Common and different genetic background for rheumatoid arthritis and coeliac disease.
Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune disorders which have commonalities in their pathogenesis. We aimed to replicate known RA loci in a Dutch RA population, and to investigate whether the effect of known RA and CD risk factors generalize across the two diseases. We selected all loci associated to either RA or CD in a GWAS and confirmed in an independent cohort, with a combined P-value cut-off P < 5 x 10(-6). We genotyped 11 RA and 11 CD loci in 1368 RA patients, 795 CD patients and 1683 Dutch controls. We combined our results in a meta-analysis with UK GWAS on RA (1860 cases; 2938 controls) and CD (767 cases; 1422 controls). In the Dutch RA cohort, the PTPN22 and IL2/IL21 variants showed convincing association (P = 3.4 x 10(-12) and P = 2.8 x 10(-4), respectively). Association of RA with the known CD risk variant in the SH2B3 was also observed, predominantly in the subgroup of rheumatoid factor-positive RA patients (P = 0.0055). In a meta-analysis of Dutch and UK data sets, shared association with six loci (TNFAIP3, IL2/IL21, SH2B3, LPP, MMEL1/TNFRSF14 and PFKFB3/PRKCQ) was observed in both RA and CD cohorts. We confirmed two known loci and identified four novel ones for shared CD-RA genetic risk. Most of the shared loci further emphasize a role for adaptive and innate immunity in these diseases.
Coenen
Marieke J H
MJ
Department of Human Genetics, Institute for Genetic and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Trynka
Gosia
G
Heskamp
Sandra
S
Franke
Barbara
B
van Diemen
Cleo C
CC
Smolonska
Joanna
J
van Leeuwen
Miek
M
Brouwer
Elisabeth
E
Boezen
Marike H
MH
Postma
Dirkje S
DS
Platteel
Mathieu
M
Zanen
Pieter
P
Lammers
Jan-Willem W J
JW
Groen
Harry J M
HJ
Mali
Willem P T M
WP
Mulder
Chris J
CJ
Tack
Greetje J
GJ
Verbeek
Wieke H M
WH
Wolters
Victorien M
VM
Houwen
Roderick H J
RH
Mearin
M Luisa
ML
van Heel
David A
DA
Radstake
Timothy R D J
TR
van Riel
Piet L C M
PL
Wijmenga
Cisca
C
Barrera
Pilar
P
Zhernakova
Alexandra
A
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D002446:Celiac Disease / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D008297:Male; D015201:Meta-Analysis as Topic; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D000098546:Interleukin-21
D007376:Interleukin-2; D007378:Interleukins; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D000098546:Interleukin-21