Recent advances in the genetics of rheumatoid arthritis

Abstract

Purpose of review: To review the recently discovered genetic risk loci in rheumatoid arthritis (RA), the pathways they implicate, and the genetic architecture of RA.

Recent findings: Since 2008 investigators have identified many common genetic variants that confer disease risk through single nucleotide polymorphism genotyping studies; the list of variants will no doubt continue to expand at a rapid rate as genotyping technologies evolve and case-control sample collections continue to grow. In aggregate, these variants implicate pathways leading to NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation, the interluekin-2 signaling pathway, and T-cell activation.

Summary: Although the effect of any individual variant is modest and even in aggregate considerably less than that of the major histocompatability complex, discovery of recent risk variants suggests immunological processes that are involved in disease pathogenesis.

Figure 1. Variance explained by rheumatoid arthritis genetic associations

I list each known rheumatoid arthritis (RA) risk variant along the bottom in the approximate order of their discovery from left to right. Each SNP is plotted along the Y-axis (left) with red bars the odds ratio of the risk allele. As time has progressed, case–control sample collections have increased in size and the ability to discover modest effect sizes has increased. On the Y-axis (right), I plot the increase in the percentage variance explained. A total of approximately 60% of the variance for RA liability is thought to be genetic. I have listed only variants shown to confer risk in European populations.

Figure 2. TNFAIP3 locus

Currently, there are three known associated single nucleotide polymorphism (SNP) loci in the TNFAIP3 locus. As indicated here, there are two risk SNPs far upstream of the gene in linkage disequilibrium with each other, but conferring independent risk of disease. A third risk SNP is located within the second intron of the gene and is not in linkage disequilibrium with the other two risk SNPs.

Figure 3. A meta-analysis of three genome-wide association studies

Here I present data from a meta-analysis of three separate genome-wide data sets. Each point represents a single nucleotide polymorphism (SNP). Along the X-axis, I plot the genomic location of an individual SNP. The height of each point indicates the strength of association for that SNP. The dark blue arrows indicate some known associations with rheumatoid arthritis (RA) at the time of this study. The pink arrows indicate SNPs that demonstrated nominal evidence of association in this study (P <0.0001) that were subsequently replicated in an independent collection of cases and controls.

Figure 4. Gene relationships across rheumatoid arthritis-associated loci

Here I list each of the known rheumatoid arthritis (RA)-associated single nucleotide polymorphisms (SNPs) along the outer ring; the internal ring represents the genes near each SNP with a box. I illustrate the literature-based functional connectivity between these genes with lines drawn between them as assessed by the gene relationships across implicated loci (GRAIL) algorithm. The more red and thicker the lines are, the stronger the connectivity between the genes is. RA SNPs implicate a small number of highly connected genes – those genes are indicated by labeled boxes.