Association of a single-nucleotide polymorphism in CD40 with the rate of joint destruction in rheumatoid arthritis.
OBJECTIVE
The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction.


METHODS
RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n=563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti-citrullinated protein antibody (ACPA)-positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study.


RESULTS
The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P=0.003 and P=0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P=0.021).


CONCLUSIONS
A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non-HLA-related genetic severity factors that has been replicated.
van der Linden
Michael P M
MP
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. M.P.M.van_der_Linden@lumc.nl
Feitsma
Anouk L
AL
le Cessie
Saskia
S
Kern
Marlena
M
Olsson
Lina M
LM
Raychaudhuri
Soumya
S
Begovich
Ann B
AB
Chang
Monica
M
Catanese
Joseph J
JJ
Kurreeman
Fina A S
FA
van Nies
Jessica
J
van der Heijde
Désirée M
DM
Gregersen
Peter K
PK
Huizinga
Tom W J
TW
Toes
René E M
RE
van der Helm-Van Mil
Annette H M
AH
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001175:Arthrography; D019013:CD40 Antigens / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006304:Health Status; D006801:Humans; D007596:Joints / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000097:blood / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D016059:Range of Motion, Articular; D012720:Severity of Illness Index
D019013:CD40 Antigens; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide