Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis

Elin Engdahl; Rasmus Gustafsson; Jesse Huang; Martin Biström; Izaura Lima Bomfim; Pernilla Stridh; Mohsen Khademi; Nicole Brenner; Julia Butt; Angelika Michel; Daniel Jons; Maria Hortlund; Lucia Alonso-Magdalena; Anna Karin Hedström; Louis Flamand; Masaru Ihira; Tetsushi Yoshikawa; Oluf Andersen; Jan A. Hillert; Lars Alfredsson; Tim Waterboer; Peter Sundström; Tomas Olsson; Ingrid Kockum; Anna Fogdell-Hahn

doi:10.1101/737932

Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis

Elin Engdahl, Rasmus Gustafsson, Jesse Huang, Martin Biström, Izaura Lima Bomfim, Pernilla Stridh, Mohsen Khademi, Nicole Brenner, Julia Butt, Angelika Michel, Daniel Jons, Maria Hortlund, Lucia Alonso-Magdalena, Anna Karin Hedström, Louis Flamand, Masaru Ihira, Tetsushi Yoshikawa, Oluf Andersen, Jan A. Hillert, Lars AlfredssonTim Waterboer, Peter Sundström, Tomas Olsson, Ingrid Kockum, Anna Fogdell-Hahn

Research output: Contribution to journal › Article › peer-review

Abstract

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8742 persons with MS and 7215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9x10^-22), and increased risk of future MS (OR = 2.22, p = 2x10^-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6x10^-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6x10^-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

Original language	English
Journal	Unknown Journal
DOIs	https://doi.org/10.1101/737932
Publication status	Published - 28-08-2019

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
Immunology and Microbiology(all)
Neuroscience(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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Engdahl, E., Gustafsson, R., Huang, J., Biström, M., Bomfim, I. L., Stridh, P., Khademi, M., Brenner, N., Butt, J., Michel, A., Jons, D., Hortlund, M., Alonso-Magdalena, L., Hedström, A. K., Flamand, L., Ihira, M., Yoshikawa, T., Andersen, O., Hillert, J. A., ... Fogdell-Hahn, A. (2019). Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis. Unknown Journal. https://doi.org/10.1101/737932

Engdahl, Elin ; Gustafsson, Rasmus ; Huang, Jesse ; Biström, Martin ; Bomfim, Izaura Lima ; Stridh, Pernilla ; Khademi, Mohsen ; Brenner, Nicole ; Butt, Julia ; Michel, Angelika ; Jons, Daniel ; Hortlund, Maria ; Alonso-Magdalena, Lucia ; Hedström, Anna Karin ; Flamand, Louis ; Ihira, Masaru ; Yoshikawa, Tetsushi ; Andersen, Oluf ; Hillert, Jan A. ; Alfredsson, Lars ; Waterboer, Tim ; Sundström, Peter ; Olsson, Tomas ; Kockum, Ingrid ; Fogdell-Hahn, Anna. / Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis. In: Unknown Journal. 2019.

@article{c7a2f212afee4950a0197b55eb602c8b,

title = "Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis",

abstract = "Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8742 persons with MS and 7215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9x10-22), and increased risk of future MS (OR = 2.22, p = 2x10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6x10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6x10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.",

author = "Elin Engdahl and Rasmus Gustafsson and Jesse Huang and Martin Bistr{\"o}m and Bomfim, {Izaura Lima} and Pernilla Stridh and Mohsen Khademi and Nicole Brenner and Julia Butt and Angelika Michel and Daniel Jons and Maria Hortlund and Lucia Alonso-Magdalena and Hedstr{\"o}m, {Anna Karin} and Louis Flamand and Masaru Ihira and Tetsushi Yoshikawa and Oluf Andersen and Hillert, {Jan A.} and Lars Alfredsson and Tim Waterboer and Peter Sundstr{\"o}m and Tomas Olsson and Ingrid Kockum and Anna Fogdell-Hahn",

note = "Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2019",

month = aug,

day = "28",

doi = "10.1101/737932",

language = "English",

journal = "Unknown Journal",

}

Engdahl, E, Gustafsson, R, Huang, J, Biström, M, Bomfim, IL, Stridh, P, Khademi, M, Brenner, N, Butt, J, Michel, A, Jons, D, Hortlund, M, Alonso-Magdalena, L, Hedström, AK, Flamand, L, Ihira, M , Yoshikawa, T, Andersen, O, Hillert, JA, Alfredsson, L, Waterboer, T, Sundström, P, Olsson, T, Kockum, I & Fogdell-Hahn, A 2019, 'Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis', Unknown Journal. https://doi.org/10.1101/737932

Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis. / Engdahl, Elin; Gustafsson, Rasmus; Huang, Jesse; Biström, Martin; Bomfim, Izaura Lima; Stridh, Pernilla; Khademi, Mohsen; Brenner, Nicole; Butt, Julia; Michel, Angelika; Jons, Daniel; Hortlund, Maria; Alonso-Magdalena, Lucia; Hedström, Anna Karin; Flamand, Louis; Ihira, Masaru ; Yoshikawa, Tetsushi; Andersen, Oluf; Hillert, Jan A.; Alfredsson, Lars; Waterboer, Tim; Sundström, Peter; Olsson, Tomas; Kockum, Ingrid; Fogdell-Hahn, Anna.

In: Unknown Journal, 28.08.2019.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis

AU - Engdahl, Elin

AU - Gustafsson, Rasmus

AU - Huang, Jesse

AU - Biström, Martin

AU - Bomfim, Izaura Lima

AU - Stridh, Pernilla

AU - Khademi, Mohsen

AU - Brenner, Nicole

AU - Butt, Julia

AU - Michel, Angelika

AU - Jons, Daniel

AU - Hortlund, Maria

AU - Alonso-Magdalena, Lucia

AU - Hedström, Anna Karin

AU - Flamand, Louis

AU - Ihira, Masaru

AU - Yoshikawa, Tetsushi

AU - Andersen, Oluf

AU - Hillert, Jan A.

AU - Alfredsson, Lars

AU - Waterboer, Tim

AU - Sundström, Peter

AU - Olsson, Tomas

AU - Kockum, Ingrid

AU - Fogdell-Hahn, Anna

N1 - Publisher Copyright: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2019/8/28

Y1 - 2019/8/28

N2 - Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8742 persons with MS and 7215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9x10-22), and increased risk of future MS (OR = 2.22, p = 2x10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6x10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6x10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

AB - Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8742 persons with MS and 7215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9x10-22), and increased risk of future MS (OR = 2.22, p = 2x10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6x10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6x10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

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