RESUMO
BACKGROUND: Genetic predictors for treatment response could optimize allocation of biological treatment in patients with psoriasis. There is minimal knowledge about pharmacogenetics of anti-IL-17 agents. OBJECTIVES: To assess whether genetic variants in the protein-coding region or untranslated regions of the IL-17A gene are associated with response to IL-17A inhibitors in patients with psoriasis. METHODS: This was a multicenter European cohort study investigating pharmacogenetics of IL-17A inhibitors in patients with psoriasis. Patients with plaque psoriasis treated with secukinumab or ixekizumab in daily practice were included. For all participants, the protein-coding region and untranslated regions of the IL-17A gene were analysed using Sanger sequencing. Identified genetic variants were tested for association with response to secukinumab/ixekizumab, measured as ∆PASI, after 12 weeks (primary outcome) and after 24 weeks (secondary outcome). Association was tested using a linear regression model with correction for baseline PASI as a fixed covariate and for biological naivety and body mass index as additional covariates. RESULTS: In total, 134 patients treated with secukinumab or ixekizumab were included. Genotyping of the cohort identified genetic variants present in untranslated regions and intronic DNA, but not in the protein-coding region of the IL-17A gene. Five genetic variants in non-coding DNA with a known or suspected functional effect on IL-17A expression were selected for association analyses: rs2275913, rs8193037, rs3819025, rs7747909 and rs3748067. After 12 weeks, 62% of patients achieved PASI75 and 39% achieved PASI90. At week 24, PASI75 and PASI90 response rates were 72% and 62%, respectively. No associations were found between the five genetic variants and ∆PASI, PASI75 or PASI90 after 12 and 24 weeks of anti-IL-17A treatment. CONCLUSIONS: Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein-coding and untranslated regions of the IL-17A gene. Pharmacogenetics of IL-17A inhibitors in the treatment of psoriasis requires further exploration.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Interleucina-17/genética , Psoríase/tratamento farmacológico , Psoríase/genética , Adulto , Estudos de Coortes , Europa (Continente) , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fases de Leitura Aberta/genética , Testes Farmacogenômicos , Resultado do Tratamento , Regiões não Traduzidas/genéticaRESUMO
BACKGROUND: Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20 and IL-24 have been implicated in autoimmune diseases and we have previously reported that genetic variants in the IL10 gene cluster were associated with psoriasis. OBJECTIVES: To analyse the relationship between genetic polymorphisms in the IL10 gene cluster and psoriasis. This study also explores whether there are gene-gene interactions among these genetic polymorphisms. METHODS: A total of 377 patients with psoriasis and 403 matched healthy controls were enrolled to carry out a case-control study for 48 single-nucleotide polymorphisms (SNPs) of the IL10 gene cluster. Genotyping for the SNPs was conducted on the Applied Biosystems 3730 DNA Analyzer using SNPlex® technology. Generalized multifactor dimensionality reduction (GMDR) analysis was applied to discover a likely gene-gene interaction model among the SNPs. RESULTS: The results showed that the allele distributions of IL10 gene cluster SNPs are significantly different between the case and control groups. Carriers of the IL10 T allele (rs1554286) and the IL20 T allele (rs1400986) conferred protection from psoriasis [odds ratio (OR) = 0·63, corrected P-value (Pc) = 0·007; OR = 0·62, Pc = 0·038, respectively]. GMDR analysis displayed a significant gene-gene interaction between IL10 (rs1554286) and IL20 (rs1518108) variants. The strongest protective effect was found with the block 1 haplotype ACATA in the IL10 gene (Pc = 0·004). CONCLUSIONS: This study presents a novel finding that the combination of the two SNPs, IL10 (rs1554286) and IL20 (rs1518108), is associated with a reduced risk of psoriasis. Our results indicate that genetic variants of the immunomodulatory IL10 and IL20 genes may offer a protective effect in Europeans from Russia. Independent studies are required to verify the results and find a possible functional explanation.
Assuntos
Interleucina-10/genética , Interleucinas/genética , Psoríase/genética , População Branca/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Epistasia Genética/genética , Feminino , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Variação Genética , Heterozigoto , Humanos , Interleucina-10/metabolismo , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Federação Russa/etnologia , População Branca/etnologia , Adulto JovemRESUMO
Schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development.
Assuntos
Fatores de Crescimento Neural/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia Paranoide/genética , Adulto , Bashkiria/etnologia , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas de Ligação ao Cálcio , Estudos de Casos e Controles , Moléculas de Adesão Celular Neuronais/genética , Etnicidade , Feminino , Predisposição Genética para Doença , Glicoproteínas/genética , Humanos , Masculino , Glicoproteínas de Membrana/genética , Fator de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa , Neuropeptídeos/genética , Proteínas Tirosina Quinases/genética , Receptor trkB , Receptor trkC/genética , Esquizofrenia Paranoide/etnologiaRESUMO
The purpose of this case-control genetic association study was to explore potential relationships between polymorphisms in the limbic system-associated membrane protein (LSAMP) gene and mood and anxiety disorders. A total of 21 single-nucleotide polymorphisms (SNPs) from the LSAMP gene were analyzed in 591 unrelated patients with the diagnoses of major depressive disorder (MDD) or panic disorder (PD) and in 384 healthy control subjects. The results showed a strong association between LSAMP SNPs and MDD, and a suggestive association between LSAMP SNPs and PD. This is the first evidence of a possible role of LSAMP gene in mood and anxiety disorders in humans.