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Distinct genetic architectures and environmental factors associate with host response to the ?2-herpesvirus infections.

ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR?=?5.71(1.58-7.12)), HIV positivity (OR?=?2.22(1.32-3.73)) and living in a more rural area (OR?=?1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p?=?6.64?×?10-09). For EBV, associations are identified for VCA (rs71542439, p?=?1.15?×?10-12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p?=?5.24?×?10-44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.

SUBMITTER: Sallah N

PROVIDER: S-EPMC7395761 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections.

Sallah Neneh N Miley Wendell W Labo Nazzarena N Carstensen Tommy T Fatumo Segun S Gurdasani Deepti D Pollard Martin O MO Dilthey Alexander T AT Mentzer Alexander J AJ Marshall Vickie V Cornejo Castro Elena M EM Pomilla Cristina C Young Elizabeth H EH Asiki Gershim G Hibberd Martin L ML Sandhu Manjinder M Kellam Paul P Newton Robert R Whitby Denise D Barroso Inês I

Nature communications 20200731 1

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on viru ...[more]

PMID: 32737300

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Project description:BackgroundHumans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.MethodsWe conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.ResultsSignals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβ1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P < 5.0 × 10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P = 5.0 × 10-15 (MCV), NTN5: P = 1.1 × 10-9 (BKV), and P2RY13: P = 1.1 × 10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.ConclusionsOur study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.

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Distinct genetic architectures and environmental factors associate with host response to the ?2-herpesvirus infections.

Publications

Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections.

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