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 - Lima Bomfim, Izaura
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
AU - Alfredsson, Lars
AU - Waterboer, Tim
AU - Sundström, Peter
AU - Olsson, Tomas
AU - Kockum, Ingrid
AU - Fogdell-Hahn, Anna
N1 - Funding Information:
This work was supported by Swedish Research Council (Grant No. 2015-02419), Swedish Brain Foundation, KAW Foundation, Margareta af Ugglas Foundation. JHu, PSt, and IK were supported partly by funding from MultipleMS Horizon 2020 Grant No. 733161. JHu was also partly supported by EndMS
Funding Information:
Conflict of Interest: JHi has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis and speaker’s fees from Biogen, Novartis, Merck-Serono, Bayer-Schering, Teva, and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, BiogenIdec, Merck, Novartis, and Sanofi-Genzyme. LA-M has received speaking honoraria from Merck-Serono and served at the advisory board for Merck-Serono and Biogen. LA received speaker honoraria from Biogen Idec and TEVA. TO has received lecture and/or Advisory board honoraria, and unrestricted MS research grants from Biogen, Novartis, Sanofi, Merck-Serono, and Roche. AF-H has received speaker’s fees from Pfizer, Biogen, Merck-Serono, and Sanofi-Genzyme. She has served as P.I. for projects, or received unrestricted research support from, Biogen Idec and Pfizer.
Funding Information:
The authors thank Dr. Steven Jacobson, Dr. Elisabetta Caselli, and Dr. Dario Di Luca for providing serum for method validation. The authors also thank Ingileif Jonsdottir and K?ri Stef?nsson for genotyping done by deCODE, and Alexander T. Dilthey at Wellcome Trust Centre for Human Genetics, University of Oxford, for contribution in HLA imputation. Funding. This work was supported by Swedish Research Council (Grant No. 2015-02419), Swedish Brain Foundation, KAW Foundation, Margareta af Ugglas Foundation. JHu, PSt, and IK were supported partly by funding from MultipleMS Horizon 2020 Grant No. 733161. JHu was also partly supported by EndMS doctoral studentship EGID: 3045 from the Multiple Sclerosis society of Canada. AH was financed by Swedish Society of Medical Research.
Publisher Copyright:
© Copyright © 2019 Engdahl, Gustafsson, Huang, Biström, Lima Bomfim, Stridh, Khademi, Brenner, Butt, Michel, Jons, Hortlund, Alonso-Magdalena, Hedström, Flamand, Ihira, Yoshikawa, Andersen, Hillert, Alfredsson, Waterboer, Sundström, Olsson, Kockum and Fogdell-Hahn.
PY - 2019/11/26
Y1 - 2019/11/26
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 (8,742 persons with MS and 7,215 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 = 9 × 10−22), and increased risk of future MS (OR = 2.22, p = 2 × 10−5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10−6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10−11). 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 (8,742 persons with MS and 7,215 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 = 9 × 10−22), and increased risk of future MS (OR = 2.22, p = 2 × 10−5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10−6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10−11). 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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U2 - 10.3389/fimmu.2019.02715
DO - 10.3389/fimmu.2019.02715
M3 - Article
C2 - 32038605
AN - SCOPUS:85076683059
VL - 10
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 2715
ER -