Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08.
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-B*08 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) ).


CONCLUSIONS
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-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis.
Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, USA. peterg@nshs.edu
Peter K
PK
Gregersen
Roman
R
Kosoy
Annette T
AT
Lee
Janine
J
Lamb
Jon
J
Sussman
David
D
McKee
Kim R
KR
Simpfendorfer
Ritva
R
Pirskanen-Matell
Frederik
F
Piehl
Qiang
Q
Pan-Hammarstrom
Jan J G M
JJ
Verschuuren
Maarten J
MJ
Titulaer
Erik H
EH
Niks
Alexander
A
Marx
Philipp
P
Ströbel
Björn
B
Tackenberg
Michael
M
Pütz
Angelina
A
Maniaol
Ahmed
A
Elsais
Chantal
C
Tallaksen
Hanne F
HF
Harbo
Benedicte A
BA
Lie
Soumya
S
Raychaudhuri
Paul I W
PI
de Bakker
Arthur
A
Melms
Henri-Jean
HJ
Garchon
Nicholas
N
Willcox
Lennart
L
Hammarstrom
Michael F
MF
Seldin
D000328:Adult; D017668:Age of Onset; D000409:Alanine / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005060:Europe; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D015795:HLA-B8 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D009157:Myasthenia Gravis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011392:Proline / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
D004268:DNA-Binding Proteins; D015795:HLA-B8 Antigen; C117046:TNIP1 protein, human; D011392:Proline; D000409:Alanine