Variation at interleukin-6 receptor gene is associated to joint damage in rheumatoid arthritis.
BACKGROUND
Interleukin-6 (IL-6) cytokine signaling is key in Rheumatoid Arthritis (RA) pathophysiology. Blocking IL-6 receptor (IL6R) has proven to be a highly effective treatment to prevent joint damage. This study was performed to investigate the association between the genetic variation at IL6R gene and the severity of joint damage in RA.


METHODS
IL6R gene tagging SNPs (n = 5) were genotyped in a discovery group of 527 RA patients from 5 different university hospitals from Spain. For each marker, a linear regression analysis was performed using an additive model and adjusting for the years of evolution of the disease, autoantibody status, gender and age. Haplotypes combining the SNPs were also estimated and tested for association with the level of joint destruction. Using an independent cohort of 705 RA patients from 6 university hospitals we performed a validation study of the SNPs associated in the discovery phase.


RESULTS
In the discovery group we found a highly significant association between IL6R SNP rs4845618 and the level of joint destruction in RA (P = 0.0058, P corrected = 0.026), and a moderate association with SNP rs4453032 (P = 0.02, P corrected = 0.05). The resulting haplotype from both SNPs was more significantly associated with joint damage (P = 0.0037, P corrected = 0.011). Using the validation cohort, we replicated the association between the two IL-6R SNPs with the degree of joint destruction in RA (P = 0.007 and P = 0.04, meta-analysis P = 0.00011 and P = 0.0021, respectively), and the haplotype association (P = 0.0058, meta-analysis P = 6.64 e-5).


CONCLUSIONS
Genetic variation at IL6R gene is associated with joint damage in RA.
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Pg Vall Hebron 119-129, 08035, Barcelona, Spain. maria.alopez@vhir.org.
Maria
M
Lopez-Lasanta
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Pg Vall Hebron 119-129, 08035, Barcelona, Spain. toni.julia@vhir.org.
Antonio
A
Julià
Rheumatology Department, Hospital del Mar, Pg Marítim, 25-29, 08003, Barcelona, Spain. jmaymo@imas.imim.es.
Joan
J
Maymó
Rheumatology Department, Hospital Clínico San Carlos, C. Prof. Martin Lagos, S/N, 28040, Madrid, Spain. bfernandez.hcsc@salud.madrid.org.
Benjamín
B
Fernández-Gutierrez
UGC Reumatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Avda. Carlos Haya, S/N, 29010, Málaga, Spain. med100082ster@gmail.com.
Inmaculada
I
Ureña-Garnica
Rheumatology Department, INIBIC-Hospital Universitario A Coruña, C. As Xubias, 84, 15006, A Coruña, Spain. fblagar@sergas.es.
Francisco J
FJ
Blanco
Rheumatology Department, Hospital Clínic de Barcelona, C. Villaroel, 170, 08036, Barcelona, Spain. jcanete@clinic.ub.es.
Juan D
JD
Cañete
Rheumatology Department, Hospital Universitario Central de Asturias, Avda. De Roma, S/N, 33011, Oviedo, Spain. mercedes_alperi@hotmail.com.
Mercedes
M
Alperi-López
Rheumatology Department, Hospital Universitari Germans Trias i Pujol, Crta. Can Ruti-Camí Escoles, S/N, 08916, Barcelona, Spain. aolive.germanstrias@gencat.cat.
Alex
A
Olivè
Rheumatology Department, Hospital Moisès Broggi, C. Jacint Verdaguer, 90, 08906, L´Hospitalet de Llobregat, Barcelona, Spain. vancor@yahoo.com.
Héctor
H
Corominas
Rheumatology Department, Hospital Universitario De Guadalajara, C. Donantes de sangre, S/N, 19002, Guadalajara, Spain. jtornero@sescam.org.
Jesus
J
Tornero
Rheumatology Department, Hospital Sant Rafael, Pg Vall Hebron, 107, 08035, Barcelona, Spain. aerra@hsrafael.es.
Alba
A
Erra
Rheumatology Department, Hospital del Mar, Pg Marítim, 25-29, 08003, Barcelona, Spain. REU0802@parcdesalutmar.cat.
Miriam
M
Almirall
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Pg Vall Hebron 119-129, 08035, Barcelona, Spain. nuria.palau@vhir.org.
Nuria
N
Palau
Rheumatology Department, Hospital Universitario La Princesa, IIS La Princesa, C. Diego Leon, 62, 28006, Madrid, Spain. lanult@yahoo.es.
Ana
A
Ortiz
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Pg Vall Hebron 119-129, 08035, Barcelona, Spain. gaby.avila.pedretti@gmail.com.
Gabriela
G
Avila
Rheumatology Department, Hospital Clínico San Carlos, C. Prof. Martin Lagos, S/N, 28040, Madrid, Spain. lrrodriguez@salud.madrid.org.
Luis
L
Rodriguez-Rodriguez
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Pg Vall Hebron 119-129, 08035, Barcelona, Spain. aralonso@ir.vhebron.net.
Arnald
A
Alonso
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Pg Vall Hebron 119-129, 08035, Barcelona, Spain. raul.tortosa@vhir.org.
Raül
R
Tortosa
Rheumatology Department, Hospital Universitario La Princesa, IIS La Princesa, C. Diego Leon, 62, 28006, Madrid, Spain. isidoro.ga@ser.es.
Isidoro
I
Gonzalez-Alvaro
Vall d'Hebron Hospital Research Institute, Rheumatology Research Group, Pg Vall Hebron 119-129, 08035, Barcelona, Spain. sara.marsal@vhir.org.
Sara
S
Marsal
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D015331:Cohort Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007596:Joints / Q000378:metabolism* / Q000473:pathology; D016014:Linear Models; D015810:Linkage Disequilibrium; D015201:Meta-Analysis as Topic; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics*; D013030:Spain
D019947:Receptors, Interleukin-6