Association of CD40 with rheumatoid arthritis confirmed in a large UK case-control study.
OBJECTIVE
A recent meta-analysis of published genome-wide association studies (GWAS) in populations of European descent reported novel associations of markers mapping to the CD40, CCL21 and CDK6 genes with rheumatoid arthritis (RA) susceptibility while a large-scale, case-control association study in a Japanese population identified association with multiple single nucleotide polymorphisms (SNPs) in the CD244 gene. The aim of the current study was to validate these potential RA susceptibility markers in a UK population.


METHODS
A total of 4 SNPs (rs4810485 in CD40, rs2812378 in CCL21, rs42041 in CDK6 and rs6682654 in CD244) were genotyped in a UK cohort comprising 3962 UK patients with RA and 3531 healthy controls using the Sequenom iPlex platform. Genotype counts in patients and controls were analysed with the chi(2) test using Stata.


RESULTS
Association to the CD40 gene was robustly replicated (p=2 x 10(-4), OR 0.86, 95% CI 0.79 to 0.93) and modest evidence was found for association with the CCL21 locus (p=0.04, OR 1.08, 95% CI 1.01 to 1.16). However, there was no evidence for association of rs42041 (CDK6) and rs6682654 (CD244) with RA susceptibility in this UK population. Following a meta-analysis including the original data, association to CD40 was confirmed (p=7.8 x 10(-8), OR 0.87 (95% CI 0.83 to 0.92).


CONCLUSIONS
In this large UK cohort, strong association of the CD40 gene with susceptibility to RA was found, and weaker evidence for association with RA in the CCL21 locus.
Epidemiology Unit, Faculty of Medical and Human Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. gisela.orozco@manchester.ac.uk
Gisela
G
Orozco
Steve
S
Eyre
Anne
A
Hinks
Xiayi
X
Ke
Anthony G
AG
Wilson
Deborah E
DE
Bax
Ann W
AW
Morgan
Paul
P
Emery
Sophia
S
Steer
Lynne
L
Hocking
David M
DM
Reid
Paul
P
Wordsworth
Pille
P
Harrison
Wendy
W
Thomson
Anne
A
Barton
Jane
J
Worthington
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D054421:Chemokine CCL21 / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
C515478:CCL21 protein, human; D019013:CD40 Antigens; D054421:Chemokine CCL21; D005819:Genetic Markers; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6