RESUMO
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.
Assuntos
Proteínas da Matriz Extracelular/genética , Testes Genéticos/métodos , Genoma Humano , Mãos , Mutação de Sentido Incorreto , Osteoartrite/genética , Sequência de Aminoácidos , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 4 , Estudos de Coortes , Proteínas da Matriz Extracelular/metabolismo , Articulações dos Dedos , Frequência do Gene , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Proteínas Matrilinas , Dados de Sequência Molecular , Osteoartrite/diagnóstico , Linhagem , Fenótipo , Polimorfismo Genético , Homologia de Sequência de AminoácidosRESUMO
OBJECTIVE: To assess the contribution of genetics to hand osteoarthritis (HOA) and its subsets in the Icelandic population. METHODS: A list of 2,919 HOA patients, constituting 1% of the Icelandic population, was compiled through nationwide sources. This patient list was cross-referenced with a comprehensive Icelandic genealogy database, enabling the use of algorithms to assess familiality of HOA. Two methods were used: the average pairwise kinship coefficient (KC) of the patients, and the relative risk (RR) of HOA in relatives of patients. In each case, the results were compared with 1,000 control sets of similar composition with regard to number, age, and sex, generated from the genealogy database. RESULTS: The KC for patients was significantly higher than for the control sets and was proportional to the degree of both interphalangeal (IP) and thumb base (first carpometacarpal [CMC] joint) involvement. The RR of HOA in sisters of women in the study was 2.0 (P < 0.001), while the RR in spouses was not significantly different from that in controls. The RR increased with the severity of the disease. Thus, sisters of women with severe IP HOA had an RR of 5.0 and sisters of those with severe first CMC involvement had an RR of 6.9. The increased risk also extended beyond the nuclear family, with significantly increased risk in cousins. CONCLUSION: Patients seeking medical services for HOA are more related to each other than matched controls, supporting the role of a genetic component in the disease. The genetic influence in both IP and first CMC HOA appears to be similar and increases with increasing severity of the disease.
