Genetic determinants of differential susceptibility to hepatitis B Infection among a general population cohort from southwestern Uganda: a genome-wide association study

Abstract

Introduction: Hepatitis B is one of the major causes of mortality and morbidity worldwide. Hepatitis B infection causes liver inflammation and damage that may progress to liver cirrhosis, liver cancer and ultimately lead to death. The outcomes of hepatitis B virus exposure are highly variable and range from resistance to infection, spontaneous viral clearance, and chronic hepatitis B infection. This variability is moderated by a number of factors such as host genetics, viral factors and environmental factors. Genetic polymorphisms such as single nucleotide polymorphisms present in individuals of particular populations can be used to determine the risk of susceptibility to infectious and complex diseases. A plethora of studies have determined the host genetic impact such as inter-individual genome variability on differential susceptibility to hepatitis B infection. However, most of these studies have been carried out in European populations. There is little data from genetic studies among African populations, which are known to be highly genetically diverse, as evidenced by high levels of phenotypic variation. This limits the generalizability of findings to African populations. This study identified the host genetic determinants influencing differential susceptibility to hepatitis B infection among a Ugandan population. It estimated the genetic variants present among Ugandans that account for differential susceptibility to hepatitis B infection.

Objective: To investigate the host genetic impact on differential susceptibility to hepatitis B infection among a general population cohort in southwestern Uganda.

Methods: Genome-wide association analysis using GEMMA software to find genomic loci that are associated with differential susceptibility to hepatitis B infection was performed, followed by fine- mapping using the Bayesian approach to determine the specific causal variants identified to be in the association. Replication of genome-wide association study findings was done to validate findings and check for reproducibility in summary statistics available on the genome-wide association study (GWAS) catalog. A two-sample Mendelian randomization (MR) was performed to determine the causal effect of hepatitis B infection on liver function biomarkers of alanine aminotransferase and aspartate transferase (ALT) and Aspartate Transferase (AST).

Results: We identified 78 significant single nucleotide polymorphisms (SNPs) in 22 genomic loci associated with susceptibility to hepatitis B infection of which all 22 were novel. The most significant SNPs mapped to nearest genes POGK, MIXL1, RP11-24121.1, RP1-97D16.1, ADRB1, and RBFOX1 which have previously been associated with the liver tissue and its enzymes. Replication of association findings was not successful in two independent cohorts of European ancestry individuals. The two sample MR revealed no causal effect of hepatitis B infection susceptibility on ALT and AST serum levels.

Conclusion: This study identified existing and novel SNPs associated with differential susceptibility to hepatitis B infection present among Ugandans in a well-characterized General Population Cohort.