Identification of host-pathogen-disease relationships using a scalable Multiplex Serology platform in UK Biobank

Mentzer, Alexander J.; Brenner, Nicole; Allen, Naomi E.; Littlejohns, Thomas J.; Chong, Amanda Y; Cortés, Adrián; Almond, Rachael; Hill, Michael; Sheard, Simon; McVean, Gil; Collins, Rory; Avs., Hill; Waterboer, Tim

doi:10.1101/19004960

Cited by 19 publications

(36 citation statements)

References 69 publications

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“…In contrast, our study demonstrated consistently higher EBV seroprevalence among all age brackets compared to a comparable older study [18] this may reflect a genuine increase in seroprevalence in the UK, differences in population sampling, or different sensitivity and specificity of the assays used (our study used VCA whereas previous studies have used EBNA). Reassuringly, our estimates closely mirror those from a recent random sampling of UK Biobank participants: among those aged 40-69 years, EBV seroprevalence was 94.7% 1 .…”

Section: Discussionsupporting

confidence: 80%

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Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom

et al. 2020

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Background: Epstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which~95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future. Methods: We conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. Results: 1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10-15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking. Conclusions: We report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.

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Section: Discussionsupporting

confidence: 80%

“…Epstein-Barr Virus (EBV) is a ubiquitous gammaherpesvirus with which~95% of healthy adults are infected [1]. EBV is the commonest causative agent of Infectious Mononucleosis (IM), a triad of pharyngitis, lymphadenopathy and fever in the context of acute EBV infection [2].…”

Section: Introductionmentioning

confidence: 99%

Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom

et al. 2020

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“…The full study population consisted of a randomly drawn subset of 9695 individuals from the UK Biobank cohort [ 32 , 36 ]. UK Biobank obtained ethics approval from the Research Ethics Committee (REC; approval number: 11/NW/0382) and informed consent from all participants enrolled.…”

Section: Methodsmentioning

confidence: 99%

Characterization of human papillomavirus (HPV) 16 E6 seropositive individuals without HPV-associated malignancies after 10 years of follow-up in the UK Biobank

et al. 2020

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Background: Antibodies against the HPV16 oncoprotein E6 are promising biomarkers for HPV16-driven oropharyngeal cancer (HPV16-OPC) due to their high sensitivity and specificity, and prospective manifestation. In previous studies, 07% of controls without HPV-associated malignancies were HPV16 E6 seropositive of which only a minority is expected to develop HPV16-driven cancer. We aimed to characterise HPV16 E6 antibodies in individuals without HPV-associated malignancies. Methods: We analysed serum antibodies against HPV16 E6, E7, L1 and HPV18 L1 in a random sample (n = 9,695) of the prospective UK Biobank cohort (UKB). Excluding individuals with potentially HPV-associated malignancies (n = 192), we assessed risk factors for seropositivity by logistic regression. Findings: In individuals without potentially HPV-associated malignancies (n = 9,503), the HPV16 E6 seroprevalence was 08%. Seropositivity against HPV16 E6 and all other HPV antigens was strongly associated with sexual behaviour. The seroprevalence of HPV16 E6, L1 and HPV18 L1 increased with the number of lifetime sex partners (p trend <0005), and all HPV antibodies were associated with same-sex intercourse (OR E6 31, 95%CI 14À69; reference category: no same-sex intercourse). HPV16 E6 and L1 seropositivity were associated with young age (17 years) at sexual debut (OR E6 20, 95%CI 11À37) compared with individuals reporting sexual debut at age 20 years. Interpretation: This is the first study characterising HPV16 E6 antibodies in the general UK population. Their strong association with sexual behaviour, and overlapping risk factor profiles with other HPV antibodies support their relevance for HPV16-OPC disease prediction. However, additional risk stratification will be required to identify individuals at highest risk to develop HPV16-OPC.

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“…We excluded variants out of Hardy-Weinberg equilibrium at p<1´10 -5 , call rate <95% (alternate allele dosage within 0.1 of the nearest hard call to be non-missing), imputation quality INFO<0.30, and MAF<0.01. Seropositivity for each antigen was determined using established cut-offs based on prior validation work 15 .…”

Section: Genome-wide Association Analysismentioning

confidence: 99%

“…High levels of specific IgG's can be the result of chronic infection, while low levels may indicate poor immunity. Viruses assayed in the UKB multiplex serology panel were previously chosen based on putative links to chronic diseases including cancer, autoimmune, and neurodegenerative conditions 15 .…”

Section: Introductionmentioning

confidence: 99%

The landscape of host genetic factors involved in immune response to common viral infections

Kachuri

Francis

Morrison

et al. 2020

Preprint

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1 Introduction: Humans and viruses have co-evolved for millennia resulting in a complex host genetic 2 architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight 3 into disease etiology and informs public health interventions.4Methods: We conducted a comprehensive study linking germline genetic variation and gene expression 5 with antibody response to 28 antigens for 16 viruses using serological data from 7924 participants in the 6 UK Biobank cohort. Using test results from 2010 UK Biobank subjects, we also investigated genetic 7 determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 8 Results: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral 9 antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited 10 pleiotropic effects across viral families. Genome-wide association analyses discovered 7 novel genetic loci 11 associated with viral antibody response (P<5.0´10 -8 ), including FUT2 (19q13.33) for human polyomavirus 12 BK (BKV), STING1 (5q31.2) for Merkel cell polyomavirus (MCV), as well as CXCR5 (11q23.3) and TBKBP1 13 (17q21.32) for human herpesvirus 7. Transcriptome-wide association analyses identified 114 genes 14 associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P=5.0×10 -15 15(MCV), NTN5: P=1.1×10 -9 (BKV), and P2RY13: P=1.1×10 -8 (Epstein-Barr virus nuclear antigen). We also 16 demonstrated pleiotropy between viral response genes and complex diseases, such as C4A expression in 17 varicella zoster virus and schizophrenia. Finally, our analyses of SARS-CoV-2 revealed the first genome-18 wide significant infection susceptibility signal in EHF, an epithelial-specific transcriptional repressor 19 implicated in airway disease. Targeted analyses of expression quantitative trait loci suggest a possible role 20 for tissue-specific ACE2 expression in modifying SARS-CoV-2 susceptibility. 21 Conclusions:Our study confirms the importance of the HLA region in host response to viral infection and 22 elucidates novel genetic determinants of host-virus interaction. Our results may have implications for 23 complex disease etiology and COVID-19. : medRxiv preprint 29Viruses have been infecting cells for a half a billion years 1 . During our extensive co-evolution viruses have 30 exerted significant selective pressure on humans; overtly during fatal outbreaks, and covertly through 31 cryptic immune interaction when a pathogen remains latent. The recent pandemic of severe acute 32 respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the paramount public health need to 33 understand human genetic variation in response to viral challenge. Clinical variation in COVID-19 severity 34 and symptomatic presentation may be due to differences host genetic factors relating to immune response 2 . 35Furthermore, many common infections are cryptically associated with a variety of complex illnesses, 36 especially those with an i...

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Identification of host-pathogen-disease relationships using a scalable Multiplex Serology platform in UK Biobank

Cited by 19 publications

References 69 publications

Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom

Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom

Characterization of human papillomavirus (HPV) 16 E6 seropositive individuals without HPV-associated malignancies after 10 years of follow-up in the UK Biobank

The landscape of host genetic factors involved in immune response to common viral infections

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