Rheumatoid arthritis: a view of the current genetic landscape

Abstract

The field of genetics and autoimmune diseases is undergoing a rapid and unprecedented expansion with new genetic findings being reported at an astounding pace. It is now clear that multiple genes contribute to each of the major autoimmune disorders, with significant genetic overlaps among them. Rheumatoid arthritis (RA) is no exception to this, and emerging data are beginning to reveal the outlines of new diagnostic subgroups, complex overlapping relationships with other autoimmune disorders and potential new targets for therapy. This review describes the evolving genetic landscape of RA, with the full knowledge that our current view is far from complete. However, with the first round of genome-wide association scans now completed, it is reasonable to begin to take stock of the direction in which the major common genetic risk factors are leading us.

Figure 1

Case–control analysis for 2221 single-nucleotide polymorphisms spanning 10.7 Mb from 6p22.2 (26.03 Mb) to 6p21.31 (36.80 Mb) across the extended major histocompatibility complex region. Chromosome position is shown on the x axis; the y axis shows the –log P-value. (a) Case–control association statistics by Amitage trend test for anti-CCP + RA vs control group. (b) Case–control association statistics by Amitage trend test for the anti-CCP– RA vs control group. Taken from Ding et al.

Figure 2

Chi-square test (χ²) statistics from the 2-by-2 allele count table of 744 case–control samples matched 1:1 by DRB1 genotype (372 cases and 372 controls). Note that χ² value = 0 at DRB1, as these samples are matched at this locus. The signals are divided into + and − according to whether the single-nucleotide polymorphisms are characteristically found on the common A1-B8-DR3 haploytpes (see Lee et al. for details).

Figure 3

Map showing the distribution of PTPN22 minor allele frequencies across Europe for the R620W (1858C > T) variant. Taken from Gregersen et al.