Objective: To assess osteoarthritis (OA) association with the human interleukin-1 (IL-1) region.
Design: Sixty-four European-descent cases with radiographic hand OA and 48 European-descent controls were genotyped at nine single nucleotide polymorphism (SNP), one variable-number-of-tandem-repeat (VNTR), and one microsatellite marker extending across loci for IL-1alpha (IL1A), IL-1beta (IL1B), and IL-1 receptor antagonist (IL1RN). The genotype data were used to reconstruct individual locus haplotypes, and then locus haplotypes were used as superalleles for extended haplotype reconstruction.
Results: Nine different extended IL1A-IL1B-IL1RN haplotypes occurred at a frequency 0.05 or greater in either cases or controls. Only two IL1A-IL1B-IL1RN extended haplotypes were consistent with previously described extended risk haplotypes and totaled n=9 in cases and n=3 in controls [odds ratio (OR) 2.1, Haldane's chi(2) 1.67, one-sided P 0.1]. Our prior report showed hand OA association with homozygous IL1B rs1143633 minor allele genotype. All except one extended risk haplotype copy also had the IL1B rs1143633 minor allele. The rs1143633 genotype association was explained by one common six-SNP IL1B haplotype bearing rs1143633 minor allele and also risk alleles at rs1143634, rs1143627, and rs16944, component markers of the previously described extended risk haplotypes. The IL1B haplotype bearing all three risk alleles was found in 16 haplotype-homozygous hand OA cases and in four haplotype-homozygous controls and conferred OR 3.4 among homozygotes (nominal P value 0.006).
Conclusion: Our evidence broadly supports the genetic association of OA phenotypes with an IL-1 region extended risk haplotype and specifically IL1B genotype. The extended risk haplotype previously associated with hip OA appears to be less frequent and has weaker genetic effect in hand OA. Hand OA risk is conferred by homozygous state for the IL1B haplotype characteristic of the extended risk haplotype.