Recent advances in the genetics of autoimmune disease

Abstract

Extraordinary technical advances in the field of human genetics over the past few years have catalyzed an explosion of new information about the genetics of human autoimmunity. In particular, the ability to scan the entire genome for common polymorphisms that associate with disease has led to the identification of numerous new risk genes involved in autoimmune phenotypes. Several themes are emerging. Autoimmune disorders have a complex genetic basis; multiple genes contribute to disease risk, each with generally modest effects independently. In addition, it is now clear that common genes underlie multiple autoimmune disorders. There is also heterogeneity among subphenotypes within a disease and across major racial groups. The current crop of genetic associations are only the start of a complete catalog of genetic factors for autoimmunity, and it remains unclear to what extent common variation versus multiple rare variants contribute to disease susceptibility. The current review focuses on recent discoveries within functionally related groups of genes that provide clues to novel pathways of pathogenesis for human autoimmunity.

Figure 1

A map of the region around the PTPN22 locus on chromosome 1p13 covering approximately 200,000 base pairs. The genes in the region are shown at the top of the figure. The blue and yellow haplotype block pattern was generated by looking at combinations of single nucleotide polymorphisms (SNP) alleles in 90 Caucasian subjects from the HapMap Project. Note that a limited number of patterns are observed, generating a kind of bar code for each subject. The lower portion of the figure shows a heat map in which the intensity of red color reflects the degree of correlation [linkage disequilibrium (LD) measured by D′] among SNPs across the region (indicated by tick marks). Note that widely separated SNPs are highly correlated. Two markers associated with type 1 diabetes (and other autoimmune diseases) are shown at the top. Marker rs2476601 is likely to be the causative variant in this region. Note that another marker (rs6679677) nearly a distance of 100 kb also strongly associates with diabetes. This emphasizes that it is difficult to assign the causative locus on the basis of associations alone, as discussed in the text.

Figure 2

The allele frequencies of the PTPN22 risk allele (T) across Europe. Note that there is a gradient of increasing frequency of this allele moving from southern to northern geographic regions. This gradient emphasizes the importance of carefully matching case and control subjects for association studies, even within European populations.

Figure 3

Genes associated with autoimmunity regulate the CD40/NF-κB signaling pathway. The CD40/NF-κB pathway regulates numerous immune-related functions, such as T and B cell proliferation and activation. After association with its ligand, CD40 trimerizes and translocates to lipid rafts, where it interacts with intracellular mediators, including TNF receptor–associated factors (TRAF)1 and 2, which mediate activation of the I κB kinase (IKK) complex. Through phosphorylation, IKK targets the I κB molecule for destruction, which releases NF-κB to translocate into the nucleus and bind to promoter regions of target genes. The NF-κB pathway is regulated by the inhibitor A20 (encoded by TNFAIP3) and by TRAF1, both found to be associated with autoimmune disorders. Interestingly, CD40 has also been detected in the nucleus of B cells, where it interacts with c-rel and initiates transcription of target genes. Both CD40 and c-rel are recently discovered candidate genes for rheumatoid arthritis (RA) (see text).