Two recently published studies point to a genetic role in knee osteoarthritis (OA), according to two separate teams of British researchers. Siblings of patients scheduled for knee replacement surgery are also more likely to have knee OA, according to a study published in the August issue of Annals of Rheumatic Diseases. The other study, published in the August issue of Arthritis & Rheumatology, identifies certain candidate genes that could be the focus of future research.

"This is the first large sibling study of knee OA and adds to the growing body of evidence that there is a genetic contribution to common forms of OA," the authors of the sibling study wrote. "Identification of the responsible genes will enhance our understanding of OA pathogenesis."

Corresponding author Michael Doherty, MD, told CiaoMed that, although many risk factors are known to be linked to knee OA, siblings of patients with knee OA are twice as likely to be affected as the general population. "When we compared the siblings to a community sample, the siblings had at least twice the risk of knee osteoarthritis," Dr. Doherty said. "This is the strongest data to date to support a genetic component to arthritis at this site. Now we have very strong evidence to go out and try to identify the specific genes. There may be more than one gene, and they may be different, for example, from the genes that would influence hip OA." He is a professor of rheumatology at the University of Nottingham in Nottingham, United Kingdom.

Dr. Doherty and co-investigators recruited 490 patients who were scheduled for total knee replacement surgery, who responded to a questionnaire about knee OA risk factors and also asked them if they had living siblings. The investigators then interviewed 737 siblings and questioned them about knee pain and risk factors for knee OA such as weight and prior knee injuries. The siblings, who were all over 40 years old, were then asked to undergo x-ray studies of their knees.

These findings were compared to those of 1,729 participants from the community who were also more than 40 years old. When adjusted for age, sex, and the presence of knee pain, the siblings were 2.9 times more likely to have tibiofemoral OA, and 1.7 times more likely to have patellofemoral OA. The difference remained even after the investigators adjusted for environmental and lifestyle risk factors, according to the authors.

In the study focusing on candidate genes, the investigators, led by Ana Valdes, PhD, at St. Thomas Hospital in London, compared human complementary DNA libraries from OA-affected and normal cartilage and synovium and identified 22 genes. Among these, they found significant associations for OA susceptibility for 5 genes, while progression was linked to 4 genes.

"None of the genes studied here showed a very large effect on any of the traits," the authors wrote. "Such results indicate that multiple genes…are involved in OA susceptibility and progression and are likely to be feature specific. Nonetheless, it is possible that combinations of genes might prove more useful than any individual polymorphism." The study, they added, may contribute to the emergence of a way to predict genetic predisposition to OA onset and progression.

The investigators scrutinized the selected genes as well as estrogen receptor alpha and vitamin D receptor genes. They then used available polymorphisms to test whether genetic variation affected knee OA susceptibility or progression over a 10-year period, using 749 women from a longitudinal study. The women were an average of 64 years old at baseline.

After adjusting for age and body mass index, they detected significant links to knee OA onset and progression at the following genes: ADAM12, BMP2, CD36, COX2, and NCOR2. They also found significant links to ADAM12, CILP, OPG, and TNA for the several OA progression traits.

The investigators caution that the individual associations are relatively weak, with nominal significance linked to 15 (P <0.05). The largest odds ratio, 1.92, was linked to ADAM12 and the presence of osteophytes. Their results suggest that multiple genes are involved in OA severity and progression, and that the genes are feature-specific.

References

Neame RL, Muir K, Doherty S, Doherty M. Genetic risk of knee osteoarthritis: a sibling study. Ann Rheum Dis . 2004;63: 1022-1027.

Valdes AM, Hart DJ, Jones KA, et al. Karen Association study of candidate genes for the prevalence and progression of knee osteoarthritis Arthritis Rheum. 2004;50(8):2497-2507.