GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders
Highlights
► A large number of associations for autoimmunity have been identified, generally involving common variants of modest effect. ► Many associations defined by GWAS are in non-coding regions and appear to regulate quantitative effects on gene expression. ► A large fraction of the common variants act through quantitative changes in thresholds for immune signaling and activation.
Section snippets
Simple model of autoimmunity: autoantigen presentation and thresholds of immune activation in the adaptive immune system
Given the diversity of autoantigens that have been identified, many models of autoimmunity understandably emphasize role of autoantigen presentation in the context of a class I or class II MHC molecule to T cells and B cells, as shown in Figure 1. Much of disease specificity (whether a person develops rheumatoid arthritis [RA] or type 1 diabetes) is likely to be determined by this combination of factors. For example, if the autoantigen is gliadin presented in a DQ2 class II MHC molecule, then a
Thresholds for TCR and BCR signaling in autoimmunity
The original PTPN22 associations with type 1 diabetes [4] and rheumatoid arthritis [5], now expanded to many other autoimmune diseases, have emphasized the importance of signaling thresholds in disease predisposition, and, at the same time have demonstrated how difficult it is to conclusively determine how these threshold effects cause disease risk. PTPN22 encodes an intracellular tyrosine phosphatase that dephosphorylates activating tyrosines on src kinases such as Lck, as well as other
Quantitative traits in cytokine pathways
Cytokines, their receptors and signaling components are clearly important for regulating a wide variety of immunological activities, and it is therefore not surprising that many of the genetic regions implicated by GWAS contain genes in these pathways. However, relatively few studies in humans have directly demonstrated an effect of disease associated polymorphisms on cytokine function. It is often challenging to identify the exact causative variant(s) that explain a genetic association,
Immune regulation by dendritic cells
Highlighted by the 2011 Nobel Prize, dendritic cells have taken center stage as potent initiators of immune responses as well as mediating immune tolerance, both central and peripheral [34]. Many of the peripheral tolerance mechanisms appear to depend on Treg cells as well as the production of TGFβ. A deficiency of TGFβ signaling in DC leads to experimental autoimmune colitis. DC specific knockout of genes associated with human autoimmunity on GWAS, such as Blimp1 and TNFAIP3, leads to
Population resources for genotype–phenotype studies of quantitative immune traits
These results suggest that many GWAS discoveries in autoimmune diseases will be associated with rather subtle changes in immune responsiveness and/or immune regulatory differences that are quantitative in nature. This may be owing to the presence of structural amino acid changes, as in PTPN22, or changes in gene regulation that are specific to particular cells and stages of differentiation. In order to dissect these relationships, a large population resource of human subjects carrying the
Conclusion
GWAS and related gene discovery approaches have revealed the importance and complexity of identifying and understanding the functional consequences of genetic variation on biological systems. As described in this review for immune-mediated traits, we are beginning to unravel the quantitative effects of risk alleles on the immune response. The examples provided here, together with the unique resources such as repositories of healthy controls and patients, offer hope that new avenues for therapy
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
PKG is supported by grants from the National Institutes of Health (RO1-AR-44422; RO1-AI-68759; RC2AR059092-01) and the Alliance for Lupus Research, in addition to support from Eileen Ludwig Greenland and the Boas family. BD is supported by the Alliance for Lupus Research. RMP is supported by grants from the NIH (R01-AR057108, R01-AR056768, U01-GM092691, R01-AR059648), and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund.
References (39)
- et al.
Five years of GWAS discovery
Am J Hum Genet
(2012) - et al.
A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis
Am J Hum Genet
(2004) - et al.
Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47
Nat Genet
(2011) - et al.
Complement factor H polymorphism in age-related macular degeneration
Science
(2005) - et al.
Genomics and the multifactorial nature of human autoimmune disease
N Engl J Med
(2011) - et al.
A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes
Nat Genet
(2004) - et al.
Protein tyrosine phosphatases in lymphocyte activation and autoimmunity
Nat Immunol
(2012) - et al.
PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells
Science
(2004) - et al.
Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant
Nat Genet
(2005) - et al.
Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes
J Immunol
(2007)
PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background
J Immunol
The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness
Nat Genet
PTPN22 alters the development of regulatory T cells in the thymus
J Immunol
Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs B cell signaling
J Immunol
The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans
J Clin Invest
Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease
Nat Genet
Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up
Hum Mol Genet
Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets
Am J Hum Genet
Cited by (15)
Myasthenia Gravis: Paradox versus paradigm in autoimmunity
2014, Journal of AutoimmunityCitation Excerpt :In addition, a functional link between TNF-α −308 allele 2 and MG was assumed since peripheral blood mononuclear cells (PBMCs) from patients positive for the TNF-α-308 allele 2 had higher secretion of TNF-α when activated in vitro [68]. Interestingly, a gender bias in MG at the HLA loci was described [69,70]. In a recent study, the allele frequency difference in female versus male patients was observed not only at the HLA-DRA but also at the TNF-α loci [57].
The putative role of proteolytic pathways in the pathogenesis of Type 1 diabetes mellitus: The 'autophagy' hypothesis
2014, Medical HypothesesCitation Excerpt :This has stimulated investigations on their etiopathogenesis. With the advent of new tools, such as genome wide association studies (GWAS) [4], evidence was provided for new susceptibility loci and candidate genes in the disease process including the immunological synapse and T cell activation [5]. Among organ-specific autoimmune disorders, insulin-dependent diabetes mellitus [Type 1 diabetes mellitus (T1D)] is a polygenic autoimmune disease, which occurs in human leukocyte antigens (HLAs) genetically predisposed individuals as a consequence of organ-specific immune destruction of the insulin-producing β cells in the islets of Langerhans within the pancreas [6] by autoreactive T cells.
Renegade homeostatic cytokine responses in T1D: Drivers of regulatory/effector T cell imbalance
2014, Clinical ImmunologyCitation Excerpt :Consistent with the functions of these cytokines, therapies that augment IL-2 or block IL-7 or IL-15 can restore a beneficial Treg/Teff ratio in animal models of lost tolerance. In many autoimmune diseases, there are inherent defects in homeostatic cytokine pathways including IL-2, IL-7 and IL-15 [19]. Thus, we suggest that signatures of IL-2, IL-7 and IL-15 may also be biomarkers of disease progression in autoimmunity and cytokine-based therapies may be used to manipulate these responses.
The Crafoord Prize in Polyarthritis 2013: Significant discoveries and remaining challenges
2013, Seminars in Arthritis and RheumatismXFOXO in the hole: Leveraging GWAS for outcome and function
2013, CellCitation Excerpt :Nevertheless, in the case of autoimmune diseases, GWASs have been particularly fruitful in terms of identifying large numbers of reproducible associations and have revealed intriguing overlaps between different autoimmune disorders that involve both the innate and adaptive immune systems (Cho and Gregersen, 2011). While coding region variants with defined effects on immune function have been identified, many GWAS associations appear to involve regulatory functions that can be tied to quantitative immune traits (Gregersen et al., 2012). The report by Lee et al. (2013) in this issue of Cell provides a beautiful integration of genetic, clinical, and functional data in mouse and human to shed light on the pathway influenced by such a noncoding SNP.
Genome-wide association studies of hematologic phenotypes: A window into human hematopoiesis
2013, Current Opinion in Genetics and DevelopmentCitation Excerpt :Rare variant studies of hematologic traits are just now being reported and will likely have improved power to detect new variants in the ensuing years [61•]. As illustrated by the studies of hematologic malignancies and autoimmune conditions, important lessons can be learned about susceptibility to these diseases by studying aspects of normal human hematopoiesis [53,56]. As new studies surmount these challenges in the coming years, our understanding of human hematopoiesis will undoubtedly improve significantly.