Association of the interleukin-1 gene cluster on chromosome 2q13 with knee osteoarthritis.
OBJECTIVE
To investigate whether the interleukin-1 (IL-1) ligand gene cluster at 2q13 encodes for genetic susceptibility to primary osteoarthritis (OA).


METHODS
Seven single-nucleotide polymorphisms (SNPs) and a variable-number tandem repeat (VNTR) polymorphism from within the IL-1 ligand genes IL1A, IL1B, and IL1RN were genotyped in a cohort of 557 OA cases and 557 age-matched controls.


RESULTS
None of the variants demonstrated association in the unstratified data set. However, when cases were stratified according to sex and site of disease (hip or knee), 4 SNPs showed marginal evidence for association (P < 0.1) in knee cases (n = 136) and male knee cases (n = 58). For 2 of these SNPs, evidence for association was enhanced when probands from 60 knee-only affected sibling pair families were genotyped and combined with the original knee cases (P < or = 0.05). Further analysis revealed that the associated alleles at 2 of these SNPs were markers for the same haplotype, the frequency of which was significantly elevated when knee cases and knee probands were combined (P = 0.01, odds ratio [OR] 1.4) and when male knee cases and male knee probands were combined (P = 0.009, OR 1.7). Furthermore, linkage analysis of 2q revealed suggestive evidence for linkage to the IL-1 gene clusters in affected sibling pairs concordant for knee OA but no evidence for linkage in affected sibling pairs concordant for hip OA.


CONCLUSIONS
The IL-1 ligand cluster encodes for susceptibility to knee OA but not to hip OA, highlighting the genetic heterogeneity of this common, complex disease.
Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. john.loughlin@ndcls.ox.uk
John
J
Loughlin
Barbara
B
Dowling
Zehra
Z
Mustafa
Kay
K
Chapman
D000368:Aged; D000369:Aged, 80 and over; D002889:Chromosomes, Human, Pair 2; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015207:Osteoarthritis, Hip / Q000235:genetics; D020370:Osteoarthritis, Knee / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012795:Sialoglycoproteins / Q000235:genetics*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins