Revisiting the genetic puzzle of autoimmune diseases

Résumé

There are more than 80 recognised autoimmune diseases, AIDs (OMIM #109100) that together affects between 3 and 10 % of the general population. Most of them are chronic and incurable, often leading to substantial disability and many of them may have life-threatening complications. AIDs constitute a major health problem that besides causing individual suffering, involve have high social cost [1]. These pathologies are characterized by an immune response from the host against its own cells and tissues. They result from complex interactions between genetic and environmental factors [2-5]. Technological advance and coordinated international efforts have increased the understanding of the genetic factors of AIDs; but it is estimated that only 5-20% of the genetic background of AIDs is known [6-8]. Keeping this in mind, we can be called the ¿missing AIDs heritability hunters¿ because our passion is to try to understand and contribute to the knowledge of the 80% of the genetic component of AIDs remaining to be discovered. There are different ways of trying to reach that goal and one of those is implemented in this thesis: the study of the common genetic component of AIDs. Now a days, the study of the genetic background of AIDs is based on the sequencing of the human genome, first published more than a decade ago [9-11]; because it has provided the comprehensive scaffold to assemble fragmentary information into landscapes of biological structure and functions, like genetic variation, recombination distance, linkage disequilibrium and association to inherited diseases, among others. The human genome sequencing has also provided a framework to connect the biology of model systems to the physiology of human beings; as well as provide a comprehensive catalogue of genomic information. In the aftermath of the human genome sequencing, our work has systematic approaches to discover the genetic variants underlying a disease. The identification of the genetic susceptibility factors is a compass and a map showing the way to discover cellular pathways and physiologic mechanisms of AIDs. This systematic approach has resulted in the identification of hundreds of loci associated with one or more AIDs [4, 12]. It has been shown that nearly half (44%) of the loci identified in genome-wide association studies (GWAS) of an individual disease influence the risk of at least two AIDs [13]. This thesis has given an important contribution to such evidence. We evaluated genetic risk polymorphisms that have been previously associated in other AIDs, in European descent case-control groups of Systemic Sclerosis (SSc), inflammatory bowel disease (IBD), Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). The studied polymorphisms were located in the loci PTPN22, STAT4, IL2-IL21, CD24, BAK1 and UBASH3a [14-20]. Our results report for the first time associations of these known susceptibility AIDs loci with diseases that has not been described before; such as the association of genetic variants in PTPN22 and CD24 with IBD, IL2-IL21 with SSc and UBASH3a with SLE [14, 16, 17, 19, 20]. Moreover, we confirmed through replication and meta-analysis studies, interesting observations like the association with an opposite effect of the rs2476601 PTPN22 SNP in Crohn¿s disease, the modest association of this SNP with SSc and the rs7574865 STAT4 variant influence in ulcerative colitis (UC), a subphenotype of IBD [14, 18]. In addition to the specific conclusions of our results we observed some important features in the study of the genetic component of the AIDs, among them: i) the associated allele of a polymorphism can confer risk to a group of AIDs while is associated with a protective effect against others autoimmune pathologies. ii) The strength of the effect of a common genetic factor associated to AIDs varies for each disease, being higher for some diseases and lower for others. These propose a hierarchy role for the common genetic factors that can be different for each AID and its subphenotypes. iii) The associated polymorphisms of a given AIDs susceptibility loci seem to be specific for each disease. iv) A significant association of a SNP works as a red flag pointing to the possible implication of the gene(s) located in or proxy to the loci where the SNP is situated, but do not determined functional implication of the polymorphisms or genes. v) The SNPs associated to AIDs vary across different human populations. vi) It is not surprising that most of the common AIDs associated polymorphisms exist in intronic or intergenic regions of the human genome. The common AIDs associated loci highlight the immunologic pathways implicated in the etiopathogenesis of these diseases and give us a starting point to the study of their specific mechanisms. The understanding of the genetic background of AIDs accumulated so far is a good beginning. The advance at various levels in this field is directly related to our understanding of the function of the human genome.