A decade ago it was difficult to visualize immune-mediated diseases (immune-mediated inflammatory and autoimmune diseases [IMDs]) sharing a big part of their heritable etiology Now, it is a clear concept that surrounds the theories of all scientists working on genetics of IMDs. Nevertheless, the complex puzzle of the common genetic network underlying IMD susceptibility is still far from being completely solved.
What made the difference? What evidence demonstrated this common genetic component? First, clinical and epidemiologic observations indicated that more than one IMD can occur in either the same individual or in closely related family members; a phenomenon observed more frequently than would be expected if the diseases’ processes were independent Citation[1]. Simultaneously, the study of pathogenic mechanisms in rodent models and in human linkage studies demonstrated that the strongest genetic influence on susceptibility to IMDs is assigned to the MHC; and there is an aberrant control in the central and peripheral checkpoints to remove the autoreactive T and B cells with similar mechanisms in the pathogenesis of IMDs. Second, classical linkage and candidate gene studies have accumulated evidence of a number of common genetic variants associated with multiple IMDs Citation[2–4]. Furthermore, during the last 6 years the revolutionary genome-wide association studies (GWAS) in IMDs, which are far more comprehensive than prior studies in the field, have strongly confirmed the existence of a common genetic component of IMDs Citation[3–7].
The best example of a non-MHC gene associated with several IMDs, the PTPN22 gene, rs2476601 located in exon 14, is a critical gatekeeper of T- and B-cell receptor signaling. This nonsynonymous single nucleotide polymorphisms (SNPs) was first described through a candidate gene study in Type 1 diabetes (T1D) and rapidly replicated in several autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE) Citation[8–10]. Recently, we reported a risk association between the rs2476601 minor allele and systemic sclerosis (SSc), and a protective influence of this allele in Crohn’s disease (CD) Citation[11,12]. The PTPN22 minor allele confers an increased predisposition to a variety of autoimmune diseases, including T1D, rheumatoid arthritis, SLE and SSc, but protects against CD and Behçet’s disease. At the same time, it has no effect on the risk of multiple sclerosis Citation[3,4,10]. Functional studies have shown that the PTPN22 minor allele increases the production of activated T and B cells and affects their appropriated central and peripheral tolerance checkpoints Citation[13,14]. Based on this example we can learn some lessons from common genetic component of IMDs: a detected genetic association for one phenotype/disease might reflect an association for other correlated phenotypes/diseases; a genetic variant could be associated with multiple, but not all, IMDs, underlying the overlap in common etiological pathways among diseases with refined immunological mechanisms for each IMD Citation[4,5,15]. The magnitude and effect size of these associations vary between diseases, suggesting that certain molecules may have diametric roles in different diseases and those common associated loci may be underbalancing selection owing to the antagonistic pleiotropic effect Citation[5,7,16].
Common genetic factors in IMDs could match at a regional level but differ in the specific genetic variant associated to each disease Citation[5–7,15–17]. For example, some SNPs of the IL2–IL21 locus on chromosome 4q27 have been associated with several autoimmune diseases Citation[4]. Evidence suggest that there are two signals in the IL2–IL21 locus, with T1D mapping on IL2 and other diseases to IL21Citation[5]. Indeed, we observed in a recent case–control study of four IL2–IL21 SNPs in SSc that the best associated signal in SSc was different to the previous reported and most associated SNP to SLE [Diaz-Gallo L-M, Unpublished Data]. A recent study identified different association signals across 3.44 megabases of the classic MHC region in seven IMDs Citation[17]. The authors highlighted the complexity and multilocus effects of those associations and observed independent secondary association signals around the NOTCH4 gene with ulcerative colitis, CD and SLE, showing once again that there are specific variants in the same genetic region associated to each disease.
Assuming that current heritability estimates of IMDs are accurate, because there is a slight possibility that an erroneously inflated heritability had been estimated, the established susceptibility genetic variants can only explain approximately 5–20% of the genetic components of IMDs Citation[18]. However, evidence exists suggesting that nearly half (44%) of loci identified in GWAS of an individual disease influence the risk of at least two IMDs, arguing for a genetic basis to comorbidity Citation[5]. Together, these propose that there is a long way to go to find the missing heritability of IMDs and that we have almost half the chance of finding a variant related to more than one disease. Given that only a small fraction of the over 10 million common genome variants are directly genotyped by current genome-wide association platforms, it is far more likely that the top-scoring markers are simply correlated markers. If a linked marker has been hit, the causal variant could be another common variant, a rare variant, a structural variant or a coding or regulatory variation Citation[18,19]. Bearing in mind the aforementioned example of the PTPN22 variant, nonsynonymous variants could explain an important part of the missing heritability component of IMDs. The analysis of the online catalog of GWAS showed that disease association signals are significantly over-represented by nonsynonymous sites and promoter regions, supporting the theory that these kind of variants have an important role in IMDs Citation[6].
Apart from the widely accepted need to analyze different ethnic groups, during the past few years a controversy has arisen about the next steps that may be taken to further investigate the heritability of IMDs Citation[20]: the study of copy number variations; the analysis of rare variants (allelic frequency <5%); the fine mapping of the hit variant regions; the sequencing of specific genomic regions, the sequencing of very well-characterized cohorts, including specific and diametric diseases phenotypes (the so-called ‘extreme risk’); and the functional studies based on the know products of the genetic association studies, among others. The answer will vary depending on the diseases to be studied and the available fund resources. The decade after the completion of the draft sequence of the human genome, has seen astounding technological and intellectual advances, including increasing evidence of the common genetic background of the IMDs. However, we should work with the same intensity and focus to apply the results to health outcomes and the clinic.
Financial & competing interests disclosure
LM Diaz-Gallo was funded by the “Ayudas Predoctorales de Formación en Investigación en Salud (PFIS-FI09/00544)” from the Instituto de Salud Carlos III. J Martin was funded by grants SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain, in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain and by Fondo Europeo de Desarrollo Regional (FEDER). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Becker KG. The common genetic hypothesis of autoimmune/inflammatory disease. Curr. Opin. Allergy Clin. Immunol.1(5), 399–405 (2001).
- Becker KG, Simon RM, Bailey-Wilson JE et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc. Natl Acad. Sci. USA95(17), 9979–9984 (1998).
- Cho JH, Gregersen PK. Genomics and the multifactorial nature of human autoimmune disease. N. Engl. J. Med.365(17), 1612–1623 (2011).
- Zhernakova A, van Diemen CC, Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat. Rev. Genet.10(1), 43–55 (2009).
- Cotsapas C, Voight BF, Rossin E et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet.7(8), e1002254 (2011).
- Manolio TA. Genomewide association studies and assessment of the risk of disease. N. Engl. J. Med.363(2), 166–176 (2011).
- Sirota M, Schaub MA, Batzoglou S, Robinson WH, Butte AJ. Autoimmune disease classification by inverse association with SNP alleles. PLoS Genet.5(12), e1000792 (2009).
- Begovich AB, Carlton VE, Honigberg LA 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.75(2), 330–337 (2004).
- Orozco G, Sanchez E, Gonzalez-Gay MA et al. Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthrit. Rheum.52(1), 219–224 (2005).
- Stanford SM, Mustelin TM, Bottini N. Lymphoid tyrosine phosphatase and autoimmunity: human genetics rediscovers tyrosine phosphatases. Semin. Immunopathol.32(2), 127–136 (2010).
- Diaz-Gallo LM, Espino-Paisan L, Fransen K et al. Differential association of two PTPN22 coding variants with Crohn’s disease and ulcerative colitis. Inflamm. Bowel Dis.17(11), 2287–2294 (2011).
- Diaz-Gallo LM, Gourh P, Broen J et al. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis. Ann. Rheum. Dis.70(3), 454–462 (2011).
- Menard L, Saadoun D, Isnardi I et al. The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest.121(9), 3635–3644 (2011).
- Zhang J, Zahir N, Jiang Q et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nat. Genet.43(9), 902–907 (2011).
- Smyth DJ, Plagnol V, Walker NM et al. Shared and distinct genetic variants in Type 1 diabetes and celiac disease. N. Engl. J. Med.359(26), 2767–2777 (2008).
- Wang K, Baldassano R, Zhang H et al. Comparative genetic analysis of inflammatory bowel disease and Type 1 diabetes implicates multiple loci with opposite effects. Hum. Mol. Genet.19(10), 2059–2067 (2010).
- Rioux JD, Goyette P, Vyse TJ et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc. Natl Acad. Sci. USA106(44), 18680–18685 (2009).
- Manolio TA, Collins FS, Cox NJ et al. Finding the missing heritability of complex diseases. Nature461(7265), 747–753 (2009).
- Ioannidis JP, Thomas G, Daly MJ. Validating, augmenting and refining genome-wide association signals. Nat. Rev. Genet.10(5), 318–329 (2009).
- Baker M. Genomics: the search for association. Nature467(7319), 1135–1138 (2010).