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. 2021 Mar 25:12:630310.
doi: 10.3389/fgene.2021.630310. eCollection 2021.

Genetic Variants in TNFSF4 and TNFSF8 Are Associated With the Risk of HCV Infection Among Chinese High-Risk Population

Zuqiang Fu  1   2 , Weihua Cai  3 , Jianguo Shao  4 , Hong Xue  5 , Zhijun Ge  6 , Haozhi Fan  7 , Chen Dong  8 , Chunhui Wang  2   9 , Jinwei Zhang  10 , Chao Shen  1   2 , Yun Zhang  1   2   9 , Peng Huang  1   2   9 , Ming Yue  11
Affiliations

Genetic Variants in TNFSF4 and TNFSF8 Are Associated With the Risk of HCV Infection Among Chinese High-Risk Population

Zuqiang Fu et al. Front Genet. .

Abstract

Background: The tumor necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) play important roles in the immune responses to infections. The aim of this study was to determine the impact of single nucleotide polymorphisms (SNPs) of several TNFSF/TNFRSF genes on the risk of hepatitis C virus (HCV) infection in the Chinese high-risk population.

Methods: The TNFSF4-rs1234313, TNFSF4-rs7514229, TNFSF8-rs3181366, TNFSF8-rs2295800, TNFRSF8-rs2298209, and TNFRSF8-rs2230625 SNPs were genotyped in 2309 uninfected controls, 597 subjects with spontaneous HCV clearance and 784 patients with persistent HCV infection using the TaqMan-MGB assay. The putative functions of the positive SNPs were determined using online bioinformatics tools.

Results: After adjusting for gender, age, high-risk population, alanine transaminase (ALT), aspartate aminotransferase (AST), IL28B-rs12979860 and rs8099917 genotypes, the non-conditional logistic regression showed that rs7514229-T, rs3181366-T, and rs2295800-C were associated with an increased risk of HCV infection (all P FDR < 0.05). Combined analysis of rs7514229-T and rs3181366-T risk alleles showed that the subjects carrying 2-4 risk alleles were more susceptible to HCV infection compared with those lacking any risk allele (all P < 0.001). Furthermore, the risk of HCV infection increased with the number of risk alleles (P trend < 0.001). In silico analysis showed that rs7514229, rs3181366, and rs2295800 polymorphisms may affect the transcription of mRNA by regulating miRNA binding, TF binding, and promoter activation, respectively, which may have biological consequences.

Conclusion: TNFSF4-rs7514229, TNFSF8-rs3181366, and TNFSF8-rs2295800 are associated with increased risk of HCV infection in the Chinese high-risk population.

Keywords: correlation analysis; hepatitis C virus; single nucleotide polymorphisms (SNPs); tumor necrosis factor receptor superfamily; tumor necrosis factor superfamily.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Flow diagram for inclusion of participants.
FIGURE 2
FIGURE 2
The influence of rs7514229 variants on TNFSF4 mRNA centroid secondary structures. Changes in the local structure were illustrated by the RNAfold Web Server. The arrows indicate the location of the mutation (50 bases upstream and 50 bases downstream of the mutation) shown in bold type. The underlined sequence has overlapping nucleotide letters. TNFSF4 rs7514229 changes the local structure and the minimum free energy of the mRNA centroid secondary structure (one with the smallest base pair distance) from −17.30 kcal/mol (A) to −16.60 kcal/mol (B). The wild-type and mutant-type sequences are also listed (available at http://rna.tbi.univie.ac.at//cgi-bin/RNAWebSuite/RNAfold.cgi).
FIGURE 3
FIGURE 3
Functional annotation for rs2295800 using ENCODE data from UCSC genome browser. Transcription Factor ChIP-seq Clusters show binding regions of transcription factors and other regulatory proteins. Based on ENCODE project and the UCSC genome browser data, rs2295800 is located on the highest peak of the histone H3 acetylated lysine 27 (H3K27Ac) histone marker and this track shows enrichment of the H3K27Ac histone mark across the genome as determined by a ChIP-seq assay. The light blue line indicates the position of SNP rs2295800 (available at http://genome.ucsc.edu/).
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