Investigation of linkage on chromosome 2q and hand and knee osteoarthritis

Gillaspy, Emma; Spreckley, Kristian; Wallis, Gillian A.; Doherty, Michael; Spector, Tim D.

doi:10.1002/art.10651

Cited by 16 publications

(13 citation statements)

References 9 publications

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“…This particular region on chromosome 2 includes the interleukin-1 (IL-1) gene cluster. Other investigators could not confirm linkage in this region when investigating families with nodal OA of the hand and knee (which included many of the families mentioned above) (14) or specifically hand OA (15). In the latter study, however, some evidence of linkage was observed for the IL-1 receptor antagonist (IL-1Ra) gene (IL1RN).…”

Section: Discussionmentioning

confidence: 92%

Association of the interleukin‐1 gene cluster with radiographic signs of osteoarthritis of the hip

Meulenbelt

Seymour

Nieuwland

et al. 2004

Arthritis & Rheumatism

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Objective. To study the role of the interleukin-1␤ gene (IL1B) and the IL-1 receptor antagonist gene (IL1RN) in relation to the occurrence of radiographic osteoarthritis (ROA) in the hip, knee, and hand and disc degeneration of the spine.Methods. The study population consisted of a random sample of 886 subjects (ages 55-65 years) from a population-based cohort (the Rotterdam study). Two polymorphisms within IL1B (3953C>T and ؊511C>T) and one within IL1RN (the variable-number tandem repeat [VNTR]) were analyzed and used in an association study of the occurrence of ROA. Haplotyping and simultaneous logistic regression analysis were performed to investigate whether the associations observed were independent.Results. Associations with a predisposition for hip ROA were observed for heterozygous and homozygous carriers of the rare IL1B allele ؊511T (crude odds ratio [OR] 1.8, 95% confidence interval [95% CI] 1.0-3.4 and OR 2.9, 95% CI 1.4-6.3, respectively) and of the IL1RN VNTR allele 2 (crude OR 2.0, 95% CI 1.1-3.4 and OR 3.3, 95% CI 1.4-7.8, respectively). An additive effect was observed for carriers of risk alleles of both polymorphisms, with a significant linear-by-linear association (P ‫؍‬ 0.00022). Conclusion.Our findings suggest that the IL-1 gene cluster polymorphisms may play a significant role in the pathogenesis of OA of the hip.Osteoarthritis (OA) is a joint disease characterized by degeneration of articular cartilage and remodeling of the subchondral bone with sclerosis. It has been demonstrated that genetic factors also play an important role in late-onset OA. Familial aggregation of OA (especially hand, knee, and hip OA) was observed in population-based studies (1-4). Candidate genes that may exert this genetic influence have been investigated by means of population-based association studies and genetic linkage studies in OA families. A large number of association studies using various definitions of OA have been performed, mainly investigating genes encoding structural proteins of the extracellular matrix of cartilage (e.g., COL2A1, CRTM, and AGN) or genes playing a role in the regulation of bone density and mass (e.g., VDR, IGF1, and ER), and have shown both positive and negative results for each of the genes (for review, see ref. 5). These differences in study results may indicate either false-positive or false-negative results, could be the result of differences in the OA phenotype investigated, or could be attributable to different linkage disequilibrium (LD) between the associated polymorphism and the causal mutation in various populations. Moreover, it is becoming increasingly clear that the genetic risk factors for OA at different joint sites may be distinct (6).Several groups of investigators have performed genome-wide screens of sibling pairs or nuclear families with OA and reported multiple chromosome areas (e.g., 2p24, 3p12, 4q32, 11q12, 4q27, Xp11.3, and 7p22) that show positive linkage to specific OA phenotypes, such as radiographic OA (ROA) in the distal interphalangeal (DIP) joints, s...

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Section: Discussionmentioning

confidence: 92%

Association of the interleukin‐1 gene cluster with radiographic signs of osteoarthritis of the hip

Meulenbelt

Seymour

Nieuwland

et al. 2004

Arthritis & Rheumatism

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“…Finer linkage analysis narrowed the locus on chromosome 2 to 2q24.3-q31.1, a region which contained 85 known genes [124], but none of these were cartilage-related genes. Other studies suggested that major susceptibility loci were unlikely to be present in this region of 2q [114,125]. For knee OA, but not hip OA, concordance with the IL-1 cluster at 2q13 could be shown [126].…”

Section: Genetics Of Osteoarthritismentioning

confidence: 94%

Pathobiology of Osteoarthritis: Pathomechanisms and Potential Therapeutic Targets

Roach¹,

Aigner²,

Söder³

et al. 2007

CDT

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Osteoarthritis, a degenerative joint disease, is the most disabling condition of the Western world. It affects first and foremost the articular cartilages and leads to a molecular and supramolecular destruction of the extracellular cartilage matrix. In addition, the cells, the chondrocytes, show severe alterations of their phenotype: they get anabolically and catabolically activated, change accordingly their gene expression pattern, lose their differentiated phenotype, and undergo focally cell death and cell degeneration. All these processes represent potential targets for therapeutic intervention and drug development. Apart from the cartilage itself, however, other joint tissues are also involved in the disease: thus, the synovial capsule and membrane as well as the subchondral bone account not only for most of the symptoms of the disease, but are also presumably involved in the progression of the degenerative process. Both, inflammation and stiffening within the joint capsule accelerate joint destruction. Stiffening of the subchondral bone increases the mechanical stress over the overlying cartilage during physiological movement. Altogether, there is a plethora of tissues, disease processes and targets for treating osteoarthritic joint degeneration, which will need to be followed up systematically in the future.

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Section: Participantsmentioning

confidence: 99%

“…Participants were patients referred to a hospital rheumatology clinic because of symptomatic large joint and/ or hand OA, together with their first degree relatives, who were identified for a nodal OA genetic study. 12 Cross sectional data on these participants were collected.Clinical and radiographic assessment HN were determined by clinical inspection and palpation for firm/hard posterolateral rounded swellings and/or joined dorsal bars, irrespective of any tenderness or symptom reporting, and classified for each finger of both hands as: grade 0 = no firm/hard swelling; grade 1 = unilateral (posterolateral) firm/hard swelling; and grade 2 = bilateral (posterolateral) firm/hard swellings. BN were similarly determined by inspection and palpation and classified as present or absent, because a previous study in our unit showed poorer agreement for BN than HN.…”

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confidence: 99%

Relationship between Heberden's nodes and underlying radiographic changes of osteoarthritis

Thaper

Zhang

Wright

et al. 2005

Annals of the Rheumatic Diseases

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Objective: To determine whether clinically determined Heberden's nodes (HN) and Bouchard's nodes (BN) are associated with underlying individual radiographic changes of osteoarthritis (OA). Methods: 232 index patients with symptomatic large joint and/or hand OA, and 257 of their first degree relatives were included. HN were graded 0-2; BN were scored as present/ absent. Joint space narrowing (JSN) and osteophyte (OST) were each scored 0-3 using the OARSI atlas. A weighted k test was used to examine intraobserver reproducibility. Odds ratio (OR) was estimated for the relationship between nodes and associated JSN and OST. Results: The adjusted OR of HN for underlying JSN in the same digit was 1.72 (95% CI 1.47 to 2.02), whereas for OST it was higher at 5.15 (95% CI 4.37 to 6.08). A similar trend was seen with BN and underlying OA, with OST having a higher OR (OR = 2.98, 95% CI 2.55 to 3.47) than JSN (OR = 1.62, 95% CI 1.37 to 1.91). Conclusion: There is a positive relationship between HN/BN and underlying radiographic changes of OA, especially OST. Nodes do appear to link pathologically to OA in interphalangeal joints. H eberden's nodes (HN) and Bouchard's nodes (BN) are firm swellings over the superolateral and dorsal aspects of distal and proximal interphalangeal joints respectively.1 2 Despite their prevalence the pathogenesis of nodes remains unclear, although bony outgrowth 3 and endochondral ossification of marginal hypertrophic fibrocartilage 4 5 are implicated in their aetiology. Nevertheless, it is widely held that nodes are associated with hand osteoarthritis (OA), [5][6][7] that they are a marker for systemic predisposition to generalised OA, 6 7 and that they reflect the presence of underlying osteophyte (OST).4 5 However, the link between HN and underlying interphalangeal OA has been questioned in one study of middle-aged female twins, 8 in which a poor correlation was found between HN and underlying radiographic OST, assessed on a 0-3 scale using a radiographic atlas. 9 In contrast, a more recent study 10 of 71 subjects with hand OA showed a reasonable correlation between HN and radiographic OA in the corresponding joint, assessed using the global Kellgren and Lawrence scale.11 Thus the postulated association between nodes and underlying OA is in doubt.We therefore undertook a cross sectional study of women and men with HN to determine whether nodes are associated with radiographic OA of the corresponding joint. Unlike previous studies 8 10 we assessed individual radiographic features of OST and joint space narrowing (JSN) and investigated the influence of sex, age, and body mass index (BMI) on the relationship. METHODS ParticipantsThe study was approved by the local research ethics committee. Participants were patients referred to a hospital rheumatology clinic because of symptomatic large joint and/ or hand OA, together with their first degree relatives, who were identified for a nodal OA genetic study. 12 Cross sectional data on these participants were collected.Clinical and radiographic assessm...

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Investigation of linkage on chromosome 2q and hand and knee osteoarthritis

Cited by 16 publications

References 9 publications

Association of the interleukin‐1 gene cluster with radiographic signs of osteoarthritis of the hip

Association of the interleukin‐1 gene cluster with radiographic signs of osteoarthritis of the hip

Pathobiology of Osteoarthritis: Pathomechanisms and Potential Therapeutic Targets

Relationship between Heberden's nodes and underlying radiographic changes of osteoarthritis

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