TY - JOUR
T1 - MS AHI1 genetic risk promotes IFNγ+ CD4+ T cells
AU - Kaskow, Belinda J.
AU - Buttrick, Thomas S.
AU - Klein, Hans Ulrich
AU - White, Charles
AU - Bourgeois, Justin R.
AU - Ferland, Russell J.
AU - Patsopoulos, Nikolaos
AU - Bradshaw, Elizabeth M.
AU - De Jager, Philip L.
AU - Elyaman, Wassim
N1 - Funding Information:
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the NIH under award number R01AI130547 (W.E.).
Funding Information:
From the Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Publisher Copyright:
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Objective To study the influence of the Abelson helper integration site 1 (AHI1) locus associated with MS susceptibility on CD4+ T cell function. Methods We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. Results Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10-13), overlaps with strong enhancer regions that are present in human naive and memory CD4+ T cells. Relative to the rs4896153 A protective allele, the rs4896153 T susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4+ T cells (p = 1.73 × 10-74, n = 213), and we replicate this effect in an independent set of subjects (p = 2.5 × 10-9, n = 32). Functional studies then showed that the rs4896153 T risk variant and the subsequent decreased AHI1 expression were associated with reduced CD4+ T cell proliferation and a specific differentiation into interferon gamma (IFNγ)-positive T cells when compared with the protective rs4896153 A allele. This T cell phenotype was also observed in murine CD4+ T cells with genetic deletion of Ahi1. Conclusions Our findings suggest that the effect of the AHI1 genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ + T cells that have previously been implicated in MS and its mouse models.
AB - Objective To study the influence of the Abelson helper integration site 1 (AHI1) locus associated with MS susceptibility on CD4+ T cell function. Methods We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. Results Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10-13), overlaps with strong enhancer regions that are present in human naive and memory CD4+ T cells. Relative to the rs4896153 A protective allele, the rs4896153 T susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4+ T cells (p = 1.73 × 10-74, n = 213), and we replicate this effect in an independent set of subjects (p = 2.5 × 10-9, n = 32). Functional studies then showed that the rs4896153 T risk variant and the subsequent decreased AHI1 expression were associated with reduced CD4+ T cell proliferation and a specific differentiation into interferon gamma (IFNγ)-positive T cells when compared with the protective rs4896153 A allele. This T cell phenotype was also observed in murine CD4+ T cells with genetic deletion of Ahi1. Conclusions Our findings suggest that the effect of the AHI1 genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ + T cells that have previously been implicated in MS and its mouse models.
UR - http://www.scopus.com/inward/record.url?scp=85044294507&partnerID=8YFLogxK
U2 - 10.1212/NXI.0000000000000414
DO - 10.1212/NXI.0000000000000414
M3 - Article
AN - SCOPUS:85044294507
SN - 2332-7812
VL - 5
JO - Neurology: Neuroimmunology and NeuroInflammation
JF - Neurology: Neuroimmunology and NeuroInflammation
IS - 1
M1 - e414
ER -
