Osteoarthritis is a multifactorial disease but all individuals are not equal in relation to the disease because each individual’s genetics is responsible for how he or she adapts to his or her environment.
What are the arguments in favour of a genetic component in osteoarthritis?
One can traditionally distinguish several stages to demonstrate the intervention of genetic vulnerability factors in a disease. The aggregation studies show the familial character of the disease. In 1941, Stecher observed that the sisters of women with Heberden's nodes in the distal interphalangeal joints had a 3 times higher risk of developing osteoarthritis than the general population.
These results have since been confirmed by Kellgren and Lawrence, and more recently by Felson and Hirsch based on data from the Framingham Osteoarthritis Study and the Baltimore Longitudinal Study on Ageing, respectively.
Studies on twins and adoption showed that this familial aggregation is linked to the intervention of genetic factors rather than a common familial environmental factor.
In osteoarthritis, a certain number of studies carried out on populations of twins confirmed the influence of genetic factors. In a population of twins, Spector found a 51.6% rate of concordance of Heberden's nodes in monozygotic twins compared with 27.3% in dizygotic twins.
How do you look for genes with a predisposition to osteoarthritis?
Once the genetic osteoarthritis component has been established, the following logical stage is to identify the genes that are responsible.
Thanks to the development of molecular biology techniques, genes with a predisposition that are likely to be involved in osteoarthritis have been identified by using two key strategies: association studies and linkage studies.
Association studies consist in comparing the frequency of a genetic marker with diseased subjects and healthy controls, chosen randomly in a same population without selection criteria other than that corresponding to the disease. Often of interest are the candidate genes whose function suggests a potential role in the disease being studied and whose location is known. One seeks to find out whether the “candidate” is really involved in the disease by using the genetic markers located on this gene. Some researchers have compared and selected from human cDNA gene banks from healthy and diseased cartilage and synovial membrane, 22 genes with significant polymorphisms: Single Nucleotide Polymorphisms (SNP) which designate the variations of a single base-pair of genomes, between individuals of a same species. These very frequent variations (1 base-pair /1000 in the human genome) represent 90% of all the human genetic variations. They then looked for an association between the presence of 1 to 2 SNPs per gene and the existence of radiographic signs of osteoarthritis of the knee in a group of patients within which they found a relationship between 9 of the SNPs of the 22 genes studied and osteoarthritis. 7 of these polymorphisms were also associated with knee osteoarthritis in men and women who were not from the group.
Over the past few years, numerous candidate genes have been studied in osteoarthritis. The 1st of them was the collagen type II gene (COL2A1) coding for the alpha 1 polypeptide chain of collagen type II, the main component of joint cartilage. Other genes coding for the constituents of the cartilaginous matrix have also been studied such as those of collagen type IX and type XI as well as the aggrecanases. However, these studies have not established that the presence of certain variants of these genes constitutes an original risk factor of osteoarthritis. However, different variants of two other candidate genes, one coding for the vitamin D receptor (VDR) and the other for the Oestrogen receptor alpha polymorphism (ESR1), have been associated with osteoarthritis.
Linkage studies are generally carried out using anonymous genetic markers (and not using candidate genes) chosen so as to cover the entire human genome. They also use deoxyribonucleic acid (DNA) polymorphisms and enable defining the regions of the genome (loci) that may contain susceptible genes: this is the systematic screening of the genome.
The in-depth study of these susceptible regions then enables defining the genetic variants responsible for the genetic susceptibility to the disease, and the way in which the environment modulates the effect of these genes. The current advances in molecular genetics make it easy and inexpensive to study a great number of genetic polymorphisms for a same individual. However, the increase in the number of tests sometimes leads to conclude that genes that are in reality “innocent” are involved!
The results of at least 5 genomic screenings carried out in populations of siblings and twins suffering from knee, hip or hand osteoarthritis have been published.
Recently, Lee and his colleagues concluded in a meta-analysis bringing together 3 genomic screening studies (893 families, 3,000 individuals suffering from osteoarthritis in Iceland, UK, USA) that the regions that most often carry genes susceptible to osteoarthritis are located on chromosomes 7, 11, 6, 2 and 15.
Today, the list of new genes susceptible to osteoarthritis never ceases to grow longer… some coding for the inflammatory molecules (IL1, IL6, COX2, IL10, etc), others for the proteases and their inhibitors (ADAM 12, etc) and still others for the factors involved in the many metabolisms (BMPs, FRZB, GDF5, etc) and, of course, those coding for the factors of deterioration and formation of the cartilaginous matrix (COL2A1, COMP, MATN3, etc)
What can one hope to gain from genetic research for osteoarthritis?
Today the increase in risk associated with the presence of a susceptible gene appears quite modest (OR between 1.1 and 1.6 for genes GDF5 and FRZB, for example), but then a question arises: does an individual increase their risk of developing osteoarthritis according to the number of susceptible genes they carry? According to some authors, the answer would appear to be “yes” with regard to osteoarthritis of the knee: the accumulated risk reaching that observed in certain studies with obesity and joint traumatism risk factors!
Even if our knowledge of the genetic basics of osteoarthritis has greatly improved over the last ten years, the genes that are responsible still remain to be defined as well as the links that unite them to the environmental factors. Genetic research into osteoarthritis will make it possible to better understand the physiopathology of the disease and perhaps in the future to spot the high-risk individuals or groups and develop individualised prevention and treatment strategies.
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- Valdes AM, Spector TD. The contribution of genes to osteoarthritis. Rheum Dis Clin N Am 2008; 34: 581-603.
- Bardin T, Cornelis F. Génétique de l’arthrose. Rev Rhum 2000; 67 (3): 138-42.