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Axial Spondyloarthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
The genome wide association studies era has resulted in good evidence for a number of new genetic associations across the SpA spectrum. Prior to 2010, many of the genetics of AxSpA publications were largely focused on HLA-B27 and variants, but since 2010, a number of new genetic associations have been further elucidated, including ERAP1, ERAP2, and IL23 receptor and MEFV.46, 47 These associations are particularly with radiographic AxSpA or AS. Most of these studies have been conducted in White patient populations of European descent and some in the East Asian population. Few large studies have examined genetic associations, beyond HLA-B27, within nrAxSpA.48, 49
Single nucleotide polymorphisms and pregnancy complications
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Federica Tarquini, Giuliana Coata, Elena Picchiassi, Gian Carlo Di Renzo
It has been recognized for many years that preeclampsia has different genetic components (22). Susceptibility genes at the 5q gene locus were also centered on a spectrum of families in a Norwegian preeclampsia cohort (1,139 cases and 2,269 controls) using SNP genotyping. There was also evidence of a genetic association with preeclampsia for the endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and 2) genes. The ERAP1 and ERAP2 genes encode enzymes that play roles in blood pressure regulation via involvement of the renin-angiotensin system in addition to the innate immune system (23). A variety of genes are involved which also interact. The mechanisms are very complicated. Gene variants in the Fas receptor, the VEGF gene, and the coagulation factor V Leiden mutation are associated with increased risk of the hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome compared to healthy women. Variants in the Bell polymorphism and the TLR-4 increased the risk of HELLP significantly more than the risk of preeclampsia (24).
Genetics
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
Of the over 50 GWA loci identified to date (Table 4.1), a large number affect innate immunity. These include responses involving NF-κB signaling (TRAF3IP2,63TNFAIP3, TNIP1, NF-KBIA [IKBA], REL, COMMD1,64 CARD14); differentiation of T-helper 17 cells (IL23R, IL12B, IRF4, IL23A); and antigen processing, recognition, and response (HLA-C, ERAP1, ERAP2). There are also associations with genes playing important roles in the epidermis (LCE3, GJB2).65 Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) correlations also revealed significant findings with the genes encoding components of the JAK-STAT (signal transducer and sctivator) signaling pathway (IL28RA, IL23R, IL13, IL12B, IL23A, STAT2, SOCS1, STAT3, TYK2) and defense response to Gram-negative bacteria or viruses/RIG-1-like receptor signaling (IL-23R, IL-12B, IL-23A, NOS2, IFIH1, DDX58, NF-KBIA, IL-23R).
ERAP1: a potential therapeutic target for a myriad of diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Emma Reeves, Yasmin Islam, Edward James
ERAP1 and ERAP2 are prominent risk factors for MHC I associated autoimmune and autoinflammatory diseases, as well as hypertension, viral infection and cancer (reviewed in [2,50]). In autoimmune conditions, the epistasis of ERAP1 with specific HLA alleles, HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29 in Ankylosing Spondylitis (AS), Behçet’s Disease (BD), Psoriasis and Birdshot Chorioretinopathy (BC) respectively, demonstrates a strong genetic influence [50]. Many of these disease associations are linked to the expression of natural polymorphic variants of ERAP1 and ERAP2 and will be discussed in more detail below. These associations suggest peptide handling and the generation of peptides by ERAP1 influences susceptibility to HLA associated diseases, and that MHC I bound peptides are highly relevant in their pathogenesis. Many studies to date have focussed on the link between ERAP1 polymorphism, HLA allele expression and autoimmune conditions, and efforts have centered around elucidation of the pathogenic mechanisms, in particular in AS. These studies have been extensively reviewed in [2,3,50–52].
Lack of Associations between Endoplasmic Reticulum Aminopeptidase 2 Gene Polymorphisms and Ankylosing Spondylitis: A Meta-analysis with Trial Sequential Analysis
Published in Immunological Investigations, 2022
Shutao Gao, Tao Xu, Chao Mao, Jie Cheng, Chuanhui Xun, Weidong Liang, Weibin Sheng
Endoplasmic reticulum aminopeptidase 2 (ERAP2) belongs to the M1 zinc metallopeptidases family (Yao et al. 2019). It is expressed in various human tissues and has substantial sequence homology with ERAP1, which is linked to an increased risk of AS (Gao et al. 2020). Inside the endoplasmic reticulum, ERAP2 plays a crucial role in trimming the N-terminal of the antigenic precursors into a suitable length and sequences for loading onto MHC-I molecules (Haroon and Inman 2010; Hattori and Tsujimoto 2013). This is a key step in inflammation- and immune-related signaling pathways. In addition to antigen presentation, ERAP2 is also involved in various biological processes and pathogenic conditions (Hattori and Tsujimoto 2013).
Association study of polymorphisms of endoplasmic reticulum aminopeptidase 1 gene with preeclampsia in Chinese populations
Published in Clinical and Experimental Hypertension, 2021
Cui Ma, Yuanyuan Zheng, Xiaowei Liu, Weiyuan Zhang
Endoplasmic reticulum aminopeptidase-1 and 2 (ERAP-1, ERAP-2) trim peptides to a length of 8–10 amino acids optimal for binding by HLA class I molecules (5). Although these two enzymes may work separately, they may also form a heterodimer to enhance trimming efficiency. The protein encoded by ERAP-1 acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by the inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene (6). The ERAP-1 allele is associated with a variety of human diseases, including autoimmune ankylosing spondylitis (AS) (7), Betch’s disease (8), psoriasis (9), liver fibrosis (5), and hypertension (10). Johnson et al. reported a novel preeclampsia risk locus, ERAP-2, in a region of known genetic linkage to this pregnancy-specific disorder in Australian and Norwegian populations (11). Moreover, Hill found an association between fetal ERAP-2 and preeclampsia in an African American population (12). ERAP-1 and 2 are involved in blood pressure regulation by the renin-angiotensin-aldosterone pathway. In vitro investigations have demonstrated that the ERAP-1 enzyme is efficiently involved in cleaving and inactivation of angiotensin II, plus its converting potential of kallidin to bradykinin (13). Due to the critical role of angiogenesis disorder and immune imbalance in the pathogenesis of preeclampsia, it is reasonably hypothesized that ERAP-1 is involved in the occurrence of preeclampsia. One recent study demonstrated that overexpression of ERAP-1 was observed in preeclampsia. Besides, the hypoxia could increase the expression of ERAP-1, which in turn contributed to the development of PE. These discoveries shed light on the role of ERAP-1 in PE pathogenesis (14). Furthermore, a study showed four haplotypes of ACGACTT, GTCAGGA, ACGACGT, and GTGACTT of single nucleotide polymorphisms (SNPs) of ERAP-1 and 2 genes were associated with preeclampsia in Iranian Women (15).