Genetic variations in genes encoding RANK, RANKL, and OPG in rheumatoid arthritis: a case-control study.
OBJECTIVE
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints, which may lead to structural damage of the cartilage and bone. The receptor activator of nuclear factor-kappaB (RANK) and the osteoprotegerin (OPG) cascade system have been reported to be essential in osteoclastogenesis. Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are thought to play roles in the susceptibility to RA.


METHODS
In our case-control study, genomic DNA was obtained from 534 patients with RA who fulfilled the American College of Rheumatology 1987 criteria and 516 healthy control blood donors (HC). We studied 7 single-nucleotide polymorphisms (SNP) in the genes of RANK (2 SNP: rs1805034, rs35211496), OPG (2 SNP: rs3102735, rs2073618), and RANKL (3 SNP: rs9533156, rs2277438, rs1054016) using TaqMan assay-guided polymerase chain reaction. Genotype and allelic frequencies comparing RA patients with HC were analyzed by chi-square test for 2 x 3 and 2 x 2 tables, respectively.


RESULTS
Genotype distributions of the SNP rs35211496 in the RANK gene as well as the SNP rs2277438 in the RANKL gene differed significantly between patients with RA and HC. The frequency of the minor allele of rs9533156 of RANKL was significantly higher in patients with RA than in HC (OR 0.84, 95% CI 0.71-0.99, p = 0.047). Multivariate analysis adjusted to sex and investigating SNP demonstrated a significantly elevated risk for RA associated with the major allele in the RANK SNP rs35211496 (p = 0.0231) and with the minor allele in the RANKL SNP rs2277438 (p = 0.0092). No significantly increased risk was detected in the other SNP.


CONCLUSIONS
The minor allele of the RANK SNP rs35211496 may be protective against RA, while the minor alleles of the RANKL SNP rs2277438 may increase susceptibility to RA.
Internal Medicine I and José Carreras Research Centre, University of Saarland Medical School, Homburg/Saar, Germany. gunter.assmann@uniklinikum-saarland.de
Gunter
G
Assmann
Jochem
J
Koenig
Michael
M
Pfreundschuh
Joerg T
JT
Epplen
Joern
J
Kekow
Klaus
K
Roemer
Stefan
S
Wieczorek
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics*; D012044:Regression Analysis
D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B