Genetic Determinants of Antibody-Mediated Immune Responses to Infectious Diseases Agents: A Genome-Wide and HLA Association Study

Abstract

Introduction Infectious diseases are causally related to a large array of non-communicable diseases (NCDs). Identifying genetic determinants of infections and antibody-mediated immune responses may shed light on this relationship and provide therapeutic targets for drug and vaccine development. Methods We used the UK biobank cohort of up to 10,000 serological measurements of infectious diseases and genome-wide genotyping. We used data on 13 pathogens to define 46 phenotypes: 15 seropositivity case-control phenotypes, and 31 quantitative antibody measurement phenotypes. For each of these, we performed genome-wide association studies (GWAS) using the fastGWA linear mixed model package, and human leukocyte antigen (HLA) classical allele and amino acid residue associations analyses using Lasso regression for variable selection. Results We included a total of 8735 individuals for case-control phenotypes, and an average of 4286 samples per quantitative analyses (range: 276 to 8555). Fourteen of the GWAS yielded a genome-wide significant (p<5x10 -8) loci at the major histocompatibility complex (MHC) on chromosome 6. Outside the MHC, we found a total of 60 loci, multiple associated with Epstein-Barr virus (EBV) related NCDs (e.g. RASA3, MED12L, and IRF4). FUT2 was also identified as an important gene for polyomaviridae. HLA analysis highlighted the importance DRB1*09:01, DQB1*02:01, DQA1*01:02, and DQA1*03:01 in EBV serologies, and of DRB1*15:01 in polyomaviridae. Conclusion We have identified multiple genetic variants associated with antibody immune response to 13 infections, many of which are biologically plausible therapeutic or vaccine targets. This may help prioritize future research and drug development.

Unpicking the Gordian knot: Mendelian randomization to elucidate the risk factors for infectious diseases, using EBV as a model pathogen

“…17 In a recent publication, Butler-Laporte et alfound similar results to our GWAS, despite slight differences in sample selection, the top SNP for EBV seropositivity documented in that publication-rs71437272showed a similarly strong result in our analysis. 16 While our GWAS results provided insight into the genetic susceptibility component of our causal framework, they also gave us the tools required to untangle the conflicted evidence reported in the literature for EBV risk factors. An increased number of sexual partners and either being or having been a smoker increased risk of EBV.…”

“…17 In a recent publication, Butler-Laporte et al .found similar results to our GWAS, despite slight differences in sample selection, the top SNP for EBV seropositivity documented in that publication-rs71437272-showed a similarly strong result in our analysis. 16…”

“…A small number of studies have also examined genetic susceptibility to EBV infection. [10][11][12][13][14][15][16] More recent studies have identified genetic variants associated with anti-EBV antibody levels 12,13,17 Although some risk factors are consistently displayed from setting to setting (age being the clearest example), the published population health literature is often contradictory. This is due in part to poor control for confounding in such studies, partly due to the cost and complexity of measuring all putative relevant factors simultaneously.…”

Exploring the possible causal role of the immune response to varicella-zoster virus on multiple traits: a phenome-wide Mendelian randomization study

“…Several MR studies removed MHC SNPs from the IV list to minimize the risk of assumption violations [15, 42]. However, MHC SNPs often have strong associations with the exposure, especially for infection-related traits [13]. Simply removing them might introduce weak instrument bias.…”

Current HLA Investigations on SARS-CoV-2 and Perspectives

“…Additional HLA typing and statistical inference of HLA alleles can refine the SNP association signals to specific HLA alleles, reflecting specific molecular functions and pathways. Such a strategy was successfully implemented for infectious diseases such as HIV, HPV, Dengue, and Ebola ( Lin et al, 2003 ; Wang et al, 2011 ; Nishida et al, 2016 ; Adebamowo and Adeyemo, 2019 ; Chen et al, 2019 ; Ekenberg et al, 2019 ; Butler-Laporte et al, 2020 ; Chaisri et al, 2020 ; Huang et al, 2020 ; Ursu et al, 2020 ; Yengo et al, 2020 ).…”