Hepatic diseases are due to the inflammation of the liver, which can originate from viral, drug-induced, toxic, or autoimmune sources. Notably, viral hepatitis, a significant subset of hepatic diseases, presents a global public health challenge, impacting millions of individuals annually [1] [2] . Among these, viral hepatitis B and C stand out as the leading to liver damage with the potential progression to cirrhosis or liver cancer in sub-Saharan Africa and South-east Asia [2] .

According to a 2014 report by the World Health Organization (WHO), viral hepatitis accounts for 1.4 million deaths each year, comparable to 1.6 million deaths from HIV/AIDS, 1.3 million from tuberculosis, and 600,000 from malaria. This report also highlights that approximately 2 billion people have been infected with the hepatitis B virus [3] . Additionally, Africa has the highest prevalence of HBV infection among children under five years of age, and 70% of new infections worldwide occur in the African region [4] . HBV and HCV strains of hepatitis notably contribute to substantial mortality and morbidity [3] . In West Africa, hepatitis B is endemic, with a prevalence of 8%, the highest worldwide [5] . Additionally, approximately 2% of the region's population carries chronic hepatitis C [5] . Burkina Faso, a West African country, is highly affected by HBV infection, with an estimated national prevalence of (12% - 14.5%) and lower prevalence of HCV (1% - 2.8%) [6] . Chronic hepatitis significantly escalates the risk of cirrhosis and primary liver cancer, which claim 900 and 1300 lives annually in the country, respectively [7] .

The outcome of the disease is linked to interactions between the immune system and the virus, and also depends on the age and immune status of the patient. Indeed, in more than 90% of cases, adults infected with HBV have developed acute hepatitis and were able to control and eliminate the virus without long-term effects [8] . However, in 10% of cases, certain adults who are unable to fight the infection develop a chronic infection that can involve in the long term into cirrhosis and/or hepatocellular carcinoma (HCC). Less than 1% of patients infected with HBV develop fulminant hepatitis which leads to their death in the absence of liver transplantation [8] .

The progression towards chronicity depends on the interaction between viral factors and host factors, such as the immune status of the individual [7] .

MAP3K14, is a widely expressed 947 amino acids, approximately 100 kDa cytoplasmic protein of the MAP kinase family, located on chr17. The gene of the same name encodes mitogen-activated protein kinase 14, NIK (NF kappa B inducing kinase), which is a serine/threonine protein kinase [9] [10] . This kinase binds to TNF receptor-associated factor 2 (TRAF2) and stimulates NF-κB activity. It is a critical kinase in the alternative NF-κB activation pathway. It shares sequence similarity with several other MAPKK [10] . In 2022, a Chinese study showed that the MAP3K14 rs2074292 allele may have a potential predictor of HBV-HCC survival probably regulating MAP3K14 mRNA expression [11] . The MAP3K14 rs2074292 variant therefore has an impact on the evolution of HBV infection.

CD40 is a 40 kDa type I glycoprotein, a member of the nerve growth factor/tumor necrosis factor receptor family. It is found on many cell types, including B lymphocytes, dendritic and follicular cells, macrophages, hematopoietic progenitors, endothelial and epithelial cells, fibroblasts, and carcinoma cells [12] . CD40 is expressed on B lymphocytes and antigen-presenting myeloid cells and plays an important role in the antiviral immune response. Studies have reported that CD40 could be activated during viral infection and its activation could increase the antiviral capacity of its host. The Chronic Hepatitis B (CHB) susceptibility study indicates that significantly induced elevated CD40 concentration in CHB patients was observed compared to healthy controls. Non-HLA region genes, such as CD40, may play an important role in chronic hepatitis B (CHB) [13] .

A comprehensive understanding of these viral, host and environmental factors is essential for prevention and effective treatment to reduce the burden of HBV-related complications. To date, several genome-wide association studies (GWAS) of HCC have discovered SNPs associated with cancer risk and survival [14] [15] . There are few studies on polymorphisms on the involvement of MAP3K14 and CD40 genes in the occurrence and progression of B viral infection, particularly in Burkina Faso. Thus, in this study we evaluated the association of a MAP3K14 (rs2074292) and CD40 (rs1883832) polymorphism and chronic hepatitis B virus carriage in a population from Burkina Faso.

The aim of this study was to investigate the involvement of MAP3K14 rs2074292 and CD40 (rs1883832) genes polymorphisms in the evolution of hepatitis B virus infection in Burkina Faso.

Analysis of data by socio-demographic characteristics showed that the mean age of our study population was 35.31 ± 11.96 years for MAP3K14 (rs2074292) and 34.51 ± 11.14 years for CD40 (rs1883832). The average age of cases was higher than that of controls (42.10 ± 15.47 years for HCC vs 30.03 ± 8.01 years for controls). Our results corroborate those of SOME et al. who argue that in sub-Saharan Africa, HCC is most often diagnosed in patients in the 40 - 50 age range [16] . Our results are close to those of previous studies carried out at the Yalgado OUEDRAOGO teaching Hospital Center, which found average ages for cirrhosis patients of 46.5 years and 46.9 years in 2002 and 2020 respectively [16] [17] . However, our results differ from those of a study carried out in America, where the average age was around 60 years [18] . The results showed that our patients were younger than those in developed countries, which could be due to the high proportion of young people in Burkina Faso. This could be explained by the fact that HBV prevalence is high in sub-Saharan Africa, and access to the healthcare system is limited compared with other regions of the world.

Analysis MAP3K14 (rs2074292) gene polymorphism data in the general study population shows that, the frequencies of the AA, AG and GG genotypes were 8.52%, 85.65% and 5.82% respectively. For allelic distribution, the wild-type A allele had a frequency of 51.35% versus 48.65% for the mutated allele. Our results differ to those of Huang et al. in China, who found 21.59% for AA genotype; 51.62% for AG genotype and 27.25% GG even if our both results show a predominance heterozygote AG [11] . Our allelic frequencies also differ to those

of Huang who obtain 53.06% for G allele and 46.94% A allele. The difference in genotype and allele frequencies in our study could be explained by the genotype of the two study populations, black versus Chinese.

We correlated MAP3K14 gene polymorphisms with different stages of HBV infection and found no significant association. These results differ from those of Hung, who showed that the AA and AG genotypes were associated with a high risk of complications of HBV infection, notably HCC [11] . Nevertheless, our results showed that the GG mutated genotype is associated with protection against severe forms of HBV infection, although this result was not significant enough.

Analysis of polymorphism data for the CD40 gene (rs1883832) in the general population studied showed that the frequencies of the CC, CT and TT genotypes were 68.2%, 17.3% and 14.5% respectively. In terms of allelic distribution, the wild-type C allele had a frequency of 76.9%, compared with 23.1% for the mutated T allele. These genotypic frequencies differ from those of Tian et al. 2019, who found 38.6%, 47% and 14.4% for the CC, CT and TT genotypes, respectively. [19] .

Our allele frequencies also differ from those of Tian et al. who obtained 62.1% for the C allele and 37.9% for the T allele. The difference in genotype and allele frequencies in our two studies could be explained by the genotype of the two populations studied, black versus Chinese. [19] .

There was an association between CD40 gene polymorphisms and different stages of HBV infection. Indeed, the mutated T allele and the heterozygous CT genotypes of rs1883832 T were associated with the progression of HBV infection towards severe forms of the disease, notably between chronic carriers and those with cirrhosis and HCC. The mutated allele would favor not only chronic infection with the virus, but also progression to cirrhosis and hepatocellular carcinoma, as shown by the ORs, CIs and p-values of the results obtained. These results correspond with those found by Jia Xuan Chen et al who demonstrated in a similar study that the SNP rs1883832 located in the 5'UTR of CD40 was involved in the risk of CHB, the rs1883832 T allele representing the risk, while the C allele is protective [20] . One possible explanation is that the presence of the T allele within the CD40 gene could affect gene translation by influencing mRNA-ribosome stability and the function of cytokines and T cells. [21] .

In addition, the homozygous mutated TT genotype and the mutated allele of the CD40 gene (rs1883832) were associated with protection against the development of cirrhosis and carcinoma in HBV infection.

However, our results differ from those of Tain et al., who associated the homozygous mutated genotype with a low risk of developing severe forms of the disease. [19] .

Analysis of the combined genotypes of the 2 polymorphisms revealed a significant association between the two heterozygous genotypes CT of rs1883832 and AG of rs2074292. Indeed, the combination of these genotypes could be associated with an elevated risk of progression from chronic infection to cirrhosis or HCC.

In contrast, the AG heterozygote of rs2074292MAP3K14 combined with the CT heterozygote and TT mutated homozygote genotypes of rs1883832CD40 was associated with protection against chronic hepatitis. Our study also demonstrated protection against HCC conferred by the combination of the TT-mutated homozygous genotype of CD40 (rs1883832) and the AG heterozygote of MAP3K14 (rs2074292).

Our study was the first to investigate the association between CD40 (rs1883832) and MAP3K14 (rs2074292) polymorphisms and the occurrence of severe forms of HBV infection in the population from Burkina Faso. This study showed that the heterozygous CT genotype and the mutated T allele of the CD40 gene (rs1883832) are involved in the progression of chronic hepatitis to cirrhosis and hepatocellular carcinoma in HBV-infected patients. Thus, this study showed that CD40 SNP rs1883832 has its unique mechanism of modulating HBV clearance in hepatocytes. However, no association was found between polymorphisms in the MAP3K14 gene (rs2074292) and the progression of HBV infection. By combining the two polymorphisms, we found associations that conferred protection against chronic hepatitis and HCC, and elevated risks of progression from chronic infection to cirrhosis and HCC.

It is possible that an interaction between several factors may better explain the emergence of severe forms of HBV infection in Burkina Faso, in order to better understand the different pathways and factors that contribute to these associations. Further research in this area is therefore needed, and could help to improve the prevention, diagnosis and treatment of HBV infection, particularly in high-prevalence regions such as Burkina Faso.

We wish to thank all the participants to this study.

This study was approved by the Ethics Committee for Health Research (reference: deliberation N˚ 2022-02-027). Written informed consent was obtained from patients and donors. We ensured the confidentiality of our database by storing it on a password-protected computer.

Not Applicable.

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

The authors declare that they have no competing interests.

The present study was supported by the Government of Burkina Faso through the “Fonds National de la Recherche et de Innovation pour le Development” (FONRID) under grants N˚ 000320 FONRlD/AAP3Malalnfect/NCP/PC/2021.

Study concept and design: LT, SVZ, FWD and JS. Sampling and laboratory analysis: LT, NN, SK, ARK, MNT, SVZ, MST and TRC. Statistical analysis and data interpretation: LT, NN, SK, MNT and AKO. Drafting of the manuscript: LT, NN, SK and AKO. Critical revision of the manuscript for important intellectual content: SVZ, AKO, MS, MST, BD, DPI, TS, ATY, BMN, FWD and JS. Administrative, technical and material support: LT, BMN, ATY, FWD and JS. Study supervision: BLN, ATY, FWD and JS. The corresponding author declares that the manuscript has been read and approved by all named authors and that the order of authorship in the manuscript has been approved by all of us.

Traore, L., Nignan, N., Kiemde, S., Koumbem, A.R., Zongo, S.V., Triande, M.N., Ouattara, A.K., Traore, M.S., Compaore, T.R., Sagna, T., Traore, I.M., Yonli, A.T., Nagalo, B.M., Djigma, F.W. and Simpore, J. (2023) Involvement of CD40 (rs1883832) and MAP3K14 (rs2074292) Genes Polymorphisms in Hepatitis B Virus Infection in Burkina Faso, West Africa. Journal of Biosciences and Medicines, 11, 343-361. https://doi.org/10.4236/jbm.2023.1112026

ALAT: Alanine Amino Transferase

CHB: Chronic Hepatitis B

DNA: Deoxyribonucleic Acid

CD40: Cluster of Differentiation 40

MAP3K14: Mitogen-Activated Protein Kinase Kinase Kinase 14

HBsAg: HBs Antigen

HBV: Hepatitis B Virus

HCC: Hepatocellular Carcinoma

HCV: Hepatitis C Virus

HIV: Human Immunodeficiency Virus

HLA: Human Leukocyte Antigen

NF-κB: nuclear Factor-Kappa B

WHO: World Health Organization

Rs: Reference of SNP

SNP: Single Nucleotide Polymorphism