Osteoarthritis has a multifactorial aetilogy with a strong genetic component.1,2 Recently, Stefansson et al3 identified a missense mutation (pT303M) in the MATN3 (matrilin‐3) gene (designated as single‐nucleotide polymorphism (SNP)5) in a large cohort of patients from Iceland, which cosegregates with hand osteoarthritis in several families and shows a frequency of approximately 2% in the Icelandic population (relative risk 2.1). Min et al4 were not able to repeat this result in two Dutch cohorts of patients with hand osteoarthritis, but reported association of this SNP with spinal disc degeneration in one of their populations (odds ratio 2.9). In contrast, they found that the A allele of SNP6 (nomenclature as in Stefansson et al3), a silent base exchange in MATN3, is associated with hand osteoarthritis in one of their cohorts (odds ratio = 2.0). Here, we carried out a case–control study of the two polymorphisms for putative association with hand osteoarthritis and knee osteoarthritis in two small cohorts of German patients.
We investigated a sample group of 50 consecutive Caucasian patients (mean age 59.2 years, 84% women) with radiographic and symptomatic hand osteoarthritis of the first carpometacarpal joint (CMC1; late‐stage arthritis, EATON stage II–IV), 176 consecutive Caucasian patients (mean age 69.8 years, 79% women) with radiographic and symptomatic knee osteoarthritis (late–stage primary osteoarthritis with complete collapse of the femorotibial joint space) and 356 unrelated Caucasian controls (mean age 38.8 years, 41% women, healthy blood donors recruited in Germany). Patients with CMC1 and knee osteoarthritis were not handled separately. Genotyping of SNP5 and SNP6 in the MATN3 gene was performed by polymerase chain reaction amplification and subsequent cycle sequencing as described previously.5
We analysed the frequency of SNP5 in patients with hand osteoarthritis and in 356 controls and observed a difference in allele frequency (χ2 = 10.84, p = 0.001). The rare T allele of SNP5 was present in 10% of the patients with hand osteoarthritis and in 2.5% of controls (table 1, χ2 = 7.35, p = 0.007). The p value remained significant even after Bonferroni correction for multiple testing. Thus, carriers of the T allele had an increased risk for developing hand osteoarthritis, with an odds ratio of 4.28 (95% CI, 1.18 to 14.8). Interestingly, three of these five patients presented with more scaphotrapezotrapezoidal (STT) joint involvement, a characteristic already described.7 Thus, we could replicate the results for hand osteoarthritis reported by Stefansson et al.3 Our data support the importance of SNP5 for this specific form of osteoarthritis, but not for knee osteoarthritis (table 1). In contrast with the recent report by Min et al,4 we did not find association of SNP6 with hand osteoarthritis (or knee osteoarthritis; table 1).
Table 1 Genotype and allele frequencies of SNP5 and SNP6 in patients with osteoarthritis and in controls.
| N | Controls | Hand osteoarthritis | Knee osteoarthritis | ||||
|---|---|---|---|---|---|---|---|
| Patients | p Value (χ2) | p Value (exact) | Patients | p Value (χ2) | p Value (exact) | ||
| 356 | 50 | 176 | |||||
| SNP5 | |||||||
| Genotype | |||||||
| C C | 347 (97.5) | 45 (90) | 172 (97.7) | ||||
| C T | 9 (2.5) | 4 (8) | 0.007* | 0.019* | 4 (2.3) | 0.857* | 1* |
| T T | 0 | 1 (2) | 0 | ||||
| Allele | |||||||
| C | 703 (98.7) | 94 (94) | 348 (98.9) | ||||
| T | 9 (1.3) | 6 (6) | 0.001 | 0.005 | 4 (1.1) | 0.858 | 1 |
| SNP6 | |||||||
| Genotype | |||||||
| A A | 16 (4.5) | 1 (2) | 0.156† | 0.167† | 9 (5.1) | 0.820† | 0.851† |
| A G | 128 (36) | 14 (28) | 64 (36.4) | ||||
| G G | 212 (59.5) | 35 (70) | 103 (58.5) | ||||
| Allele | |||||||
| A | 160 (22.5) | 16 (16) | 0.141 | 0.155 | 82 (23.3) | 0.763 | 0.756 |
| G | 552 (77.5) | 84 (84) | 270 (76.7) | ||||
SNP, single‐nucleotide polymorphism
Genotypes and allele frequencies % were compared using the χ2 and Fisher's exact test on a 2×2 contingency table. A value of p <0.05 was considered as significant. The value for SNP5 (in bold) remained significant even after correction for multiple testing . Both SNPs were in Hardy–Weinberg equilibrium in controls as calculated by the program Haploview.6
*TT + CT v CC in genotype analysis.
†AA + AG v GG in genotype analysis.
The partly contradictory data between the different studies may possibly be due to differences in common diagnostic criteria,7 or in allele frequencies in the control group.4 In this respect, it has to be emphasised that our control cohort was randomly selected and is thus not age/sex matched or specifically evaluated for any signs of osteoarthritis. Nevertheless, the fact that the group of patients with knee osteoarthritis (n = 176) exhibit genotype and allele distributions very similar to that of the control cohort (table 1) strongly supports the present association data.
Although the exact role of MATN3 and MATN3 variations in osteoarthritis is still not clear,8,9 the present data support the importance of variations in the MATN3 gene region for the aetiology of specific forms of osteoarthritis.
Acknowledgements
We are grateful to our patients for their participation in this study.
Footnotes
This work was supported by a grant from the Bundesministerium für Bildung und Forschung (BMBF) to AW, and from the Deutsche Forschungsgemeinschaft (DFG) to OP and BS.
Competing interests: None.
References
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