Elsevier

Human Immunology

Volume 80, Issue 5, May 2019, Pages 325-334
Human Immunology

Influence of ERAP1 and ERAP2 gene polymorphisms on disease susceptibility in different populations

https://doi.org/10.1016/j.humimm.2019.02.011Get rights and content

Abstract

The endoplasmic reticulum aminopeptidases (ERAPs), ERAP1 and ERAP2, makes a role in shaping the HLA class I peptidome by trimming peptides to the optimal size in MHC-class I-mediated antigen presentation and educating the immune system to differentiate between self-derived and foreign antigens. Association studies have shown that genetic variations in ERAP1 and ERAP2 genes increase susceptibility to autoimmune diseases, infectious diseases, and cancers. Both ERAP1 and ERAP2 genes exhibit diverse polymorphisms in different populations, which may influence their susceptibly to the aforementioned diseases. In this article, we review the distribution of ERAP1 and ERAP2 gene polymorphisms in various populations; discuss the risk or protective influence of these gene polymorphisms in autoimmune diseases, infectious diseases, and cancers; and highlight how ERAP genetic variations can influence disease associations.

Section snippets

ERAPs play an important role in the antigen presentation process

An important part of the human immune system is the presentation of endogenous peptides by major histocompatibility complex (MHC) class I molecules to CD8+ T cells. This educates the immune system to differentiate between self-derived and foreign antigens, resulting in the clearance of infected or tumor cells. This presentation process is the result of a series of reactions: 1) antigens are degraded in the cytosol into peptide precursors by the proteasome; 2) these precursors translocate, via

Polymorphisms of the ERAP1 gene in different populations

Since the genetic diversity of different ethnicities may contaminate the disease association results, we collected all the SNPs that were reported to be associated with autoimmune disease, infectious disease, and cancer, and compared their distributions across several ethnicities: African (AFR), Admixed American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS) (https://www.ncbi.nlm.nih.gov/snp/?termā€Æ=ā€ÆERAP1). Some polymorphic variation distal from the active site of ERAP1 can

Association of ERAP1 alleles and genotypes with autoimmune diseases

In 2007, a genome-wide association study (GWAS) of autoimmune diseases conducted by the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium reported the association of ERAP1 with ankylosing spondylitis (AS) [30]. Then, Australo-Anglo-American Spondyloarthritis C et al. confirmed this result [31]. Studies have indicated that ERAP1 SNPs may influence the creation of antigen-derived peptides for presentation to the immune system, shedding light on the

Conclusion

ERAP is a critical component of the MHC class I antigen presentation and processing complex. ERAPs makes a role in shaping the HLA class I peptidome by trimming peptides to the optimal size for the generation of a proper adaptive immune response. The following are the major conclusions from our review: ā‘  The population differences in genetic structure may influence the disease process at both the SNP and haplotype level. ā‘” The SNP risk alleles that encode the enzymatic activity of ERAP and

Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (31570918, 81573206), Yunnan Applied Basic Research Projects (2016FA034) and the Special Funds for High-Level Health Talents of Yunnan Province (D-201669 and L-201615).

Conflicts of interest

The authors declare that there are no conflicting interests.

References (110)

  • A. Das et al.

    Associations of ERAP1 coding variants and domain specific interaction with HLA-C *06 in the early onset psoriasis patients of India

    Hum. Immunol.

    (2017)
  • J. Lysell et al.

    Genetic association with ERAP1 in psoriasis is confined to disease onset after puberty and not dependent on HLA-C*06

    J, Invest. Dermatol.

    (2013)
  • B. Su et al.

    Y-Chromosome evidence for a northward migration of modern humans into Eastern Asia during the last Ice Age

    Am. J. Hum. Genet.

    (1999)
  • S. Liu et al.

    The ERAP gene is associated with HCV chronic infection in a Chinese Han population

    Hum. Immunol.

    (2017)
  • T.G. Tan et al.

    Identification of T. gondii epitopes, adjuvants, and host genetic factors that influence protection of mice and humans

    Vaccine

    (2010)
  • C. Alvarez-Navarro et al.

    Lopez de Castro JA: Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen

    Mol. Cell. Proteom.

    (2015)
  • J. Neefjes et al.

    Towards a systems understanding of MHC class I and MHC class II antigen presentation

    Nat. Rev. Immunol.

    (2011)
  • J.M. Vyas et al.

    The known unknowns of antigen processing and presentation

    Nat. Rev. Immunol.

    (2008)
  • T. Saric et al.

    An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides

    Nat. Immunol.

    (2002)
  • L. Saveanu et al.

    Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum

    Nat. Immunol.

    (2005)
  • E. Reeves et al.

    Naturally occurring ERAP1 haplotypes encode functionally distinct alleles with fine substrate specificity

    J. Immunol.

    (2013)
  • S.C. Chang et al.

    The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a ā€œmolecular rulerā€ mechanism

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

    (2005)
  • T. Serwold et al.

    ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum

    Nature

    (2002)
  • A. Hattori et al.

    Endoplasmic reticulum aminopeptidases: biochemistry, physiology and pathology

    J. Biochem.

    (2013)
  • A. Hattori et al.

    Molecular cloning of adipocyte-derived leucine aminopeptidase highly related to placental leucine aminopeptidase/oxytocinase

    J. Biochem.

    (1999)
  • G. Kochan et al.

    Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

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

    (2011)
  • A. Gandhi et al.

    Structural insights into the molecular ruler mechanism of the endoplasmic reticulum aminopeptidase ERAP1

    Sci. Rep.

    (2011)
  • A. Hattori et al.

    Genomic organization of the human adipocyte-derived leucine aminopeptidase gene and its relationship to the placental leucine aminopeptidase/oxytocinase gene

    J. Biochem.

    (2001)
  • A.L. Hanson et al.

    Genetic variants in ERAP1 and ERAP2 associated with immune-mediated diseases influence protein expression and the isoform profile

    Arthritis Rheumatol.

    (2018)
  • J.R. Birtley et al.

    The crystal structure of human endoplasmic reticulum aminopeptidase 2 reveals the atomic basis for distinct roles in antigen processing

    Biochemistry

    (2012)
  • A. Hearn et al.

    The specificity of trimming of MHC class I-presented peptides in the endoplasmic reticulum

    J. Immunol.

    (2009)
  • I. Evnouchidou et al.

    ERAP1-ERAP2 dimerization increases peptide-trimming efficiency

    J. Immunol.

    (2014)
  • I. Evnouchidou et al.

    Cutting edge: coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme

    J. Immunol.

    (2011)
  • I. Evnouchidou et al.

    A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing

    J. Immunol.

    (2012)
  • E. Zervoudi et al.

    Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides

    Biochem. J.

    (2011)
  • R. Cagliani et al.

    Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV-1 infection

    Hum. Mol. Genet.

    (2010)
  • R. Cagliani et al.

    Balancing selection is common in the extended MHC region but most alleles with opposite risk profile for autoimmune diseases are neutrally evolving

    BMC Evol. Biol.

    (2011)
  • A.M. Andres et al.

    Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation

    PLoS Genet.

    (2010)
  • D. Forni et al.

    An evolutionary analysis of antigen processing and presentation across different timescales reveals pervasive selection

    PLoS Genet.

    (2014)
  • Wellcome Trust Case Control C et al.

    Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

    Nat. Genet.

    (2007)
  • C. Australo-Anglo-American Spondyloarthritis et al.

    Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

    Nat. Genet.

    (2010)
  • D.M. Evans et al.

    Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

    Nat. Genet.

    (2011)
  • D.L. Vanhille et al.

    A novel ERAP2 haplotype structure in a chilean population: implications for ERAP2 protein expression and preeclampsia risk

    Mol. Genet. Genom. Med.

    (2013)
  • L.D. Hill et al.

    Fetal ERAP2 variation is associated with preeclampsia in African Americans in a case-control study

    BMC Med. Genet.

    (2011)
  • D. Harvey et al.

    A common functional variant of endoplasmic reticulum aminopeptidase 2 (ERAP2) that reduces major histocompatibility complex class I expression is not associated with ankylosing spondylitis

    Rheumatology (Oxford)

    (2011)
  • M. Biasin et al.

    Endoplasmic reticulum aminopeptidase 2 haplotypes play a role in modulating susceptibility to HIV infection

    AIDS

    (2013)
  • J.J. Kuiper et al.

    A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy

    Hum. Mol. Genet.

    (2014)
  • L. Zhou et al.

    Combination of genetic markers and age effectively facilitates the identification of people with high risk of preeclampsia in the Han Chinese population

    Biomed Res. Int.

    (2018)
  • P. Castro-Santos et al.

    ERAP1 and HLA-C interaction in inflammatory bowel disease in the Spanish population

    Innate Immun.

    (2017)
  • J.J.W. Kuiper et al.

    Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

    Hum. Mol. Genet.

    (2018)
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