Abstract
BackgroundIn search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q. In this study we targeted a 470 kb region on 2q11.2 presenting the locus with most evidence for linkage to severe OA of distal interphalangeal joints (DIP) in our genome wide scan families.MethodsWe genotyped 32 single nucleotide polymorphisms (SNPs) in this 470 kb region comprising six genes belonging to the interleukin 1 superfamily and monitored for association with individual SNPs and SNP haplotypes among severe familial hand OA cases (material extended from our previous linkage study; n = 134), unrelated end-stage bilateral primary knee OA cases (n = 113), and population based controls (n = 436).ResultsFour SNPs in the IL1R1 gene, mapping to a 125 kb LD block, provided evidence for association with hand OA in family-based and case-control analysis, the strongest association being with SNP rs2287047 (p-value = 0.0009).ConclusionsThis study demonstrates an association between severe hand OA and IL1R1 gene. This gene represents a highly relevant biological candidate since it encodes protein that is a known modulator of inflammatory processes associated with joint destruction and resides within a locus providing consistent evidence for linkage to hand OA. As the observed association did not fully explain the linkage obtained in the previous study, it is plausible that also other variants in this genome region predispose to hand OA.
Highlights
In search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q
To collect knee OA material, we reviewed case reports of 852 patients visiting ORTON Orthopaedic Hospital between 1994-2001 having knee OA and identified 220 patients with primary bilateral knee OA severe enough to fulfill the criteria for knee arthroplasty: pain, walking disability and radiologically at least stage 3/4 osteoarthritic changes according to Kellgren and Lawrence classification [20]
Out of 32 SNPs, four SNPs in IL1R1 gene in 125 kb area showed some evidence for association to hand OA (p-values < 0.05), in a family-based association analysis using the Pseudomarker program and/or in the case-control analysis (Table 2)
Summary
In search for genes predisposing to osteoarthritis (OA), several genome wide scans have provided evidence for linkage on 2q. In this study we targeted a 470 kb region on 2q11.2 presenting the locus with most evidence for linkage to severe OA of distal interphalangeal joints (DIP) in our genome wide scan families. The marker providing strongest evidence for linkage in Finnish distal interphalangeal joint (DIP) OA families resides within the IL1R1 gene (LOD score 2.34), and some evidence for a shared haplotype among the affected individuals was observed with markers D2S2264, IL1R1, D2S373, and D2S1789 (p-value of 0.012) [6]. A handful of association studies have shown a potential role for interleukin-1 gene family in knee and hip OA [10,11,12]
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