IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.
In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.
Shin
J-H
JH
Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, British Columbia, Canada.
Janer
M
M
McNeney
B
B
Blay
S
S
Deutsch
K
K
Sanjeevi
C B
CB
Kockum
I
I
Lernmark
A
A
Graham
J
J
Arnqvist
Hans
H
Björck
Elizabeth
E
Eriksson
Jan
J
Nyström
Lennarth
L
Ohlson
Lars Olof
LO
Scherstén
Bengt
B
Ostman
Jan
J
Aili
M
M
Bååth
L E
LE
Carlsson
E
E
Edenwall
H
H
Forsander
G
G
Granström
B W
BW
Gustavsson
I
I
Hanås
R
R
Hellenberg
L
L
Hellgren
H
H
Holmberg
E
E
Hörnell
H
H
Ivarsson
Sten-A
SA
Johansson
C
C
Jonsell
G
G
Kockum
K
K
Lindblad
B
B
Lindh
A
A
Ludvigsson
J
J
Myrdal
U
U
Neiderud
J
J
Segnestam
K
K
Sjöblad
S
S
Skogsberg
L
L
Strömberg
L
L
Ståhle
U
U
Thalme
B
B
Tullus
K
K
Tuvemo
T
T
Wallensteen
M
M
Westphal
O
O
Aman
J
J
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013548:Sweden
D001323:Autoantibodies; C484030:GIMAP5 protein, human; C096322:ICA512 autoantibody; D019204:GTP-Binding Proteins