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Submitted on July 22, 2005
Accepted on December 15, 2005
Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
* To whom correspondence should be addressed. E-mail: s.c.gough{at}bham.ac.uk.
CONTEXT: Recently, six DNA variants, two of which (M55V and 001Msp) are present in NF-
B inhibitors SUMO-4 and MAP3K7IP2, and four of which (fcrl3 3, fcrl3 4, fcrl3 5 and fcrl3 6) modulate NF-B binding and production of the B cell surface molecule FCRL3, have been reported to be associated with a number of autoimmune diseases (AIDs).
OBJECTIVE: The aim of this study was to investigate the association of these polymorphisms with disease in a large UK Caucasian Graves' disease (GD) dataset.
DESIGN: A case control association study of six polymorphisms.
SETTING: UK Academic Department of Medicine
PATIENTS OR PARTICIPANTS: 1056 Graves' disease patients and 864 controls.
INTERVENTIONS: N/A
MAIN OUTCOME MEASURES: Tests for association with disease.
RESULTS: No association with disease was found for the M55V single nucleotide polymorphism (SNP). Association was however found between GD and the 001Msp SNP (OR = 1.19 [95% 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 TSHR autoantibodies (OR = 1.75, 95% CI = 1.09-2.79).
CONCLUSION: 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 datasets and fine mapping of the surrounding gene regions is needed to confirm the magnitude of the effect and location of the etiological variant(s) present within these gene regions.
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