RESUMO
UNLABELLED: Background and aim. Leukocyte antigen DQ (HLA-DQ) and interferon-λ4 (IFNL4) gene polymorphisms were associated with susceptibility to chronic hepatitis B and C virus infection. This study further confirmed that variants of these genes were associated with susceptibility and spontaneous clearance of HBV infection in a Chinese population. MATERIAL AND METHODS: A total of 1,069 subjects were recruited and divided into three groups i.e. 397 with CLD (HBV-related chronic liver disease), 434 with SC (spontaneous clearance), and 238 HC (healthy controls). HLA-DQrs9275319 and IFNL4rs368234815, rs12971396, rs12979860, and rs8099917SNPs were genotyped using the Sequenom MassARRAY MALDI-TOF system. RESULTS: HLA-DQ rs9275319 showed a significant association with HBV infection (allele model, OR, 0.514; 95% CI, 0.359-0.738, adjusted p = 0.0003) and with natural clearance (allele model, OR, 1.659; 95% CI, 1.197-2.300, adjusted. However, there was no association between IFNL4 polymorphism and HBV susceptibility or natural clearance (all p > 0.05). The multifactor dimensionality reduction (MDR) test with permutation correction showed that a three-way interaction between IFNL4 and HLA-DQ SNPs was identified for HBV susceptibility (permutation p = 0.009 for the best factor model) and clearance (permutation p = 0.014 for the best factor model). CONCLUSIONS: The data from the current study provided additional evidence for an SNP-SNP interaction between HLA-DQ and IFNL4 in regulation to HBV infection and natural clearance.
Assuntos
Povo Asiático/genética , Antígenos HLA-DQ/genética , Hepatite B Crônica/genética , Interleucinas/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
BACKGROUND: Previous studies have shown that multiple inhibitory genes play an important role in HBV-specific CD8+ T cell exhaustion and dysfunction in the setting of chronic HBV infection. Polymorphic variants of these genes are thought to be predisposing factors for HBV susceptibility, clearance, and disease progression. The aim of this retrospective study was to identify variants affecting chronic HBV infection in a Chinese Han population. METHODS: We chose 28 tgSNPs from HapMap data on 5 key genes. They were genotyped on a total of 858 chronic HBV patients, 429 patients who underwent spontaneous recovery, and 239 healthy controls. We evaluated the correlation between the polymorphisms and HBV susceptibility, spontaneous clearance, and disease progression. RESULTS: The association of rs3827537 of BIM genotype TA and allele A was significantly different (P=0.016, OR=2.049; P=0.031, OR=1.925) between HBV patients and healthy controls. The rs36084323 of PD-1, as well as rs3766377, rs485618, rs4656942 of CD244 showed significant associations with the risk for HBV-related cirrhosis and hepatocellular carcinoma (HCC) (P=0.009, OR=0.482; P=0.009, OR=4.573; P=0.015, OR=0.580; P=0.028, OR=2.855). MDR analysis revealed that the four SNPs (rs36084323, rs3766377, rs485618, rs4656942) modulated the predisposition to cirrhosis and HCC in patients with chronic HBV infection (P=0.006). Using a luciferase reporter assay, we demonstrated that various alleles of rs3766377 had differential effects, and rs3766377 and rs485618 might have interactive effects. CONCLUSIONS: The present study reveals genetic associations among PD-1 and CD244 variants that may be involved in the development of cirrhosis and HCC in patients with chronic HBV infection. The BIM variant was associated with HBV susceptibility.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Predisposição Genética para Doença , Hepatite B Crônica/genética , Hepatite B Crônica/virologia , Imunomodulação/genética , Polimorfismo Genético , Adulto , Idoso , Alelos , Antígenos CD/genética , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Haplótipos , Vírus da Hepatite B , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Humanos , Testes de Função Hepática , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1/genética , Proteínas Proto-Oncogênicas/genética , Receptores Imunológicos/genética , Família de Moléculas de Sinalização da Ativação Linfocitária , Carga ViralRESUMO
Single nucleotide polymorphisms (SNPs) of HLA-DQ and granulysin (GNLY) are reportedly associated with HBV infection. The aim of this study was to investigate the effects of interactions between SNPs in HLA-DQ and GNLY on the outcome of hepatitis B virus (HBV) infection in Chinese Han subjects. HLA-DQ (rs9275572) and GNLY (rs1866139 and rs11127) were genotyped in 310 subjects with HBV-related chronic liver disease, 295 in whom spontaneous clearance of HBV had occurred and 316 who had not been exposed to HBV. HLA-DQ rs9275572 was significantly correlated with HBV clearance (dominant genetic model: OR, 1.84; 95% CI, 1.30-2.61; adjusted P = 0.001). There was no statistical association of GNLY rs1866139 and rs11127with HBV infection outcomes. However, significant sex-specific associations with HBV susceptibility were observed in men who carried rs1866139 CG or rs11127 TC and in women who carried rs1866139 GG or rs11127 CC. The findings were the same in the validation cohort, which was composed of 829 subjects. Based on a multifactor dimensionality reduction test with permutation correction, a three-way interaction between SNPs in HLA-DQ and GNLY was identified in terms of HBV clearance. In conclusion, additional evidence for an association of HLA-DQ and GNLY SNPs with HBV infection outcomes has been identified and a SNP-SNP interaction between HLA-DQ and GNLY on HBV clearance observed.
