Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications
Abstract Background Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. Methods We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-co...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | BMC Infectious Diseases |
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| Online Access: | https://doi.org/10.1186/s12879-024-09217-z |
| _version_ | 1797247444468105216 |
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| author | Hedwig D. Vrijmoeth Jeanine Ursinus Javier Botey-Bataller Yunus Kuijpers Xiaojing Chu Freek R. van de Schoor Brendon P. Scicluna Cheng-Jian Xu Mihai G. Netea Bart Jan Kullberg Cees C. van den Wijngaard Yang Li Joppe W. Hovius Leo A. B. Joosten |
| author_facet | Hedwig D. Vrijmoeth Jeanine Ursinus Javier Botey-Bataller Yunus Kuijpers Xiaojing Chu Freek R. van de Schoor Brendon P. Scicluna Cheng-Jian Xu Mihai G. Netea Bart Jan Kullberg Cees C. van den Wijngaard Yang Li Joppe W. Hovius Leo A. B. Joosten |
| author_sort | Hedwig D. Vrijmoeth |
| collection | DOAJ |
| description | Abstract Background Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. Methods We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients—divided into a discovery and validation cohort—were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments. Results We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses. Conclusions Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures. Trial registration The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015–02-13). |
| first_indexed | 2024-04-24T19:58:47Z |
| format | Article |
| id | doaj.art-023b3359336f429c8886cecd6f302253 |
| institution | Directory Open Access Journal |
| issn | 1471-2334 |
| language | English |
| last_indexed | 2024-04-24T19:58:47Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Infectious Diseases |
| spelling | doaj.art-023b3359336f429c8886cecd6f3022532024-03-24T12:11:43ZengBMCBMC Infectious Diseases1471-23342024-03-0124111610.1186/s12879-024-09217-zGenome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implicationsHedwig D. Vrijmoeth0Jeanine Ursinus1Javier Botey-Bataller2Yunus Kuijpers3Xiaojing Chu4Freek R. van de Schoor5Brendon P. Scicluna6Cheng-Jian Xu7Mihai G. Netea8Bart Jan Kullberg9Cees C. van den Wijngaard10Yang Li11Joppe W. Hovius12Leo A. B. Joosten13Department of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Internal Medicine, Division of Infectious Diseases, Amsterdam UMC, Location AMC, University of AmsterdamDepartment of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection ResearchDepartment of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection ResearchDepartment of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Applied Biomedical Science, Faculty of Health Sciences, Mater Dei Hospital, University of MaltaDepartment of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterNational Institute for Public Health and Environment (RIVM), Center for Infectious Disease ControlDepartment of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterDepartment of Internal Medicine, Division of Infectious Diseases, Amsterdam UMC, Location AMC, University of AmsterdamDepartment of Internal Medicine and Radboudumc Center for Infectious Diseases, Radboud University Medical CenterAbstract Background Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. Methods We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients—divided into a discovery and validation cohort—were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments. Results We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses. Conclusions Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures. Trial registration The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015–02-13).https://doi.org/10.1186/s12879-024-09217-zLyme borreliosisDisease susceptibilityGWASCytokinesmTOR pathway |
| spellingShingle | Hedwig D. Vrijmoeth Jeanine Ursinus Javier Botey-Bataller Yunus Kuijpers Xiaojing Chu Freek R. van de Schoor Brendon P. Scicluna Cheng-Jian Xu Mihai G. Netea Bart Jan Kullberg Cees C. van den Wijngaard Yang Li Joppe W. Hovius Leo A. B. Joosten Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications BMC Infectious Diseases Lyme borreliosis Disease susceptibility GWAS Cytokines mTOR pathway |
| title | Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications |
| title_full | Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications |
| title_fullStr | Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications |
| title_full_unstemmed | Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications |
| title_short | Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications |
| title_sort | genome wide analyses in lyme borreliosis identification of a genetic variant associated with disease susceptibility and its immunological implications |
| topic | Lyme borreliosis Disease susceptibility GWAS Cytokines mTOR pathway |
| url | https://doi.org/10.1186/s12879-024-09217-z |
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