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1.
Arch Med Sci ; 17(2): 417-433, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33747278

RESUMO

INTRODUCTION: Despite intensive research and a long history of glucocorticoids being applied in various clinical areas, they still generate a challenge for personalized medicine by causing resistance or dependence in nearly 50% of patients treated. The objective of the present study was to determine the genetic predictors of variable reactions in inflammatory bowel disease patients to glucocorticoid therapy. Therefore, based on the current knowledge on how glucocorticoids act, we have compiled a panel of 21 genes for variant analysis: NR3C1, NLRP1, IPO13, FKBP5, HSPA4, ABCB1, STIP1, HSP90AA1, IL-1A, IL-1B, IL-2, IL-4, CXCL8, IL-10, NFKBIA, JUN, MIF, TNF, MAPK14, CYP3A4, and CYP3A5. MATERIAL AND METHODS: These genes were analyzed using the amplicon next-generation sequencing method in a group of 139 diagnosed and clinically characterized inflammatory bowel disease patients with a confirmed glucocorticoid response. RESULTS: Analysis of all the targeted DNA sequences for the whole patient group indicated 121 different functional variants. After association analyses of 31 selected variants, the polymorphism c.1088A>G in the NR3C1 gene was linked with glucocorticoid resistance (p = 0.002), variant c.241+6A>G of the FKBP5 gene with glucocorticoid sensitivity (p = 0.040), and deletion c.306-7delT in the MAPK14 gene with an adverse therapeutic effect (dependency and resistance, p = 0.041) in ulcerative colitis patients. In Crohn's disease, the change c.2685+49T>C of the ABCB1 gene related to glucocorticoid resistance (p = 0.034). CONCLUSIONS: Among the 21 analyzed genes, four (NR3C1, FKBP5, MAPK14, and ABCB1) revealed a significant impact on the glucocorticoid treatment response, which could result in valuable pharmacogenetic biomarkers after being confirmed in other populations and in functional studies.

2.
Adv Med Sci ; 65(2): 291-297, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32446200

RESUMO

PURPOSE: We aimed to examine the polymorphism of the promoter and exon 5 of the TNFSF11 gene and their impact on bone mineral density (BMD) and the frequency of bone fractures. TNFSF11 encodes the receptor activator of the NF-kB ligand (RANKL), a key regulator of bone metabolism and osteoporosis drug targets. BMD is an essential measure in diagnosing osteoporosis and assessing the risk of fractures. In vivo, RANKL expression research suggests that promoter TNFSF11 variants influence BMD. Moreover, exon 5 polymorphism of a linear epitope sequence for a denosumab could be related to the effectiveness of biological therapy. PATIENTS AND METHODS: The study included 114 postmenopausal osteoporosis patients. BMD was measured in the lumbar spine and the femoral neck. Genetic analysis was performed using Sanger sequencing. Genotypes data for 263 female European population group were obtained from the 1000Genomes database. RESULTS: We identified six promoter polymorphisms (rs9525641, rs9533155, rs9533156, rs11839112, rs28926171, rs183599708) and one silent TNFSF11 variant in exon 5 (rs9562415). Three of the sequence variants detected (rs9525641, rs9533155, rs9533156) proved to be polymorphic, whereas the others four occurred at a frequency below 2%. The statistical analysis demonstrated no significant differences between polymorphisms and BMD, and bone fractures. However, variant rs9533156 was relevant with the lumbar spine T-score (p = 0.0273), and no association with BMD was of borderline significance (p = 0.0529). CONCLUSIONS: Variant rs9533156 may contribute to the genetic regulation of BMD in Polish postmenopausal osteoporosis, while the exon 5 sequence of the TNFSF11 gene is very conservative.


Assuntos
Osteoporose Pós-Menopausa/genética , Ligante RANK/genética , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/genética , Densidade Óssea/fisiologia , Feminino , Colo do Fêmur/metabolismo , Fraturas Ósseas/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Grupos Populacionais , Regiões Promotoras Genéticas/genética
3.
Pharmacogenomics J ; 19(4): 358-367, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30293984

RESUMO

Biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies significantly increased the effectiveness of autoimmune disease treatment compared with conventional medicines. However, anti-TNF-α drugs are relatively expensive and a response to the therapy is reported in only 60-70% of patients. Moreover, in up to 5% of patients adverse drug reactions occur. The various effects of biological treatment may be a potential consequence of interindividual genetic variability. Only a few studies have been conducted in this field and which refer to single gene loci. Our aim was to design and optimize a methodology for a broader application of pharmacogenetic studies in patients undergoing anti-TNF-α treatment. Based on the current knowledge, we selected 16 candidate genes: TNFRSF1A, TNFRSF1B, ADAM17, CASP9, FCGR3A, LTA, TNF, FAS, IL1B, IL17A, IL6, MMP1, MMP3, S100A8, S100A9, and S100A12, which are potentially involved in the response to anti-TNF-α therapy. As a research model, three DNA samples from Crohn's disease (CD) patients were used. Targeted genomic regions were amplified in 23 long-range (LR) PCR reactions and after enzymatic fragmentation amplicon libraries were prepared and analyzed by next-generation sequencing (NGS). Our results indicated 592 sequence variations located in all fragments with coverage range of 5-1089. We demonstrate a highly sensitive, flexible, rapid, and economical approach to the pharmacogenetic investigation of anti-TNF-α therapy using amplicon libraries and NGS technology.


Assuntos
Anticorpos Monoclonais/farmacologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Testes Farmacogenômicos/métodos , Reação em Cadeia da Polimerase/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antineoplásicos/farmacologia , Humanos
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