Background and aim: A genome-wide association study has indicated the association of numerous genes in the 6p21.3 region with chronic hepatitis B virus (HBV) infection. In this study, we screened 12 representative single-nucleotide polymorphisms (SNPs) from the 6p21.3 region and investigated their association with the risk of chronic hepatitis B (CHB) to better understand the molecular etiology underlying CHB risk in the Han Chinese population.
Methods: Between March 2021 and November 2022, we included 183 patients with CHB (case group) and 196 with natural HBV clearance (control group). Allele typing of the selected SNPs was performed using snapshot technology. The correlation between the 12 chosen SNPs and the risk of chronic HBV infection was examined using binary logistic regression analysis. Interacting genes of the variants were identified, and expression quantitative trait loci (eQTL) were analyzed using the 3DSNP database.
Results: We validated 12 previously reported CHB susceptibility sites, including rs1419881 of transcription factor 19 (TCF19), rs3130542 and rs2853953 of human leukocyte antigen (HLA)-C, rs652888 of euchromatic histone-lysine-methyltransferase 2 (EHMT2), rs2856718, rs9276370, rs7756516, and rs7453920 of HLA-DQ, rs378352 of HLA-DOA, and rs3077, rs9277535, and rs9366816 of HLA-DP. Logistic regression analyses revealed that polymorphisms such as rs9276370, rs7756516, rs7453920, rs3077, rs9277535, and rs9366816 were positively correlated with natural HBV clearance in the dominant model. Conversely, rs3130542 and rs378352 were identified as risk factors for CHB. Haplotype analysis revealed that rs9276370, rs7756516, and rs7453920 in HLA-DQ were TTG and GCA haplotypes. Although the TTG haplotype was positively correlated with a higher risk of CHB, the GCA haplotype significantly influenced the natural clearance of HBV. Bioinformatics analysis demonstrated that rs378352, rs3077, and rs9366816 were located within enhancer states; rs3077 and rs9366816 overlapped with nine transcription factor-binding sites, whereas rs378352 altered five sequence motifs. Furthermore, eQTL analysis demonstrated the functional tendencies of eight statistically significant SNPs (rs3130542, rs9276370, rs7756516, rs7453920, rs378352, rs3077, rs9277535, and rs9366816).
Conclusions: Genetic variations within the 6p21.3 region were associated with chronic HBV infection in the Han Chinese population in southern China. Furthermore, the GCA haplotype including rs9276370, rs7756516, and rs7453920 of HLA-DQ contributed significantly to natural HBV clearance, implying that multiple SNPs exert a cumulative allelic effect on HBV infection.
Data availability statement
Data are contained in this manuscript or supplementary mate-rial. The data presented in this study are available on request from the corresponding authors. The functionality score data for all eight variants were obtained from the 3DSNP database.
Authors’ contributions
Jiancheng Huang: Writing-Original draft preparation. Mingkuan Su: Data Collection and Statistical Analysis. Hongbin Chen and Shuiqing Wu: Sample Collection, DNA Extraction, and Biochemical Index Detection. Fanhui Kong: Technical Support. Haiying Wu and Jianfeng Guo: Conceptualization and Designing of the Study. All authors approved the final version of this manuscript.
Declaration of competing interest
The authors declare that they have no conflict of interest.
Acknowledgements
This study was funded by The Ningde Science and Technology Plan Project of China (Grant No. 20170013).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.livres.2024.02.001.
| [1] |
Wu TW, Chou CL, Chen CF, Wang LY. Common genetic variants of response to hepatitis B vaccines correlate with risks of chronic infection of hepatitis B virus: a community-based case-control study. Int J Mol Sci. 2023;24:9741. https://doi.org/10.3390/ijms24119741.
|
| [2] |
Jeng WJ, Papatheodoridis GV, Lok ASF. Hepatitis B. Lancet. 2023;401: 1039-1052. https://doi.org/10.1016/S0140-6736(22)01468-4.
|
| [3] |
Liu J, Liang W, Jing W, Liu M. Countdown to 2030: eliminating hepatitis B disease, China. Bull World Health Organ. 2019;97:230-238. https://doi.org/10.2471/BLT.18.219469.
|
| [4] |
Naderi M, Hosseini SM, Behnampour N, Shahramian I, Moradi A. Association of HLADQ-B1 polymorphisms in three generations of chronic hepatitis B patients. Virus Res. 2023;325:199036. https://doi.org/10.1016/j.virusres.2022.199036.
|
| [5] |
Kramvis A, Chang KM, Dandri M, et al. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol. 2022;19:727-745. https://doi.org/10.1038/s41575-022-00649-z.
|
| [6] |
Chu YJ, Yang HI, Hu HH, et al. HBV genotype-dependent association of HLA variants with the serodecline of HBsAg in chronic hepatitis B patients. Sci Rep. 2023;13:359. https://doi.org/10.1038/s41598-023-27570-y.
|
| [7] |
Pang Y, Lv J, Kartsonaki C, et al. Genetic and healthy lifestyle factors in relation to the incidence and prognosis of severe liver disease in the Chinese popula-tion. Chin Med J (Engl). 2023;136:1929-1936. https://doi.org/10.1097/CM9.0000000000002754.
|
| [8] |
He J, Gai J. Genome-wide association studies (GWAS). Methods Mol Biol. 2023;2638:123-146. https://doi.org/10.1007/978-1-0716-3024-2_9.
|
| [9] |
Gao H, Wang X, Ma H, et al. METTL16 regulates m6A methylation on chronic hepatitis B associated gene HLA-DPB1 involved in liver fibrosis. Front Genet. 2022;13:996245. https://doi.org/10.3389/fgene.2022.996245.
|
| [10] |
Kulski JK, Suzuki S, Shiina T. Human leukocyte antigen super-locus: nexus of genomic supergenes, SNPs, indels, transcripts, and haplotypes. Hum Genome Var. 2022;9:49. https://doi.org/10.1038/s41439-022-00226-5.
|
| [11] |
Chen J, Li L, Yin Q, Shen T. A review of epidemiology and clinical relevance of Hepatitis B virus genotypes and subgenotypes. Clin Res Hepatol Gastroenterol. 2023;47:102180. https://doi.org/10.1016/j.clinre.2023.102180.
|
| [12] |
Chinese Society of Infectious Diseases. Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. [The guidelines of pre-vention and treatment for chronic hepatitis B (2019 version)]. Zhonghua Gan Zang Bing Za Zhi. 2019;27:938-961. https://doi.org/10.3760/cma.j.issn.1007-3418.2019.12.007.
|
| [13] |
Mbarek H, Ochi H, Urabe Y, et al. A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population. Hum Mol Genet. 2011;20:3884-3892. https://doi.org/10.1093/hmg/ddr301.
|
| [14] |
Kim YJ, Kim HY, Lee JH, et al. A genome-wide association study identified new variants associated with the risk of chronic hepatitis B. Hum Mol Genet. 2013;22:4233-4238. https://doi.org/10.1093/hmg/ddt266.
|
| [15] |
Jiang DK, Ma XP, Yu H, et al. Genetic variants in five novel loci including CFB and CD 40 predispose to chronic hepatitis B. Hepatology. 2015;62:118-128. https://doi.org/10.1002/hep.27794.
|
| [16] |
Kamatani Y, Wattanapokayakit S, Ochi H, et al. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet. 2009;41:591-595. https://doi.org/10.1038/ng.348.
|
| [17] |
Hu Z, Liu Y, Zhai X, et al. New loci associated with chronic hepatitis B virus infection in Han Chinese. Nat Genet. 2013;45:1499-1503. https://doi.org/10.1038/ng.2809.
|
| [18] |
Quan C, Ping J, Lu H, Zhou G, Lu Y.3DSNP 2.0:update and expansion of the noncoding genomic variant annotation database. Nucleic Acids Res. 2022;50:D950eD955. https://doi.org/10.1093/nar/gkab1008.
|
| [19] |
Xiao Y, Cui Z, Sun L, et al. Lack of geographical and ethnic distribution of Hepatitis B virus genotypes in Hainan Island, China. Infect Genet Evol. 2023;107:105401. https://doi.org/10.1016/j.meegid.2022.105401.
|
| [20] |
Zhang XL, Ni XC, Jia JH, et al. Association of the rs3077 and rs 9277535 poly-morphisms in HLA-DP with hepatitis B virus infection and spontaneous clearance: a meta-analysis. Scand J Gastroenterol. 2013;48:736-744. https://doi.org/10.3109/00365521.2013.787643.
|
| [21] |
Liao Y, Cai B, Li Y, et al. Association of HLA-DP/DQ and STAT4 polymorphisms with HBV infection outcomes and a mini meta-analysis. PLoS One. 2014;9: e111677. https://doi.org/10.1371/journal.pone.0111677.
|
| [22] |
Wang L, Wu XP, Zhang W, et al. Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese: two independent case-control studies. PLoS One. 2011;6:e17608. https://doi.org/10.1371/journal.pone.0017608.
|
| [23] |
Koukoulioti E, Fischer J, Schott E, et al. Association of HLA-DPA1 and HLA-DPB 1 polymorphisms with spontaneous HBsAg seroclearance in Caucasians. Liver Int. 2019;39:646-654. https://doi.org/10.1111/liv.14008.
|
| [24] |
Kaissarian NM, Meyer D, Kimchi-Sarfaty C. Synonymous variants: necessary nuance in our understanding of cancer drivers and treatment outcomes. J Natl Cancer Inst. 2022;114:1072-1094. https://doi.org/10.1093/jnci/djac090.
|
| [25] |
Kikutake C, Suyama M. Possible involvement of silent mutations in cancer pathogenesis and evolution. Sci Rep. 2023;13:7593. https://doi.org/10.1038/s41598-023-34452-w.
|
| [26] |
Yige L, Dandan Z. Progress on functional mechanisms of colorectal cancer causal SNPs in post-GWAS. Yi Chuan. 2021;43:203-214. https://doi.org/10.16288/j.yczz.20-320.
|
| [27] |
Cano-Gamez E, Trynka G. From GWAS to function: using functional genomics to identify the mechanisms underlying complex diseases. Front Genet. 2020;11: 424 https://doi.org/10.3389/fgene.2020.00424.
|
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