Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease.
BACKGROUND
Recently six DNA variants, two of which (M55V and 001Msp) are present in nuclear factor-kappaB inhibitors SUMO-4 and MAP3K7IP2 and four of which (fcrl3_3, fcrl3_4, fcrl3_5, and fcrl3_6) modulate nuclear factor-kappaB binding and production of the B cell surface molecule FCRL3, have been reported to be associated with a number of autoimmune diseases.


OBJECTIVE
The aim of this study was to investigate the association of these polymorphisms with disease in a large UK Caucasian Graves' disease (GD) data set.


METHODS
The study was a case-control association study of six polymorphisms.


METHODS
The study was conducted at a UK academic department of medicine.


METHODS
Study population included 1056 GD patients and 864 controls.


METHODS
There were no interventions.


METHODS
Tests for association with disease were measured.


RESULTS
No association with disease was found for the M55V single-nucleotide polymorphism (SNP). Association was, however, found between GD and the 001Msp SNP [odds ratio (OR) 1.19 (95% confidence interval [CI]) 1.03-1.37], fcrl3_3 SNP [OR 1.17 (95% CI 1.02-1.34)], fcrl3_5 SNP [OR 1.18 (95% CI 1.04-1.35)], and fcrl3_6 SNP [OR 1.20 (95% CI 1.05-1.36)]. The 001Msp SNP was found to be associated with the presence of TSH receptor autoantibodies [OR 1.75 (95% CI 1.09-2.79)].


CONCLUSIONS
Functional evidence suggests that the 001Msp, fcrl3_3, fcrl3_5, and fcrl3_6 SNPs could cause changes in B cell signaling and activation pathways that could account for their association with GD. Further replication in independent data sets and fine mapping of the surrounding gene regions are needed to confirm the magnitude of the effect and location of the etiological variant(s) present within these gene regions.
Simmonds
M J
MJ
Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.
Heward
J M
JM
Carr-Smith
J
J
Foxall
H
H
Franklyn
J A
JA
Gough
S C L
SC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001483:Base Sequence; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics*; D012016:Reference Values; D044465:White People
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C457775:FCRL3 protein, human; D011971:Receptors, Immunologic; C410585:TAB2 protein, human; D004247:DNA