ReviewGenetics of digital osteoarthritis
Introduction
With all genetic study methods, the phenotype constitutes the basis for interpreting and comparing the results. The phenotype of hand osteoarthritis is complex and heterogeneous. The joints that may be involved are the trapeziometacarpal joint and the proximal and distal interphalangeal joints of the long fingers. Nodes may be visible at the interphalangeal joints. Disease severity at each joint can be assessed radiographically based on joint space narrowing, osteophytes, and/or the Kellgren-Lawrence score, which is a composite score reflecting both abnormalities. Thus, the phenotype of hand osteoarthritis varies both qualitatively and quantitatively, and the presence of nodes characterizes yet another entity known as nodal osteoarthritis. Nodal osteoarthritis is usually defined as osteoarthritis of multiple interphalangeal joints in at least two rays of each hand, with Heberden's nodes and with or without Bouchard's nodes, in patients with no known history of trauma [1]. The genetic study of digital osteoarthritis encompasses all these phenotypic patterns.
Section snippets
Family studies, heritability, and modes of inheritance
All three classical strategies for assessing the genetic risk of a disease based on family studies have been used in digital osteoarthritis and Heberden's nodes: twin studies, studies of disease risk in first-degree relatives, and family aggregation studies [2]. Heritability, a statistical parameter reflecting the contribution of genetic factors to the risk of a specific phenotype in a given population, has been estimated in most forms of digital osteoarthritis.
Associations between hand osteoarthritis and HLA alleles
Early genetic association studies in digital osteoarthritis produced conflicting results regarding the HLA-A1, B8, and DR4 alleles. The most recent association with HLA-A1B8 was found in a British study of patients with interphalangeal osteoarthritis in at least three rays and Heberden's nodes (27% of patients vs. 11.5% of controls, P = 0.004) [18]. However, in an Italian case-control study, HLA-A, B, C, DR, and DQ genotype determination showed that primary hand osteoarthritis was significantly
Mutations in the matrilin-3 gene
Matrilin 3, the third member of the matrilin family, is an adapter protein in the extracellular cartilage matrix that plays a role in cartilage development and homeostasis [21]. Several mutations in the matrilin-3 gene (MATN3) are associated with autosomal dominant forms of multiple epiphyseal dysplasia and bilateral hereditary microepiphyseal dysplasia, as well as with autosomal recessive forms of spondylo-epi-metaphyseal dysplasia [21]. A genome-wide screen in Icelanders with hand
Genome-wide association screens using microsatellite markers
The results of eight genome-wide microsatellite association screens in populations with the various qualitative and quantitative phenotypes of hand osteoarthritis have been published (Table 1). Half of these studies were done in pairs of affected first-degree relatives and the other half in affected families, although the late age at phenotype expression was an obstacle to the collection of large pedigrees [2]. Table 1 shows that two independent studies found similar linkage intervals at 2p
Other candidate genes
In addition to the genes discussed above, several other candidate genes have been the focus of association studies in various hand osteoarthritis phenotypes (Table 2). Among these studies, all but one used a case-control design. The exception was a study of the ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1). ENPP1 is mutated in generalized arterial calcification of infancy. In murine models, ENPP1 mutations are associated with periarticular calcification or ectopic joint
Telomeres and hand osteoarthritis
Telomeres are tandem repeats located at the ends of chromosomes. They are crucial to chromosome replication and stability. Telomere length is determined by genetic factors and by environmental factors such as inflammation and oxidative stress. Telomere shortening has been documented in several age-related diseases in humans. A decrease in mean telomere length with advancing age was found in chondrocytes, most notably at sites involved with osteoarthritis. In a British study that focused on
Conclusion
Although the digital osteoarthritis phenotype has no universally accepted definition, genetic epidemiology and molecular genetics studies have established a role for genetic factors in susceptibility to the disease. Future studies will build on recent work to identify the main genes involved in the pathogenesis of digital osteoarthritis, which may prove to hold promise as treatment targets.
Conflict of interest statement
The author declares no conflict of interest.
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