Genetics of Rheumatic Disease

Alex Clarke; Timothy J Vyse


Arthritis Res Ther. 2009;11(5):248 

In This Article

Genetics of Rheumatic Disease

The spectrum of rheumatic disease is wide and includes conditions with diverse pathology, although most have in common a heritable risk with a complex genetic basis. There has therefore been intense effort to understand the contribution of genotype to the expression of disease in terms of both basic pathogenesis and clinical characteristics. Recent technical advances in genotyping and statistical analysis and international collaborations assembling large cohorts of patients have led to a wealth of new data. In this review we describe insights gained into the pathogenesis of autoimmune rheumatic disease by the techniques of modern genetics, in particular evidence from genome-wide association (GWA) studies, which provide support for the existence of a common genetic risk basis to several diseases. To reflect the new data from GWA studies, our discussion will be confined to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS), which in some cases share a common autoimmune pathogenesis. Osteoarthritis and osteoporosis are also complex genetic traits but limitations of space are such that these two conditions will not be considered in this review.

The concept of a systematic, GWA study became practical with the cataloguing of libraries of common polymorphisms. Currently, over 20 million single nucleotide polymorphisms (SNPs) have been identified[1] and platforms are available to type up to 1 million of these in a single reaction. Although not all SNPs are currently genotyped, as the human genome is arranged into haplotype blocks in linkage disequilibrium, it is only necessary to type so-called tag SNPs, which identify these areas of limited variability,[2] to achieve good representation of the total amount of genetic variation. Most typed SNPs are relatively common (minor allele frequency of > 5%) and if associated with disease are likely, therefore, to have only modest pathogenic effects (odds ratios (ORs) usually between 1.2 and 2), as otherwise they would become depleted in a population due to natural selection. It is necessary, therefore, to invoke the 'common-disease common-variant' (CD-CV) model,[3] which assumes an accumulation of risk caused by the carriage of multiple deleterious alleles, to explain current experimental findings.

One of the revolutionary advantages of the GWA study is the freedom from a required gene-centric hypothesis, which provides an unprecedentedly effective technique for risk gene discovery. Many disease-associated genes identified by GWA studies were completely unsuspected to be relevant - for example, the autophagy system in Crohn's disease.[4] However, because in essence up to 1 million independent hypotheses are being tested in each genotyping reaction, sample sizes powered to detect even the stronger associations must be large, and criteria for significance stringent. The general consensus is that significance can be defined as a P-value smaller than 5 × 10−7, which in a cohort such as the Wellcome Trust Case Control Consortium (WTCCC) of 2,000 cases, for example, approximates to a power of 43% rising to 80% to detect alleles with ORs of 1.3 and 1.5, respectively.[5] However, the genome is subject to variation at more than the SNP level, and individuals also differ in the copy number of sections of DNA of greater than several kilobases in size, so called copy number variation (CNV), which in fact accounts for more total nucleotide difference between individuals than SNPs.[6,7] CNV can affect gene expression levels[8] and has been linked to autoimmune disease,[9,10] including SLE.[11] Whilst the latest genotyping platforms include assessment of CNV, earlier products actively excluded SNPs within regions of the most variation as they were more likely to fail quality control steps. Association studies based on CNV are, therefore, in their relative infancy. Finally, the genome is subject to modification without a change in DNA sequence; epigenetic mechanisms can have profound effects on gene expression. These include DNA methylation and changes in chromatin structure.[12]

It has become apparent that SLE, RA, and AS, which have divergent clinical features, may share a common genetic risk framework, and we aim in our review to illustrate this.


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