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. 2025 Feb 24;61(3):303–312. doi: 10.1007/s11262-025-02145-3

Plasma proteins and herpes simplex virus infection: a proteome-wide Mendelian randomization study

Canya Fu 1,2,#, Wenjie Xu 2,#, Xia Xu 3,4, Fei Zhao 1,2, Canjie Zheng 2, Zhiying Yin 2,✉
PMCID: PMC12053213  PMID: 39992613

Abstract

Proteomics plays a pivotal role in clinical diagnostics and monitoring. We conducted proteome-wide Mendelian randomization (MR) study to estimate the causal association between plasma proteins and Herpes simplex virus (HSV) infection. Data for 2,923 plasma protein levels were obtained from a large-scale protein quantitative trait loci study involving 54,219 individuals, conducted by the UK Biobank Pharma Proteomics Project. HSV-associated SNPs were derived from the FinnGen study, which included a total of 400,098 subjects infected with HSV. MR analysis was performed to assess the links between protein levels and the risk of HSV infection. Furthermore, a Phenome-wide MR analysis was utilized to explore potential alternative indications or predict adverse drug events. Finally, we evaluated the impact of 1,949 plasma proteins on HSV infection, identifying 48 proteins that were negatively associated with HSV infection and 54 proteins that were positively associated. Genetically higher HLA-E levels were significantly associated with increased HSV infection risk (OR = 1.39, 95% CI: 1.17–1.65, P = 2.13 × 10−4, while ULBP2 showed a significant negative association with HSV infection risk (OR = 0.81, 95% CI: 0.73–0.90, P = 6.25 × 10−5) in the primary analysis. No significant heterogeneity or pleiotropy was observed in any of the results. Additionally, we found a suggestive association of Lymphotoxin-beta, SMOC1, MICB_MICA, ASGR1, and ANXA10 with HSV infection risk (P < 0.003). In Phenome-wide MR analysis, HLA-E was associated with 214 phenotypes (PFDR < 0.10) while ULBP2 did not show significant associations with any diseases after FDR adjustment. The comprehensive MR analysis established a causal link between multiple plasma proteins and HSV infection, emphasizing the roles of HLA-E and ULBP2. These results provide new insights into the biological mechanisms of HSV and support the potential for early intervention and treatment strategies, although further research is needed to validate these plasma protein biomarkers.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11262-025-02145-3.

Keywords: Herpes simplex virus, Plasma protein, Mendelian randomization, PheWAS, Drug target

Introduction

Herpes simplex virus (HSV) is an enveloped, double-stranded DNA virus classified within the Herpesviridae family and the alpha Herpesviruses subgroup, which is highly prevalent worldwide [1]. In 2016, an estimated 4.2 billion individuals worldwide were seropositive for HSV, indicating widespread prevalence of the virus [2]. Notably, HSV infection represents a lifelong condition characterized by intermittent reactivation at the primary infection site [2, 3]. HSV infection can result not only in the development of oral and genital ulcers but also in a variety of other severe conditions, including herpes stromal keratitis, meningitis, and encephalitis [1]. The long-lasting effects of this infection contribute to a significant disease burden. Nevertheless, certain existing therapies fail to prevent recurrences triggered by the reactivation of latent virus [4]. Therefore, the quest for diagnostic and therapeutic targets for HSV remains of paramount public health importance.

Proteomics plays a pivotal role in clinical diagnostics and monitoring, with studies demonstrating its potential to identify novel proteins in serum and diseased tissues [5, 6]. Previous studies have shown that certain proteins may facilitate HSV entry into cells and increase the likelihood of specific complications, highlighting their potential significance in the pathogenesis and treatment of HSV [7–9]. For instance, a case–control study involving 90 individuals found that the apoE4 protein exacerbates viral latency and is linked to heightened oxidative damage in the central nervous system [10]. Another case report study indicated that serum levels of TRIM5 alpha proteins could restrict HSV infection, suggesting the therapeutic potential of this protein for HSV [11]. In addition, some experiments showed that seminal plasma protein, co-chaperone BAG3, IFN regulatory factors might influence the replication of such that the virus reached its replicative peak more quickly or slowly which implicates a potential new target for the prevention of HSV infection [12–14]. However, these associations were primarily derived from observational studies, which are prone to confounding factors and reverse causation owing to small sample sizes, inadequate experimental design, and limited assay screening methods. Fortunately, advancements in genome-wide association studies (GWAS) focusing on circulating protein levels, along with larger sample sizes and the identification of protein quantitative trait loci (pQTLs), have enabled the discovery of causative genes and the elucidation of disease pathways [15–17].

Mendelian randomization (MR) leverages the randomness of genetic variation to overcome confounders and reverse causality bias in observational studies [18]. It is frequently employed to ascertain the causal relationship between exposure and outcome. Single nucleotide polymorphisms (SNP) identified by GWAS serve as instrumental variables (IVs) for causality analysis, providing robust evidence for identifying disease diagnostic markers and drug targets. It has been widely used to detect causal relationships between plasma proteins and various diseases [19–23]. Therefore, together with the accessibility of blood plasma database, the causal effects of 2,923 plasma proteins on HSV infection were explored using two-sample MR analysis and Phenome-wide MR (Phe-MR) analysis to identify the potentially causal circulating proteins and novel drug targets in HSV infection.

Materials and methods

Study design

The study design is illustrated in Fig. 1. Briefly, we first conducted MR analyses to examine the association between plasma proteins and HSV infection using summary data from published GWAS. In order to be an appropriate pQTLs as IVs, a genetic variant must demonstrate a robust association with the exposure of interest, no association with potential confounders, or a common cause with the outcome variable [24–26]. Then Phe-MR analysis was carried out to determine the draggability potential of the identified protein indicators, with the goal of prioritizing potential treatment targets. In order to ensure the clear and transparency of our MR study, we adhered to the Strengthening the Reporting of Observational Studies in Epidemiology-MR (STROBE-MR) guidelines (Supplementary Table 1) [27].

Fig. 1.

Fig. 1

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An overall design of the present study. Abbreviations: MR Mendelian randomization; UKB-PPP UK Biobank Pharma Proteomics Project.

Given that this study relies exclusively on preexisting publications and publicly available databases, additional ethical approval or consent to participate was deemed unnecessary.

Exposure data sources for plasma proteins

Index SNPs associated with the levels of plasma proteins were obtained from a large-scale GWAS in the UK Biobank Pharma Proteomics Project (UKB-PPP) [17]. UKB-PPP performed a proteomic analysis, using the Olink platform, on plasma samples from 54,219 UK Biobank participants and collected data on 2,923 unique proteins (Supplementary Table 2) [17]. It identified 14,287 primary genetic associations, of which 85% were new, and independent secondary associations were observed in 87% of cis and 30% of trans loci, expanding the repertoire of genetic tools for further analysis [17]. Selection criteria for instruments and proteins were as follows [28]: (i) A genome-wide significance threshold of P < 5 × 10–8 used to identify highly correlated SNPs with plasma proteins; (ii) Threshold of the linkage disequilibrium (LD) parameter (r2) set at 0.001 and a genetic distance of 10,000 kb to mitigate the effect of LD on independent SNPs; (iii) SNP within a vicinity of ± 1 Mb around the gene region is defined as cis-pQTLs. Finally, the strength of each instrument was assessed by examining the F-statistic, calculated using the equation:F=betabetasese2. We excluded instruments with an F < 10, which suggests weak mechanisms (Supplementary Table 3) [29].

Outcome data sources for HSV infection

Herpes simplex virus-associated SNPs were derived from the FinnGen study, a large-scale genomic research initiative that integrates genetic data from over 500,000 Finnish biobank samples with comprehensive health records to investigate disease mechanisms and genetic predispositions [30]. Infection with HSV was defined using the International Classification of Diseases, 10th Revision (ICD-10) code B00. For this analysis, we utilized the most recent release data on Herpesviral [herpes simplex] (HSV) infections from the FinnGen study R10 (https://r10.finngen.fi/). A total of 400,098 subjects of European descent for HSV infection (3,723 cases and 396,375 controls) were extracted from the summary data labeled as Certain infectious and parasitic diseases (AB1). Detailed data are provided in Supplementary Table 2.

Statistical analysis

For plasma proteins with only one SNP, we used the Wald ratio method to estimate the odds change in HSV infection risk for per standard deviation (SD) increment of circulating protein levels as proxied by the IVs [29]. The inverse-variance weighted (IVW) approach was employed to derive the MR effect estimates for proteins that had multiple instruments [29]. Additionally, we supplemented weighted median, simple median, and maximum-likelihood method to validate the accuracy of our results [31], which relied on different assumptions compared to IVW. The simple median technique offers the median individual SNP ratio estimate, while the weighted median estimator was applied to yield robust causal estimates even when up to 50% of IVs were invalid [32]. Assuming a linear relationship between exposure and outcome, the maximum likelihood-based method offered per unit change for the infer association infer the causal [33]. These multiple evaluators could be conducive to assessing the robustness of MR estimates and complexities in MR studies.

To further account for potential pleiotropy, series sensitivity analyses were performed. Cochran's Q test quantified the heterogeneity of the IVs, with Cochran’s Q-derived P < 0.05 indicating the presence of heterogeneity. If heterogeneity was detected, the random-effect IVW method was utilized. MR-Egger method was used as a weighted linear regression with intercepts to assess the presence of horizontal pleiotropy among the IVs [34]. A P value of the MR-Egger intercept of more than 0.05 indicates no horizontal pleiotropic effects. These MR techniques provide relatively reliable estimates, accounting for SNP validity and adjusting for horizontal pleiotropy through the regression slope and intercept [34].

The analyses in this research were conducted using R software version 4.1.3 with the 'TwoSampleMR' package (version 0.5.8). All results are presented as odds ratio (OR) and 95% confidence interval (CI). To avoid type I error, we defined significance statistically at false discovery rate (FDR) of 0.10 for each MR analysis [35]. A PFDR > 0.10 while the P value < 0.05 was considered as suggestive evidence.

Phenome-wide MR analysis

To interrogate the on-target side effects of theoretical druggable targets, elucidating mechanisms of action and predicting adverse drug events, a Phe-MR analysis was conducted with significant plasma protein associated with HSV as exposure and disease summary statistics as outcomes [36]. To avoid redundancy in the data, we utilized the FinnGen R10 cohort (https://r10.finngen.fi/), comprising 412,181 participants. Disease outcomes were categorized using "PheCodes" for systematic genetic analysis of disease traits [37]. A total of 2,406 traits with over 50 cases were retained due to statistical power for Phe-MR analyses. MR analyses were subsequently conducted to infer causal relationships between the druggable genes and the selected traits using the IVW method. The findings revealed the risk or protective effects linked to each standard deviation increase in plasma protein levels.

Results

MR analysis

We selected a total of 5,952 SNPs as IVs for 1,949 proteins, with F-statistic value > 10, suggesting that no weak instrument effect on the association between proteins with HSV infection (Supplementary Table 3). Using the Wald ratio or IVW method, we identified 102 plasma proteins that were potentially associated with HSV infection (P < 0.05), 48 proteins were negatively associated with HSV infection, and 54 proteins were positively associated with HSV infection (Fig. 2 and Supplementary Table 4). Especially, genetically predicted higher levels of HLA class I histocompatibility antigen, alpha chain E (HLA-E) were significantly associated with an increased risk of HSV infection (OR = 1.39, 95% CI: 1.17–1.65, P = 2.13 × 10–4, PFDR = 0.098) using IVW method. The association was similarly found by the weighted median method (OR = 1.40; 95% CI: 1.17–1.69; P = 3.42 × 10–4) and maximum-likelihood method (OR = 1.39; 95% CI: 1.17–1.65; P = 2.19 × 10–4). Conversely, UL16-binding protein 2 (ULBP2) was found to be significant negatively associated with HSV infection risk (OR = 0.81, 95% CI: 0.73–0.90, P = 6.25 × 10−5, PFDR = 0.098) in the primary analysis. These associations were generally consistent in additional analyses, including weighted median, simple median, and maximum-likelihood method, except for MR-Egger (Fig. 2). Furthermore, no significant heterogeneity (Pheterogeneity > 0.05) or pleiotropy (Ppleiotropy > 0.05) was observed in any of the results.

Fig. 2.

Fig. 2

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A: The causal relationship between plasma protein and risk of herpes simplex virus infection in the MR analysis. B: Forest plot of Mendelian randomization analyses for the associations between HLA-E, ULBP2, and risk of herpes simplex virus infection. Abbreviations: HLA-E HLA class I histocompatibility antigen, alpha chain E, IVW Inverse-variance weighted, ULBP2 UL16-binding protein 2

In addition, we also found a suggestive association of Lymphotoxin-beta (LT-β), 5'-AMP-activated protein kinase subunit beta-1 (SMOC1), MHC class I polypeptide-related sequence B_A (MICB_MICA), Asialoglycoprotein receptor 1 (ASGR1), and Annexin A10 (ANXA10) with HSV infection risk (PFDR < 0.5). These five plasma proteins had a positive effect on HSV infection risk with 1.58 (95% CI: 1.23–2.04, P = 4.41 × 10−4), 1.48 (95% CI: 1.16–1.88, P = 0.001), 1.09 (95% CI: 1.04–1.16, P = 0.002), 1.56 (95% CI: 1.18–2.05, P = 0.002), and 4.19 (95% CI: 1.69–10.36, P = 0.002), respectively. More details are shown in Supplementary Table 4.

Phenome-wide MR analysis

To comprehensively explore the health effect of HLA-E and ULBP2, which were found to be significant associated with HSV infection risk, we conducted a Phe-MR association analysis, screening over 2000 traits from the Finnish biobank (version 10). Our findings revealed that HLA-E was associated with 214 phenotypes (PFDR < 0.10; Fig. 3). Specifically, we found HLA-E was associated with increased risk of many autoimmune diseases such as sicca syndrome (OR = 3.45, 95% CI: 2.46–4.83, PFDR = 2.37 × 10–10) and hypothyroidism (OR = 1.30, 95% CI: 1.20–1.41, PFDR = 8.68 × 10–9) (Supplementary Table 5). However, we did not find any diseases were significant associated with ULBP2 after the FDR adjustment, indicating that the plausibility is suggestive (Supplementary Table 6).

Fig. 3.

Fig. 3

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The phenome-wide MR analysis for HLA-E and ULBP2

Conclusion and discussion

This study based on large-scale GWAS data is the first to utilize a series of rigorous analyses including comprehensive MR analysis, and Phe-MR analysis to investigate the potential causal relationships between 1,949 plasma proteins and HSV infection risk. Our findings revealed that genetically predicted levels of 54 plasma proteins exhibited a potentially positive association with HSV infection, while 48 plasma proteins showed a potentially negative association. Particularly, we found HLA-E might significantly associated with higher risk of HSV infection while ULBP2 was associated with lower risk of HSV infection. In addition, we observed that several diseases were significantly associated with HLA-E, while no significant traits were identified for UKBP2 in the Phe-MR analysis. These findings suggested that the identified plasma proteins might be valuable for the early diagnosis, treatment, and prevention of HSV infection.

HLA-E is a uniquely oligomorphic class Ib major histocompatibility complex (MHC) molecule that typically binds to specific leader sequences derived from class Ia MHC molecules [38]. Upon presentation on the cell surface, it modulates the cytotoxic activity of natural killer (NK) cells [38]. Importantly, prior GWAS and transcriptomic studies have pinpointed susceptibility regions for various common infections within the HLA gene [39, 40]. A case–control study involving 49 adult patients with confirmed herpes simplex virus encephalitis (HSE) and 247 matched controls found that the homozygous variants HLA-E0101:0101 and HLA-E0103:0103, as well as the rs9916629CC genotype, were significantly more prevalent in HSE patients compared to controls (P < 0.001) [41]. Another cross-sectional study involving 212 Caucasian adults found that the presence of HLA-A and HLA-8 alleles was significantly associated with a history of herpes simplex infection [42]. Herpes viruses predominantly replicate within the cytoplasm of nucleated cells, giving rise to endogenous antigens that are subsequently presented by class I MHC molecules, some of which might exhibit associations with HLA-E [43]. Considering these insights, HLA-E emerges as a promising therapeutic target for managing herpes simplex infection. Furthermore, we noticed HLA-E were significantly associated with the development of several traits especially autoimmune disease in the Phe-MR analysis, suggesting the importance of this gene. Nonetheless, further research with larger sample sizes is necessary to corroborate these findings.

ULBP2, a recently discovered member of the MHC class I-related molecules (MICs), was identified for its capacity to interact with the human cytomegalovirus glycoprotein UL16 [44]. Recent research has revealed that ULBP2 is pivotal in the immune response against tumors and cells infected with particular viruses and bacteria by stimulating NK cells [45–47]. For example, a case–control study with 32 participants observed that surface expression of the ULBP2 ligand is reduced during HSV infection, aligning with the results of our research [48]. Another study revealed that viral infection can upregulate ULBP gene expression, thereby engaging the innate immune response mediated by NK cells to aid in tissue repair [49]. According to the preceding evidence, ULBP2 might stimulate NK cells to bolster their ability to identify and eradicate HSV-infected cells which highlights the essential role of ULBP in immune defense mechanisms [50, 51]. In addition, we did not find any significant benefits or the adverse drug events in the Phe-MR analysis. Although current pharmacological data on UL16 is limited, it continues to be a promising prognostic biomarker and therapeutic target for herpes simplex infections. Given the constraints of previous studies, including limited sample sizes and the potential for reverse causality, our results offer more robust and reliable evidence for establishing causality.

LT-β, part of the tumor necrosis factor (TNF) superfamily of cytokines, carries out various functions, including the control of inflammation and autoimmunity [52]. Multiple investigations utilizing LT-β or LT-β receptor deficient mice have revealed that the collective immune responses of antiviral cytotoxic T cells are compromised, resulting in delayed or impeded viral eradication across various models of systemic herpes simplex infection [53, 54]. Furthermore, infectious disease models have elucidated the significance of LT-β pathways in orchestrating both innate and adaptive immune responses crucial for host defense [55]. Specifically, the regulation of interferon-beta by LT-β and TNFR signaling is proposed to play a pivotal role in certain viral infections [55]. Though our investigation revealed a positive correlation regarding LT-β risk, the evidence was suggestive and the methods we used were limited. Given these contradictory outcomes, additional rigorous studies are warranted to evaluate its viability as a therapeutic target.

We also identified suggestive evidence of correlations between circulating levels of SMOC1, MICB_MICA, ASGR1, and ANXA10 and the risk of HSV infection (PIVW < 0.003). However, the observational study on the relationship between these proteins and HSV was limited. Nonetheless, we found that these proteins might play a crucial role in triggering the immune response and inflammation and could even influence viral entry into human cells [56, 57]. Notably, this comprehensive proteome MR study identified 100 genetically predicted plasma proteins that were suggestively linked to HSV infection risk, with 47 proteins being down-regulated and 53 up-regulated in the context of HSV development. Although many plasma proteins were not discussed in detail, this does not imply their lack of significance in HSV infection. Further research is needed to validate their roles for HSV infection in the future.

In our study, we observed that the effect sizes of the proteins we identified differed by more than 10% at distance 1, indicating a high degree of differentiation and biological activity. In brief, effect size is a critical measure of the magnitude of biological changes induced by manipulating a specific protein [58]. Larger effect sizes generally suggest a stronger biological role for the target protein, which, in turn, indicates a higher likelihood of druggability [58]. A robust and clinically relevant effect size often implies that a drug targeting this protein could lead to significant therapeutic outcomes [58]. To be noted, the sensitivity of detection methods is crucial for accurately measuring protein expression and activity [59]. High-sensitivity assays allow for the detection of even small changes in protein levels or activity, which are essential for accurately assessing the true effect size of potential drugs [60]. Equally important is the precision with which a drug can modulate its target protein [61]. Drugs that specifically target the intended protein with minimal off-target effects are more likely to demonstrate a larger and more predictable effect size [62]. Achieving this precision is crucial for maximizing therapeutic benefit while minimizing potential side effects [62]. Therefore, we believe that the relationship between effect size, detection sensitivity, and drug manipulation precision is crucial for evaluating the druggability of a protein. Identifying effective proteins, coupled with the use of highly sensitive detection techniques and drugs capable of specifically and effectively targeting these proteins, will enhance the accuracy of predicting their therapeutic potential.

This study’s merits include delving into the causal connections between multiple plasma proteins and HSV infection at genetic level, pinpointing plasma proteins significantly correlated with herpes simplex infections, and underscoring their public health relevance for advancing the diagnosis and treatment of future cases. Secondly, this study relies on extensive GWAS analyses encompassing sizable sample cohorts and robust statistical power. Furthermore, this study incorporates multiple methodological strategies to mitigate potential confounders and biases. These include MR to counteract reverse causality, prioritizing cis-pQTLs over trans-pQTLs to strengthen the credibility of evidence. These analyses underscore the robustness of the study findings, demonstrating resilience against horizontal pleiotropy or confounding variables.

However, our research has certain limitations. Initially, it's worth noting that this study draws from a European database, which may constrain the generalizability of its findings to the broader human population. Additionally, to elucidate the relationships between specific plasma proteins and HSV infection, along with their underlying mechanisms, additional research calls for a more comprehensive GWAS database with large sample, along with advanced analytical methods or experimental validation. Moreover, due to the utilization of a restricted number of IVs for certain proteins, the statistical power may have been insufficient to detect significant associations, thereby limiting the identification of meaningful proteins following rigorous corrections. Hence, we applied a less stringent threshold (PFDR < 0.10) to identify potential drug targets that could be associated. Finally, owing to the limited number of available GWAS studies on HSV and constraints within the study cohorts, replication studies with larger sample sizes are necessary to further validate our findings. Subsequent research endeavors could enrich our insights by integrating basic experiments to unravel specific mechanisms for targeted therapy in herpes simplex infections.

In summary, this study established a causal link between various plasma proteins and HSV infection through a comprehensive MR analysis, highlighting HLA-E and ULBP2. These findings offered fresh insights into the biological mechanisms of HSV and support the exploration of early intervention and treatment strategies. Nonetheless, additional research is required to validate these potential plasma protein biomarkers.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 39 KB) (38.9KB, docx)
Supplementary file2 (XLSX 2391 KB) (2.3MB, xlsx)

Acknowledgements

We are grateful to the UK Biobank Pharma Proteomics Project and the Finnish database for supplying data on summary statistics for MR analyses. We also want to thank all the researchers who shared these data and the study participants.

Author contributions

Canya Fu: Writing-review & editing, Writing-original draft, Methodology, Investigation, Formal analysis, Data curation. WenJie Xu: Software, Methodology, Formal analysis. Xia Xu: Writing-review & editing. Fei Zhao: Formal analysis. Canjie Zheng: Visualization, Validation. Zhiying Yin: Writing-review & editing, Supervision, Conceptualization. All authors approved the manuscript and provided relevant suggestions.

Funding

This work was supported by Science and Technology Bureau of Quzhou, Zhejiang, China (Project No. 2023K178).

Data availability

Data availability statement Datasets used for the analyses are available under reasonable requests. Data on plasma proteins were contributed by Sun et al., (2023) and were downloaded from https://www.synapse.org/#!Synapse:syn51365301. The summary statistics of the genome-wide association study of herpes virus are available at the website (https://storage.googleapis.com/finngen-public-data-r10/summary_stats/finngen_R10_AB1_HERPES_SIMPLEX.gz).

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

The summary-level data of our MR study was approved by their Institutional Review Board (IRB) or an equivalent committee and written informed consent was obtained from all participants.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Canya Fu and Wenjie Xu have contributed equally to this work.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 39 KB) (38.9KB, docx)
Supplementary file2 (XLSX 2391 KB) (2.3MB, xlsx)

Data Availability Statement

Data availability statement Datasets used for the analyses are available under reasonable requests. Data on plasma proteins were contributed by Sun et al., (2023) and were downloaded from https://www.synapse.org/#!Synapse:syn51365301. The summary statistics of the genome-wide association study of herpes virus are available at the website (https://storage.googleapis.com/finngen-public-data-r10/summary_stats/finngen_R10_AB1_HERPES_SIMPLEX.gz).

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