Review articleImmunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways
Section snippets
Systemic sclerosis: a complex disease
Systemic sclerosis or scleroderma (SSc) is a complex autoimmune disease (AD) with heterogeneous clinical manifestations. SSc pathogenesis involves vascular damage, deregulation of the immune system and extensive fibrosis in the skin and different internal organs. Immune imbalance includes autoantibody production, particularly anticentromere (ACA), antitopoisomerase (ATA) and anti-RNA polymerase III autoantibodies (ARA) [1]. SSc patients are commonly classified in two main subgroups according to
HLA
The major histocompatibility complex (MHC) is a genetic region of the chromosome 6 with an extreme gene density and long-range linkage disequilibrium (LD) patterns. In human, the MHC is the most polymorphic region of the genome and its gene products are called Human Leucocyte Antigen (HLA). The first genetic associations reported for ADs were found in MHC loci and for most of them, including SSc, these loci represent the strongest associations.
Several studies have addressed the role of the HLA
Insights into missing heritability
Heritability is defined as: 1) in a broad sense (H2), the proportion of phenotypic variance among individuals that can be attributed to genetic factors, 2) in a narrow sense (h2), the proportion that comprises only the genetic variation that is due to additive genetic values [104]. However, in the case of complex traits, the contribution of genetic variance to phenotypic differences can be difficult to estimate. SSc is not an exception, and the heritability of SSc remains controversial.
A
Exploring the functional roles of genetic susceptibility loci
GWAS do not often identify the causal variants for the described peaks of association, instead these analyses often point out non-coding variants located in regions with multiple genes. Moreover, due to the linkage disequilibrium patterns through the genome, the identified SNPs tag tens to hundreds of highly linked variants that could be the real causal variant/s. However, the combination of genetic data with functional annotation is a useful tool to provide clues for future functional
Shared risk factors: links with other autoimmune diseases
From a biological perspective, ADs show an important overlap of clinical and immunological features. Furthermore, co/poly-autoimmunity, the occurrence of two or more ADs simultaneously in the same individual, is common among AD patients, for example, 25.7% of SSc patients suffer an additional AD [19], [122]. Remarkably, genetic susceptibility loci are common to different ADs [123]. It should be considered that more than 70 genetic regions have been associated with at least two different ADs
Concluding remarks
In the present review, we have revisited the firmest genetic associations with SSc and their possible functional implication in the disease pathogenesis. As commented, the genetic markers for SSc susceptibility are involved in different processes, but there is a clear preponderance of immune response loci, either in the innate or in the adaptive immune compartment. However, well-powered studies including large cohorts and high through-put genotyping platforms have contributed to identify novel
Acknowledgements
The present manuscript was supported by the following grants: Molecular reclassification to find clinically useful biomarkers for systemic autoimmune diseases (PRECISESAD) Innovative Medicines Initiative (IMI) partnership between the European Commission (FP7/2007–2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) (ref: 115565); Identificación de nuevos factores genéticos comunes en enfermedades autoinmunes sistémicas mediante el análisis conjunto de estudios
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