What is next after the genes for autoimmunity?

Abstract

Clinical pathologies draw us to envisage disease as either an independent entity or a diverse set of traits governed by common physiopathological mechanisms, prompted by environmental assaults throughout life. Autoimmune diseases are not an exception, given they represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. Although they are pleiotropic outcomes of non-specific disease genes underlying similar immunogenetic mechanisms, research generally focuses on a single disease. Drastic technologic advances are leading research to organize clinical genomic multidisciplinary approaches to decipher the nature of human biological systems. Once the currently costly omic-based technologies become universally accessible, the way will be paved for a cleaner picture to risk quantification, prevention, prognosis and diagnosis, allowing us to clearly define better phenotypes always ensuring the integrity of the individuals studied. However, making accurate predictions for most autoimmune diseases is an ambitious challenge, since the understanding of these pathologies is far from complete. Herein, some pitfalls and challenges of the genetics of autoimmune diseases are reviewed, and an approximation to the future of research in this field is presented.

Figure 1

Etiopathogenesis of autoimmune diseases. Outline showing the plausible stages for a multifactorial etiology to develop over time. Each stage shows the known phenomena that cumulatively will be the causative scenario for the onset of disease(s). First, heritable factors (that is, genetics, including ancestry, and epigenetics) impact over the life of the individuals. They converge and interact to create and increase or decrease the liability an individual would have to develop the phenotype depending on risk and protective effects. Women are more affected than men. Second, the autoimmune ecology is characterized by the interactions between an individual and its environment, which acting stochastically will also influence the risk and course of disease. The additive effects of heritable and environmental risk factors favor the loss of autoimmune tolerance. Then, a preclinical stage characterized by B and T cell dysregulation arises. This third phase may take years before the phenotype becomes clinically evident. Adapted from Anaya [4] (with permission from Elsevier). This model may apply to all complex diseases. TCR, T cell receptor.

Figure 2

Weighted list created from the reported significant mapped genes in the current genome-wide association studies curated from the National Human Genome Research Institute and the database of genotypes and phenotypes. The word cloud shows the frequency of genes and its associated variants relative to their font size using a freely available java applet [24]. Both databases (accessed April 2013) [25,26] were queried taking into account P-values reported for the genetic variants associated with autoimmune disease. For the National Human Genome Research Institute, a total of 12,064 genetic variants were encountered, out of which 1,370 were variants significantly associated with autoimmune disease susceptibility. In the database of genotypes and phenotypes, out of 31,246 reported variants, 972 were mutually exclusive from the National Human Genome Research Institute, for a grand total of 2,342 genetic variants related to genes associated in a genome-wide association study of any population. The autoimmune diseases of interest were autoimmune thyroid disease, Behcet’s disease, celiac disease, rheumatoid arthritis, inflammatory bowel disease, juvenile rheumatoid arthritis, Kawasaki disease, multiple sclerosis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, systemic sclerosis, systemic lupus erythematosus, type 1 diabetes and vitiligo.

Figure 3

Histogram showing the percentage of autoimmune diseases with significant reported genetic variants in the current genome-wide association studies curated from the National Human Genome Research Institute and the database of genotypes and phenotypes. Both databases [25,26] were accessed in April 2013. AITD, autoimmune thyroid disease; BD, Behcet’s disease; CD, celiac disease; IBD, inflammatory bowel disease; JRA, juvenile rheumatoid arthritis; KD, Kawasaki disease; MS, multiple sclerosis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; PSO, psoriasis; RA, rheumatoid arthritis; SCL, systemic sclerosis; SLE, systemic lupus erythematosus; SSC, systemic sclerosis; T1D, type 1 diabetes; VIT, vitiligo.