Human genomics of the humoral immune response against polyomaviruses

Hodel, Flavia; Chong, Amanda Y; Šćepanović, Petar; Xu, Zhi Ming; Naret, Olivier; Thorball, Christian W; Rüeger, Sina; Marques‐Vidal, Pedro; Vollenweider, Péter; Begemann, Martin; Ehrenreich, Hannelore; Brenner, Nicole; Bender, Noemi; Waterboer, Tim; Mentzer, Alexander J.; Hill, Adrian V. S.; Hammer, Christian; Fellay, Jacques

doi:10.1093/ve/veab058

Cited by 12 publications

(13 citation statements)

References 72 publications

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“…Of particular interest is the identification of multiple variants in NFKB1 as a common locus associated with antibody responses across multiple pathogens and pathogen types, including EBV, human papillomavirus type 18 (HPV18), HIV, HTLV-1, Kaposi’s sarcoma-associated herpesvirus (KSHV), and T. gondii . To confirm the likely contribution of this locus to multiple infectious antigen responses we replicated this association demonstrating a consistent direction of effect for three antigens (EBV EAD, EBV ZEBRA and HHV-7 U14) using an independently recruited cohort (CoLaus/PsyCoLaus; see Supplementary Table 2, Extended Data Table 4, 16 ) where data using the same Multiplex Serology technology was available but with a different set of antigens (Fig. 1b).…”

Section: Main Textmentioning

confidence: 71%

“…Genetic analyses of antibody response levels against vaccine preventable infections, such as hepatitis B virus, have demonstrated a strong influence of genetic loci, including the major histocompatibility locus (MHC) in predicting antibody magnitude overlapping with GWAS of disease susceptibility 14 . The MHC has also been implicated in varied antibody responses to infections including JC virus, and influenza [15][16][17] . Furthermore, primary immunodeficiencies such as common variable immunodeficiency (CVID) and X-linked agammaglobulinaemia are well recognised disorders that increase the risk of multiple infections owing to impaired humoral function and antibody deficiencies [18][19][20] .…”

Section: Main Textmentioning

confidence: 99%

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A frequent ancestral NFKB1 variant predicts risk of infection or allergy

Chong

Brenner

Jimenez-Kaufmann

et al. 2022

Preprint

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Infectious agents contribute significantly to the global burden of diseases, through both acute infection and their chronic sequelae. We leveraged the UK Biobank to identify genetic loci that influence humoral immune response to multiple infections. From 45 genome-wide association studies in 9,611 participants from UK Biobank, we identifiedNFKB1as a locus associated with quantitative antibody responses to multiple pathogens including those from the herpes, retro- and polyoma-virus families. An insertion-deletion variant thought to affectNFKB1expression (rs28362491), was mapped as the likely causal variant. This variant has persisted throughout hominid evolution and could play a key role in regulation of the immune response. Using 121 infection and inflammation related traits in 487,297 UK Biobank participants, we show that the deletion allele was associated with an increased risk of infection from diverse pathogens but had a protective effect against allergic disease. We propose that altered expression ofNFKB1, as a result of the deletion, modulates haematopoietic pathways, and likely impacts cell survival, antibody production, and inflammation. Taken together, we show that disruptions to the tightly regulated immune processes may tip the balance between exacerbated immune responses and allergy, or increased risk of infection and impaired resolution of inflammation.

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Section: Main Textmentioning

confidence: 71%

Section: Main Textmentioning

confidence: 99%

A frequent ancestral NFKB1 variant predicts risk of infection or allergy

Chong

Brenner

Jimenez-Kaufmann

et al. 2022

Preprint

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“…DNA samples from 5399 CoLaus|PsyCoLaus participants were genotyped for 799,653 SNPs using the BB2 GSK-customized Affymetrix Axiom Biobank array. Quality control procedures and imputation of genotypes have been previously described in Hodel et al [ 23 ]. A total of 9,031,263 SNPs from the CoLaus|PsyCoLaus dataset were included for further analyses (flowchart of the inclusion/exclusion criteria are in Additional file 1 : Fig.…”

Section: Methodsmentioning

confidence: 99%

The combined impact of persistent infections and human genetic variation on C-reactive protein levels

Hodel

Naret

Bonnet

et al. 2022

BMC Med

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Multiple human pathogens establish chronic, sometimes life-long infections. Even if they are often latent, these infections can trigger some degree of local or systemic immune response, resulting in chronic low-grade inflammation. There remains an incomplete understanding of the potential contribution of both persistent infections and human genetic variation on chronic low-grade inflammation. We searched for potential associations between seropositivity for 13 persistent pathogens and the plasma levels of the inflammatory biomarker C-reactive protein (CRP), using data collected in the context of the UK Biobank and the CoLaus|PsyCoLaus Study, two large population-based cohorts. We performed backward stepwise regression starting with the following potential predictors: serostatus for each pathogen, polygenic risk score for CRP, and demographic and clinical factors known to be associated with CRP. We found evidence for an association between Chlamydia trachomatis (P-value = 5.04e − 3) and Helicobacter pylori (P-value = 8.63e − 4) seropositivity and higher plasma levels of CRP. We also found an association between pathogen burden and CRP levels (P-value = 4.12e − 4). These results improve our understanding of the relationship between persistent infections and chronic inflammation, an important determinant of long-term morbidity in humans.

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“…The BB2 GSK-customized Affymetrix Axiom Biobank array was used to genotype DNA samples from 5’399 participants at approximately 800’000 single nucleotide polymorphisms (SNPs). After genotype imputation and quality control procedures, approximately 9 million SNPs were available for analysis (30). We then calculated, based on the risk effects of common SNPs, the CHD polygenic risk score (PRS) for each study participant.…”

Section: Methodsmentioning

confidence: 99%

Associations of genetic and infectious risk factors with coronary heart disease

Hodel

Thorball

et al. 2022

Preprint

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Background and Purpose. Coronary heart disease (CHD) is one of the most pressing health problems of our time and a major cause of preventable death. CHD results from complex interactions between genetic and environmental factors. Using multiplex serological testing for persistent or frequently recurring infections and genome-wide analysis in a prospective population study, we delineate the respective and combined influences of genetic variation, infections, and low-grade inflammation on the risk of incident CHD. Participants and Methods. Study participants are enrolled in the CoLaus|PsyCoLaus study, a longitudinal, population-based cohort with baseline assessments from 2003 through 2008 and follow-up visits every five years. We analyzed a subgroup of 3'459 individuals with available genome-wide genotyping data and immunoglobulin G levels for 22 persistent or frequently recurring pathogens. All reported CHD events were evaluated by a panel of specialists. We identified independent associations with incident CHD using univariable and multi-variable stepwise Cox proportional hazards regression analyses. Results. Of the 3'459 study participants, 210 (6.07%) had at least one CHD event during the 12 years of follow-up. Multivariable stepwise Cox regression analysis, adjusted for known cardiovascular risk factors, socioeconomic status and statin intake, revealed that high polygenic risk (hazard ratio (HR) 1.31, 95% CI 1.10-156, P = 2.64e-03) and infection with Fusobacterium nucleatum (HR 1.63, 95% CI 1.08-2.45, P = 1.99e-02) were independently associated with incident CHD. Conclusion. In a prospective, population-based cohort, high polygenic risk and infection with Fusobacterium nucleatum have a small, yet independent impact on CHD risk.

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Human genomics of the humoral immune response against polyomaviruses

Cited by 12 publications

References 72 publications

A frequent ancestral NFKB1 variant predicts risk of infection or allergy

A frequent ancestral NFKB1 variant predicts risk of infection or allergy

The combined impact of persistent infections and human genetic variation on C-reactive protein levels

Associations of genetic and infectious risk factors with coronary heart disease

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