TY - JOUR
T1 - Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08
AU - Gregersen, Peter K.
AU - Kosoy, Roman
AU - Lee, Annette T.
AU - Lamb, Janine
AU - Sussman, Jon
AU - McKee, David
AU - Simpfendorfer, Kim R.
AU - Pirskanen-Matell, Ritva
AU - Piehl, Frederik
AU - Pan-Hammarstrom, Qiang
AU - Verschuuren, Jan J G M
AU - Titulaer, Maarten J.
AU - Niks, Erik H.
AU - Marx, Alexander
AU - Ströbel, Philipp
AU - Tackenberg, Björn
AU - Pütz, Michael
AU - Maniaol, Angelina
AU - Elsais, Ahmed
AU - Tallaksen, Chantal
AU - Harbo, Hanne F.
AU - Lie, Benedicte A.
AU - Raychaudhuri, Soumya
AU - De Bakker, Paul I W
AU - Melms, Arthur
AU - Garchon, Henri Jean
AU - Willcox, Nicholas
AU - Hammarstrom, Lennart
AU - Seldin, Michael F.
PY - 2012/12
Y1 - 2012/12
N2 - Objective: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). Methods: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. Results: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10 -92; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B08 proves to be the major associated allele (p = 2.87 × 10 -113; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 × 10-10), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 × 10-10). Interpretation: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B08 allele suggests that CD8+ T cells may play a key role in disease initiation or pathogenesis. Copyright © 2012 American Neurological Association.
AB - Objective: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). Methods: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. Results: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 × 10 -92; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B08 proves to be the major associated allele (p = 2.87 × 10 -113; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 × 10-10), an imputed coding variant (rs2233290) at position 151 (Pro→Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 × 10-10). Interpretation: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-κB signaling. The localization of the major HLA signal to the HLA-B08 allele suggests that CD8+ T cells may play a key role in disease initiation or pathogenesis. Copyright © 2012 American Neurological Association.
U2 - 10.1002/ana.23691
DO - 10.1002/ana.23691
M3 - Article
C2 - 23055271
SN - 0364-5134
VL - 72
SP - 927
EP - 935
JO - Annals of Neurology
JF - Annals of Neurology
IS - 6
ER -