Genes versus environment

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It is now well established that RA is a complex disease for which susceptibility and severity is likely to be influenced by combinations of both genetic and environmental factors. The environmental factors implicated in RA include obesity, diet, smoking and a number of infectious agents including parvovirus, proteus and various retroviruses [13, 14]. Interestingly the pattern of increased risk associated with the non-infectious agents is common to various cancers and other chronic inflammatory conditions such as cardiovascular disease.

Most studies investigating risk factors have however been carried out with cross-sectional case identification and analysis based on retrospective data, making for significant difficulties and possible bias. In contrast The Norfolk Arthritis Register (NOAR) in the UK is a prospective study of RA initiated in 1989 with recruitment through general practitioners [1]. This dataset confirmed the association with obesity and smoking but there was only weak evidence of parvovirus infection [15]. Interestingly there was a higher than expected frequency of tetanus immunisation in the 6 weeks prior to onset and an association with prior blood transfusion again suggesting that various challenges to the immune system could be precipitating events. The geographical overlap of NOAR and part of the European Prospective Investigation of Cancer (EPIC) provided a unique opportunity to study diet, based on a 7-day food record collected prior to the onset of arthritis. Cases were found to have a low vitamin C and high red meat intake compared to controls matched for age, gender and time of recruitment to EPIC [16, 17].

While some of the population differences described above might appear to be most readily explained by environmental exposures, underlying genetic factors clearly have a role. This is best illustrated by the HLA-DRB1 gene locus, the major genetic factor associated with RA, to date. The definition of the shared epitope (SE), the sequence of amino acids common to HLA-DRB1 alleles associated with RA, arose out of HLA association studies carried out in different populations and it is widely reported that SE positive HLA-DRB1 alleles are at a low frequency in populations in which RA is relatively rare (for full review see Chapter 2). The relative importance of genetic and environmental factors and the contribution of individual loci can be investigated using twin and family based studies.

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