Elsevier

Joint Bone Spine

Volume 78, Issue 4, July 2011, Pages 347-351
Joint Bone Spine

Review
Genetics of digital osteoarthritis

https://doi.org/10.1016/j.jbspin.2010.09.012Get rights and content

Abstract

Genetic factors contribute to the development of digital osteoarthritis, whose heritability has been estimated at 48 to 65%. Among the manifestations of digital osteoarthritis, only Heberden's nodes are transmitted by Mendelian inheritance, as a dominant trait in women and a recessive trait in men. The other forms of digital osteoarthritis are multifactorial, with a major gene and a residual multifactorial component that probably interacts with environmental factors. Hindrances to molecular studies include the absence to date of a universally accepted definition of the phenotype and the late onset of the manifestations. Genetic association studies of selected class I and II HLA genes produced conflicting results. The T303M polymorphism of the MATN3 gene, which was initially described as associated with hand osteoarthritis, may be more closely linked to trapeziometacarpal osteoarthritis than to digital osteoarthritis. Genome-wide scans have identified numerous loci linked to digital osteoarthritis. Replication has been achieved for some of these loci, most notably those located at 2p, 2q, 3p, 4q, and 7p. A recently published genome-wide association study showed that an A2BP1 gene polymorphism was significantly associated with hand osteoarthritis. Many candidate-gene studies found associations with AGC1, ASPN, ENPP1, HFE, KL, VDR, IL-1 cluster, and IL-6, although the results were not consistently reproducible. In one study, women with hand osteoarthritis had significant telomere shortening. Telomere shortening has also been reported in other age-related conditions.

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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