Interleukin-1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study.
OBJECTIVE
To assess whether genetic variation in the interleukin-1 (IL-1) gene cluster contributes to familial osteoarthritis (OA) by influencing innate ex vivo production of IL-1beta or IL-1 receptor antagonist (IL-1Ra).


METHODS
Innate ex vivo IL-1beta and IL-1Ra production upon lipopolysaccharide (LPS) stimulation of whole blood cells was measured in subjects from the Genetics, Osteoarthritis and Progression (GARP) Study, which includes sibling pairs in which at least one sibling has symptomatic OA at multiple sites. Radiographic OA (ROA) was assessed by Kellgren/Lawrence score. Subjects from the GARP Study and controls from the Rotterdam Study were genotyped for 7 single-nucleotide polymorphisms (SNPs) encompassing the IL-1 gene cluster on chromosome 2q13. Linkage disequilibrium analysis and genotype and haplotype association analysis were performed to assess the relationship between the IL-1 gene cluster SNPs, innate ex vivo cytokine production, and OA.


RESULTS
Among subjects in the GARP Study, the haplotype variable-number tandem repeat in intron 2/T+8006C/T+11100C 2/2/1 of the IL1RN gene was significantly associated with reduced innate ex vivo bioavailability of IL-1beta upon LPS stimulation (P = 0.026) and with ROA at the highest number of joint locations.


CONCLUSIONS
These results show that genetic variation at the IL-1 gene cluster is associated with lower IL-1beta bioavailability and with OA at a large number of joint locations. The data further indicate that, among subjects with OA affecting the highest number of joints, the innate immune system may be activated, thereby obscuring possible underlying mechanisms.
Meulenbelt
Ingrid
I
Leiden University Medical Center, 2333 ZC Leiden, The Netherlands. i.meulenbelt@lumc.nl
Bos
Steffan D
SD
Kloppenburg
Margreet
M
Lakenberg
Nico
N
Houwing-Duistermaat
Jeanine J
JJ
Watt
Iain
I
de Craen
Anton J
AJ
van Duijn
Cornelia M
CM
Slagboom
P Eline
PE
D000328:Adult; D000368:Aged; D001847:Bone Diseases / Q000000981:diagnostic imaging / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging; D016207:Cytokines / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D050276:Hand Bones / Q000000981:diagnostic imaging; D006621:Hip Joint / Q000000981:diagnostic imaging; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics*; D007719:Knee Joint / Q000000981:diagnostic imaging; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics; D010003:Osteoarthritis / Q000235:genetics*; D011859:Radiography; D035781:Siblings; D044465:White People / Q000235:genetics
D016207:Cytokines; D007375:Interleukin-1