Polymorphisms in the interleukin-1 receptor antagonist and interleukin-6 genes affect risk of osteolysis in patients with total hip arthroplasty.
OBJECTIVE
To determine whether osteolysis after total hip arthroplasty (THA) is associated with common polymorphisms within the genes encoding the interleukin-1 (IL-1) family and IL-6, and to determine whether polymorphisms that are associated with osteolysis affect in vitro messenger RNA (mRNA) expression in human peripheral blood mononuclear cells (PBMCs) in response to wear particles.


METHODS
Unrelated white subjects of North European descent (n=612) were recruited a mean of 11 years after cemented THA for primary osteoarthritis. Of these subjects, 272 had previous osteolysis and 340 had no radiographic evidence of osteolysis (control group). Genomic DNA was genotyped for the following single-nucleotide polymorphisms (SNPs): IL1A +4845, IL1B +3954, IL1B -3737, IL1B -511, IL1RA +2018, IL6 -174, IL6 -572, and IL6 -597. In a subset of 60 subjects, PBMCs were extracted and stimulated with titanium particles and/or endotoxin, and cytokine mRNA expression was measured using quantitative real-time reverse transcriptase-polymerase chain reaction.


RESULTS
The odds ratio (OR) for osteolysis associated with carriage of the IL1RA +2018C allele was 0.66 (95% confidence interval [95% CI] 0.48-0.91) (P=0.012). The remaining SNPs were not individually associated with osteolysis. The uncommon IL6 haplotype -174G/-572G/-597A (osteolysis group frequency 2.4%, control group frequency 0.8%) was associated with osteolysis (P=0.02, calculated using Haploview software). The IL1RA +2018CC genotype was associated with increased mRNA expression compared with the +2018TT genotype in both unstimulated and stimulated PBMCs (P=0.01 by analysis of variance, after Bonferroni correction).


CONCLUSIONS
The IL1RA +2018C allele is associated with a decreased risk of osteolysis after THA and with increased IL-1 receptor antagonist mRNA expression in vitro. An uncommon haplotype within the promoter region of the gene for IL-6 is positively associated with osteolysis.
Gordon
Andrew
A
University of Sheffield, and Academic Unit of Bone Metabolism, Northern General Hospital, Sheffield, UK.
Kiss-Toth
E
E
Stockley
Ian
I
Eastell
Richard
R
Wilkinson
J Mark
JM
D000368:Aged; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010014:Osteolysis / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics
C507763:IL1RN protein, human; C508600:IL6 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6