Elsevier

Journal of Autoimmunity

Volume 64, November 2015, Pages 53-65
Journal of Autoimmunity

Review article
Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways

https://doi.org/10.1016/j.jaut.2015.07.005Get rights and content

Highlights

  • 18 non-HLA genetic loci have been selected as consistent SSc risk factors.

  • We observed that the genetic component of SSc is higher than initially reported by twin studies.

  • Functional annotation may offer a good approach to prioritize causal variants in SSc-associated loci.

  • SSc presents a considerable genetic overlap with other autoimmune diseases such as RA, PBC and especially SLE.

Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous connective tissue disorder of complex etiology. The development of large-scale genetic studies, such as genome-wide association studies (GWASs) or the Immunochip platform, has achieved remarkable progress in the knowledge of the genetic background of SSc. Herein, we provide an updated picture SSc genetic factors, offering an insight into their role in pathogenic mechanisms that characterize the disease. We review the most recent findings in the HLA region and the well-established non-HLA loci. Up to 18 non-HLA risk factors fulfilled the selected criteria and they were classified according to their role in the innate or adaptive immune response, in apoptosis, autophagy or fibrosis. Additionally, SSc heritability has remained as a controversial question since twin studies provided low SSc heritability estimates. However, we have recalculated the lower bond of narrow sense SSc heritability using GWAS data. Remarkably, our results suggest a greater influence of genetics on SSc than previously reported. Furthermore, we also offer a functional classification of SSc-associated SNPs and their proxies, based on annotated data, to provide clues for the identification of causal variants in these loci. Finally, we explore the genetic overlap between SSc and other autoimmune diseases (ADs). The vast majority of SSc risk loci are shared with at least one additional AD, being the overlap between SSc and systemic lupus erythematous the largest. Nevertheless, we found that an important portion of SSc risk factors are also common to rheumatoid arthritis or primary biliary cirrhosis. Considering all these evidences, we are confident that future research will be successful in understanding the relevant altered pathways in SSc and in identifying new biomarkers and therapeutic targets for the disease.

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

References (147)

  • N.M. Levinson et al.

    Structural basis for the recognition of c-Src by its inactivator Csk

    Cell.

    (2008 Jul 11)
  • E. Fiorillo et al.

    Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue

    J. Biol. Chem.

    (2010 Aug 20)
  • C.L. Leonardi et al.

    Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1)

    Lancet

    (2008 May 17)
  • K.A. Papp et al.

    Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2)

    Lancet

    (2008 May 17)
  • P. Gourh et al.

    Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations

    J. Autoimmun.

    (2010 Mar)
  • Y. Errami et al.

    Apoptotic DNA fragmentation may be a cooperative activity between caspase-activated deoxyribonuclease and the poly(ADP-ribose) polymerase-regulated DNAS1L3, an endoplasmic reticulum-localized endonuclease that translocates to the nucleus during apoptosis

    J. Biol. Chem.

    (2013 Feb 1)
  • M. Okamoto et al.

    Involvement of DNase gamma in the resected double-strand DNA breaks in immunoglobulin genes

    Biochem. Biophys. Res. Commun.

    (2005 Feb 4)
  • A. Gabrielli et al.

    Scleroderma

    N. Engl. J. Med.

    (2009 May 7)
  • E.C. LeRoy et al.

    Scleroderma (systemic sclerosis): classification, subsets and pathogenesis

    J. Rheumatol.

    (1988 Feb)
  • M. Elhai, J. Avouac, U.A. Walker, M. Matucci-Cerinic, G. Riemekasten, P. Airo, et al., A gender gap in primary and...
  • M.D. Mayes et al.

    Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population

    Arthritis Rheum.

    (2003 Aug)
  • J.D. Reveille

    Ethnicity and race and systemic sclerosis: how it affects susceptibility, severity, antibody genetics, and clinical manifestations

    Curr. Rheumatol. Rep.

    (2003 Apr)
  • J. Barnes et al.

    Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers

    Curr. Opin. Rheumatol.

    (2012 Mar)
  • F.C. Arnett et al.

    Increased prevalence of systemic sclerosis in a Native American tribe in Oklahoma. Association with an Amerindian HLA haplotype

    Arthritis Rheum.

    (1996 Aug)
  • G.F. Mora

    Systemic sclerosis: environmental factors

    J. Rheumatol.

    (2009 Nov)
  • L.A. Hindorff et al.

    Potential etiologic and functional implications of genome-wide association loci for human diseases and traits

    Proc. Natl. Acad. Sci. U. S. A.

    (2009 Jun 9)
  • D. Welter et al.

    The NHGRI GWAS catalog, a curated resource of SNP-trait associations

    Nucleic Acids Res.

    (2014 Jan)
  • X. Zhou et al.

    HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans

    Arthritis Rheum.

    (2009 Dec)
  • T.R. Radstake et al.

    Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

    Nat. Genet.

    (2010 May)
  • Y. Allanore et al.

    Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis

    PLoS Genet.

    (2011 Jul)
  • M. Parkes et al.

    Genetic insights into common pathways and complex relationships among immune-mediated diseases

    Nat. Rev. Genet.

    (2013 Sep)
  • F.C. Arnett et al.

    Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls

    Ann. Rheum. Dis.

    (2010 May)
  • F.C. Gilchrist et al.

    Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP

    Genes Immun.

    (2001 Apr)
  • L. Beretta et al.

    Analysis of Class II human leucocyte antigens in Italian and Spanish systemic sclerosis

    Rheumatol. Oxf.

    (2012 Jan)
  • B. Vigone et al.

    Role of class II human leucocyte antigens in the progression from early to definite systemic sclerosis

    Rheumatol. Oxf.

    (2015 Apr)
  • S. Raychaudhuri et al.

    Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis

    Nat. Genet.

    (2012 Mar)
  • X. Jia et al.

    Imputing amino acid polymorphisms in human leukocyte antigens

    PLoS One

    (2013)
  • S. Eyre et al.

    High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

    Nat. Genet.

    (2012 Dec)
  • M.J. Ombrello et al.

    Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

    Proc. Natl. Acad. Sci. U. S. A.

    (2014 Jun 17)
  • L.B. Ivashkiv et al.

    Regulation of type I interferon responses

    Nat. Rev. Immunol.

    (2014 Jan)
  • M. Wu et al.

    The role of type 1 interferon in systemic sclerosis

    Front. Immunol.

    (2013)
  • I. Ito et al.

    Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese population

    Arthritis Rheum.

    (2009 Jun)
  • P. Dieude et al.

    Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis

    Arthritis Rheum.

    (2009 Jan)
  • P. Dieude et al.

    Phenotype-haplotype correlation of IRF5 in systemic sclerosis: role of 2 haplotypes in disease severity

    J. Rheumatol.

    (2010 May)
  • F.D. Carmona et al.

    The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

    PLoS One

    (2013)
  • L.C. Kottyan et al.

    The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

    Hum. Mol. Genet.

    (2015 Jan 15)
  • R. Sharif et al.

    IRF5 polymorphism predicts prognosis in patients with systemic sclerosis

    Ann. Rheum. Dis.

    (2012 Jul)
  • O. Gorlova et al.

    Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy

    PLoS Genet.

    (2011 Jul)
  • M. Arismendi et al.

    Identification of NF-kappaB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis

    Arthritis Res. Ther.

    (2015)
  • F.D. Carmona et al.

    Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis

    Ann. Rheum. Dis.

    (2012 Jan)
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