) over males (28%) (p < 0.001). A total of 55.5% patients with positive anti-TPO antibodies had abnormal TSH levels. Clinically significant hypothyroidism was found in 29.6% and subclinical hypothyroidism in 22.2% of patients with positive anti-TPO. Hyperthyroidism was present in only 3% of them. Our results demonstrate the high prevalence of autoimmune thyroiditis in patients with type 1 diabetes and the need for these patients of regular screening to make a precocious diagnosis of thyroid dysfunction.
Asunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Hipotiroidismo/inmunología , Adolescente , Autoanticuerpos/sangre , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/inmunología , Brasil/epidemiología , Niño , Comorbilidad , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Humanos , Hipertiroidismo/epidemiología , Hipertiroidismo/inmunología , Hipotiroidismo/epidemiología , Yoduro Peroxidasa/inmunología , Masculino , Prevalencia , Tirotropina/sangre , Adulto JovenAsunto(s)
Dermatitis Atópica/epidemiología , Dermatitis Atópica/genética , Lectina de Unión a Manosa/genética , Alelos , Brasil/epidemiología , Niño , Preescolar , ADN/análisis , Cartilla de ADN , Dermatitis Atópica/etiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Población Blanca/genéticaRESUMEN
Mannose-binding lectin is an important constituent of the innate immune system, the serum levels of which are greatly affected by polymorphisms of the MBL2 gene: three polymorphisms in exon 1, as well as nucleotide variations in the promoter region of the gene, have been associated with protein deficiency and some infectious and autoimmune disease. The aim of this study was to investigate a possible association between MBL2 gene polymorphisms in patients who have developed type 1 diabetes during childhood and adolescence. We evaluated MBL2 gene polymorphisms in 214 children and adolescents with type 1 diabetes and compared them with a healthy control group, finding significant differences in genotypic and allelic frequencies (p = 0.004 and p = 0.0008, respectively). Our results suggest that patients with type 1 diabetes possessing the 0 allele have a higher risk for developing type 1 diabetes during childhood and adolescence, and that this risk factor is not related to age at diagnosis.