GENETIC EPIDEMIOLOGY OF RHEUMATOID DISEASE

The aetiology of rheumatoid arthritis (RA) has both genetic and environmental origins. However, the relationship of these with each other and with RA disease is complicated as both genes and environment may be protective or render individuals susceptible. Diagnostic certainty and disease heterogeneity have posed serious hurdles for investigating RA. Patients with similar disease phenotypes may have different aetiologies and it may now be more appropriate to investigate genetic susceptibility with respect to disease process or characteristic immunopathology. Disease concordance studies have been a classical approach to estimating the upper threshold of the genetic contribution to RA and recent studies have approximately halved the much quoted figure of 32% reported by Lawrence for RA concordance in monozygotic twins. However, the interpretation of twin data has to be treated with caution as MZ twins can differ in terms of somatic rearrangement/mutation of immunoglobulin and T cell receptor genes, X chromosome inactivation in females, genomic imprinting and in utero immune relationship, Calculations based on heritability put the genetic component in RA much higher. HLA is an important genetic factor in RA and risk is thought to be associated with a consensus sequence of amino acids within the third hypervariable region of certain DRB1 alleles. It is now clear that HLA is not particularly associated with onset of synovitis but is more associated with progression and severity of the disease process. The HLA-DRBI(*)0401/0404 genotype is particularly associated with severe, erosive and seropositive RA. Clear differences in RA susceptibility exist between males and females and this may be attributed to hormonal status. Males have a higher threshold requirement for developing RA and this may explain why RA in males is more associated with HLA risk alleles. We have now reached a critical time for the investigation of RA aetio-pathology. Recent advances in molecular biology and automated microsatellite gene scanning technology are making it possible to map disease susceptibility genes over the whole genome in common disorders such as RA. This will require large numbers of well characterised multiplex affected families. It is anticipated that some of the genes identified will fit in with our current concepts of which inflammatory and immune processes are pathologically important in RA. However others may be a major surprise.