Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease.
BACKGROUND
Genome wide association studies, replicated by numerous well powered validation studies, have revealed a large number of loci likely to play a role in susceptibility to many multifactorial diseases. It is now well established that some of these loci are shared between diseases with similar aetiology. For example, a number of autoimmune diseases have been associated with variants in the PTPN22, TNFAIP3 and CTLA4 genes. Here we have attempted to define overlapping genetic variants between rheumatoid arthritis (RA), type 1 diabetes (T1D) and coeliac disease (CeD).


METHODS
We selected eight SNPs previously identified as being associated with CeD and six T1D-associated SNPs for validation in a sample of 3,962 RA patients and 3,531 controls. Genotyping was performed using the Sequenom MassArray platform and comparison of genotype and allele frequencies between cases and controls was undertaken. A trend test P-value < 0.004 was regarded as significant.


RESULTS
We found statistically significant evidence for association of the TAGAP locus with RA (P = 5.0 × 10-4). A marker at one other locus, C1QTNF6, previously associated with T1D, showed nominal association with RA in the current study but did not remain statistically significant at the corrected threshold.


CONCLUSIONS
In exploring the overlap between T1D, CeD and RA, there is strong evidence that variation within the TAGAP gene is associated with all three autoimmune diseases. Interestingly a number of loci appear to be specific to one of the three diseases currently studied suggesting that they may play a role in determining the particular autoimmune phenotype at presentation.
Eyre
Stephen
S
Arthritis Research UK, Epidemiology Unit, Stopford Building, Oxford Road, The University of Manchester, Manchester M13 9PT, UK. steve.eyre@manchester.ac.uk
Hinks
Anne
A
Bowes
John
J
Flynn
Edward
E
Martin
Paul
P
Wilson
Anthony G
AG
Morgan
Ann W
AW
Emery
Paul
P
Steer
Sophia
S
Hocking
Lynne J
LJ
Reid
David M
DM
Harrison
Pille
P
Wordsworth
Paul
P
Thomson
Wendy
W
Worthington
Jane
J
Barton
Anne
A
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002446:Celiac Disease / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide
D020690:GTPase-Activating Proteins; C557017:TAGAP protein, human