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The association between the genetic polymorphisms of LMP2/LMP7 and the outcomes of HCV infection among drug users.

ABSTRACT: OBJECTIVE:To investigate a possible association of LMP2/LMP7 genes with chronic hepatitis C virus (HCV) infection, and to assess whether LMP2/LMP7 genes could influence the outcomes of HCV infection among drug users. METHODS:Genomic DNAs of 362 anti-HCV sero-positive drug users and 225 control drug users were extracted from the peripheral blood leukocytes. The sero-positive patients were divided into those who had persistent infection and those who had spontaneously cleared the infection. Polymorphisms of LMP genes were determined by PCR combined with restriction fragment length polymorphism (RFLP). RESULTS:The distribution of LMP2 genotypes among the control, persistent infection and spontaneous clearance groups were not different. However, the LMP7 codon 145 Gln/Lys, Lys/Lys, and Gln/Lys+Lys/Lys genotypes were found significantly more frequent in the persistent infection group than in control group (OR=1.75, 95%CI=1.06?2.90; OR=3.16, 95%CI=1.23-8.12; OR = 1.94, 95%CI=1.21-3.12, respectively). Similarly, the frequencies of the codon 145 Gln/Lys, Lys/Lys, and Gln/Lys+Lys/Lys genotypes were found significantly more frequent in the persistent infection group than in the spontaneous clearance group (OR=1.64, 95%CI=1.04-2.57; OR=2.40, 95%CI=1.09-5.28; OR=1.76, 95%CI=1.15-2.69, respectively). Stratified analysis indicated that combined genotype Gln/Lys + Lys/Lys of the LMP7 gene was related to an increasing susceptibility to HCV infection (OR=1.91, 95%CI=1.02-3.55; OR=2.19, 95%CI=1.24-3.89; OR=1.91, 95%CI=1.05-3.48, OR=2.86, 95%CI=1.41-5.78, respectively) and the risk of persistent HCV infection (OR=1.94, 95%CI=1.12-3.34; OR=2.02, 95%CI=1.21-3.38; OR=1.78, 95%CI=1.12-2.85, OR=2.23, 95%CI=1.09-4.58, respectively) among > 30-year-old, males, the injection drug user (IDU) subjects and/or the shorter duration drug users (?5 y). CONCLUSION:These results suggest that polymorphism of the LMP7 gene may have an influence on the outcomes of HCV infection, and is one of the factors accounting for the genetic susceptibility to HCV infection among drug users.

SUBMITTER: Cui Q

PROVIDER: S-EPMC3596683 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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The association between the genetic polymorphisms of LMP2/LMP7 and the outcomes of HCV infection among drug users.

Cui Qian Q Zhang Yongxiang Y Su Jing J Shi Chao C Lei Na N Ding Keqin K Li Jun J Yu Rongbin R Wang Lu L Wang Ning N

Journal of biomedical research 20100901 5

<h4>Objective</h4>To investigate a possible association of LMP2/LMP7 genes with chronic hepatitis C virus (HCV) infection, and to assess whether LMP2/LMP7 genes could influence the outcomes of HCV infection among drug users.<h4>Methods</h4>Genomic DNAs of 362 anti-HCV sero-positive drug users and 225 control drug users were extracted from the peripheral blood leukocytes. The sero-positive patients were divided into those who had persistent infection and those who had spontaneously cleared the in ...[more]

PMID: 23554652

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Project description:The Kazakh population in Xinjiang Province in northwestern China exhibits a high incidence of esophageal squamous cell carcinoma (ESCC). Although the etiology of esophageal carcinoma (EC) has not been elucidated, there are reports of the involvement of an immunologic mechanism. In the current study, 268 Kazakh ESCC patients and 500 age- and sex-matched control subjects were recruited. DNA was extracted from paraffin-embedded tumor specimens from the patients and peripheral blood lymphocytes from the controls and used for LMP2/LMP7 genotyping. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect LMP2/LMP7 gene single-nucleotide polymorphisms (SNPs). We found a clear increased risk of ESCC in the Kazakh population for the heterozygous LMP2 R/C genotype and the homozygous C/C genotype (OR = 1.470, 95%CI = 1.076-2.008, p = 0.015 forLMP2R/C; OR = 2.048, 95% CI = 1.168-3.591, p = 0.011 for LMP2 C/C). Conversely, the heterozygous LMP7 Q/K polymorphism was found to decrease the risk of ESCC in this population (OR = 0.421, 95% CI = 0.286-0.621, p = 8.83×10-6). Moreover, LMP2 R/C+C/C genotype was associated with increased tumor invasion depth (p = 0.041). Haplotype analysis showed that haplotype A, which includes wild-type homozygous LMP2/TAP1 and mutant LMP7, decreases susceptibility to ESCC in the Kazakh population; in contrast, haplotype E, which includes wild-type homozygous LMP2/LMP7/TAP1, acts as a risk factor for increased susceptibility to ESCC. This is the first study to report that the heterozygous LMP2 R/C and homozygous C/C genotypes increase susceptibility to ESCC in the Kazakh population and that the heterozygous LMP7 Q/K genotype decreases susceptibility to ESCC in this population. Nevertheless, neither LMP2 nor LMP7 was associated with human papillomavirus (HPV) infection. Understanding LMP2/LMP7 genetic variability will provide a new therapeutic perspective for Kazakh patients with ESCC.

Project description:BackgroundDetectable HCV-specific cellular immune responses in HCV antibody and RNA negative people who inject drugs (PWID) raise the question of whether some are resistant to HCV infection. Immune responses from people who have been exposed to hepatitis C virus (HCV) and remain anti-HCV negative are of interest for HCV vaccine development; however, limited research addresses this area.ObjectivesIn a cohort of HCV antibody and RNA negative PWID, we assessed whether the presence of HCV-specific IFN-γ responses or genetic associations provide any evidence of protection from HCV infection.Patients and methodsOne hundred and ninety-eight participants were examined longitudinally for clinical, behavioral, social, environmental and genetic characteristics (IFNL3 genotype [formally IL-28B] and HLA type). Sixty-one of the 198 participants were HCV antibody and RNA negative, with 53 able to be examined longitudinally for HCV-specific IFN-γ ELISpot T cell responses.ResultsTen of the 53 HCV antibody and RNA negative participants had detectable HCV-specific IFN-γ responses at baseline (18%). The magnitude of IFN-γ responses averaged 131 +/- 96 SFC/106 PBMC and the breadth was mean 1 +/- 1 pool positive. The specificity of responses were mainly directed to E2, NS4b and NS5b. Participants with (10) and without (43) HCV-specific IFN-γ responses did not differ in behavioral, clinical or genetic characteristics (P > 0.05). There was a larger proportion sharing needles (with 70%, without 49%, P = 0.320) and a higher incidence of HCV (with 35.1 per 100 py, 95% CI 14.6, 84.4, without 16.0 per 100 py, 95% CI 7.2, 35.6, P = 0.212) in those with IFN-γ responses, although not statistically significant. Half the participants with baseline IFN-γ responses became HCV RNA positive (5/10), with one of these participants spontaneously clearing HCV. The spontaneous clearer had high magnitude and broad Th1 responses, favorable IFNL3 genotype and favorable HLA types.ConclusionsThis study demonstrated the detection of HCV-specific IFN-γ responses in HCV antibody and RNA negative individuals, with a tendency for HCV-specific IFN-γ responses to be associated with HCV exposure. The potential role of HCV-specific IFN-γ responses in those who remained HCV RNA negative is of value for the development of novel HCV therapeutics.

Dataset Information

The association between the genetic polymorphisms of LMP2/LMP7 and the outcomes of HCV infection among drug users.

Publications

The association between the genetic polymorphisms of LMP2/LMP7 and the outcomes of HCV infection among drug users.

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