Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort.
BACKGROUND
This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort.


METHODS
The magnitude of association for each genotype was assessed in 1,046 RA subjects from the Yorkshire Early RA cohort and in 5,968 healthy UK controls. Additional exploratory subanalyses were undertaken in subgroups defined by autoantibody status (rheumatoid factor and anti-cyclic citrullinated peptide) or disease severity (baseline articular erosions, Health Assessment Questionnaire (HAQ) score and swollen joint count (SJC)).


RESULTS
In the total RA inception cohort, the HLA-DRB1 shared epitope (per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated with RA. The magnitude of association for these loci was increased in those patients who were autoantibody-positive. PTPN22 was associated with autoantibody-negative RA (per-allele OR = 1.3, trend P = 0.04). There was no evidence of association between these five genetic loci and baseline erosions or SJC in the total RA cohort, after adjustment for symptom duration. TRAF1/C5 was significantly associated with baseline HAQ, however, following adjustment for symptom duration (P trend = 0.03).


CONCLUSIONS
These findings support the mounting evidence that different genetic loci are associated with autoantibody-positive and autoantibody-negative RA, possibly suggesting that many of the genes identified to date are associated with autoantibody production. Additional studies with a specific focus on autoantibody-negative RA will be needed to identify the genes predisposing to this RA subgroup. The TRAF1/C5 locus in particular warrants further investigation in RA as a potential disease severity locus.
Morgan
Ann W
AW
NIHR - Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Molecular Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK. a.w.morgan@leeds.ac.uk
Robinson
James I
JI
Conaghan
Philip G
PG
Martin
Stephen G
SG
Hensor
Elizabeth M A
EM
Morgan
Michael D
MD
Steiner
Lori
L
Erlich
Henry A
HA
Gooi
Hock-Chye
HC
Barton
Anne
A
Worthington
Jane
J
Emery
Paul
P
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001323:Autoantibodies / Q000097:blood / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D000939:Epitopes / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006304:Health Status; D006801:Humans; D007596:Joints / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012217:Rheumatoid Factor / Q000032:analysis; D012720:Severity of Illness Index
D001323:Autoantibodies; D015415:Biomarkers; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; D011506:Proteins; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor