Osteoarthritis (OA) is the most common human joint disease, characterized by loss and/or remodeling of joint synovium, cartilage, and bone. Here, we describe a genomewide linkage analysis of patients ...with idiopathic hand OA who were carefully phenotyped for involvement of either or both the distal interphalangeal (DIP) joints and the first carpometacarpal (CMC1) joints. The best linkage peaks were on chromosomes 4q and 3p and on the short arm of chromosome 2. Genomewide significance was reached for a locus on chromosome 2 for patients with affected CMC1 joints (LOD = 4.97); this locus was also significant for patients with OA in both CMC1 and DIP joints (LOD = 4.44). The peak LOD score at this locus coincides with a gene,
MATN3, encoding the noncollagenous cartilage extracellular matrix protein, matrilin-3. Subsequent screening of the genomic sequence revealed a missense mutation, of a conserved amino acid codon, changing threonine to methionine in the epidermal growth factor–like domain in matrilin-3. The missense mutation cosegregates with hand OA in several families. The mutation frequency is slightly more than 2% in patients with hand OA in the Icelandic population and has a relative risk of 2.1.
Objective
To describe a large kinship with inherited hip osteoarthritis (OA) and its associated susceptibility locus.
Methods
Four generations of a kinship with familial hip OA were identified and ...characterized by family history and by clinical, radiographic, and histopathologic examination. In the genome‐wide search for a susceptibility locus, OA cases were defined as those who had undergone total hip replacement associated with a clinical and radiographic diagnosis of hip OA. A genome‐wide scan was performed using a framework set of microsatellite markers with an average spacing of 10 cM.
Results
The hip OA of this family was indistinguishable from that of idiopathic, nonfamilial hip OA. There was no apparent evidence of spondyloepiphyseal dysplasia or other dysplasias usually associated with mutations in collagen genes. The genome‐wide scan revealed a locus on chromosome 16p between 28 cM and 47 cM from the telomere, and this locus met the criteria for suggestive linkage (multipoint allele‐sharing logarithm of odds LOD score 2.58, P = 1.6 × 10−4). Two additional regions with LOD scores of >1.5 were obtained.
Conclusion
We have identified and described the largest kinship with familial hip OA reported to date. Evidence for linkage in this family suggests that a gene for susceptibility to hip OA exists on chromosome 16p. This represents an independent identification of a susceptibility locus previously reported for hip OA in this geographic region.
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