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.
Loughlin
John
J
Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. john.loughlin@ndcls.ox.uk
Dowling
Barbara
B
Mustafa
Zehra
Z
Chapman
Kay
K
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