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Maria Carmela Padula, Pietro Leccese, Nancy Lascaro, Teresa Carbone, Michele Gilio, Angela Anna Padula, Giuseppe Martelli, Salvatore D'Angelo
The endoplasmic reticulum aminopeptidase protein 1 gene (ERAP1) is related to several human diseases, including Behçet syndrome (BS), a multisystemic disorder with unknown etiology. ERAP1 is involved in immune response and its role can be influenced by gene single nucleotide variations (SNVs). We genotyped the ERAP1 whole structure in 50 consecutive BS patients and 50 ethnically-matched healthy controls using both bioinformatics and molecular methodologies. We identified two novel heterozygous missense SNVs of ERAP1 exon3 responsible for the p...
February 8, 2019: Human Immunology
Maryam Hemmatzadeh, Farhad Babaie, Fatemeh Ezzatifar, Fatemeh S Mohammadi, Mehrdad Ebrazeh, Shirin Golabi Aghdam, Mehrzad Hajaliloo, Gholamreza Azizi, Arezoo Gowhari Shabgah, Najibeh Shekari, Nasrin Sehati, Ramin Hosseinzadeh, Hamed Mohammadi, Zohreh Babaloo
AIM: To evaluate the association of ERAP1 gene single nucleotide polymorphisms (SNPs) with the risk of ankylosing spondylitis (AS) and their role in modulation of the inflammatory interleukin (IL)-17/IL-23 axis in the disease. METHODS: For genotyping, 190 AS cases and 190 healthy controls were enrolled. After DNA extraction, all the subjects were genotyped for rs17482078, rs469876, and rs27038 polymorphisms using single specific primer polymerase chain reaction (PCR) assay...
February 10, 2019: International Journal of Rheumatic Diseases
Fabiana Paladini, Maria Teresa Fiorillo, Valentina Tedeschi, Alberto Cauli, Alessandro Mathieu, Rosa Sorrentino
The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B* 2706 in Asia and the HLA-B* 2709 in Sardinia, have not been found to be associated with AS. The highly homogenous genetic structure of the Sardinian population has favored the search of relevant variants for disease-association studies. Moreover, malaria, once endemic in the island, has been shown to have contributed to shape the native population genome affecting the relative allele frequency of relevant genes...
2019: Frontiers in Immunology
Satoshi Watanabe, Yuta Amagai, Sara Sannino, Tiziana Tempio, Tiziana Anelli, Manami Harayama, Shoji Masui, Ilaria Sorrentino, Momo Yamada, Roberto Sitia, Kenji Inaba
Zinc ions (Zn2+ ) are imported into the early secretory pathway by Golgi-resident transporters, but their handling and functions are not fully understood. Here, we show that Zn2+ binds with high affinity to the pH-sensitive chaperone ERp44, modulating its localization and ability to retrieve clients like Ero1α and ERAP1 to the endoplasmic reticulum (ER). Silencing the Zn2+ transporters that uptake Zn2+ into the Golgi led to ERp44 dysfunction and increased secretion of Ero1α and ERAP1. High-resolution crystal structures of Zn2+ -bound ERp44 reveal that Zn2+ binds to a conserved histidine-cluster...
February 5, 2019: Nature Communications
Wanda Niepiekło-Miniewska, Anastasia Mpakali, Efstratios Stratikos, Łukasz Matusiak, Joanna Narbutt, Aleksandra Lesiak, Piotr Kuna, Karolina Wilczyńska, Izabela Nowak, Andrzej Wiśniewski, Katarzyna Zwolińska, Joanna Ponińska, Rafał Płoski, Jacek C Szepietowski, Piotr Kuśnierczyk
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease of complex etiology, with interactions between susceptibility genes and environmental factors. We have previously described a protective effect of the KIR2DS1 gene encoding the NK cell receptor, whose ligands are HLA-C molecules. Here, we found an association of HLA-C*05:01 allele with AD. KIR-HLA-C interactions are affected by peptides presented by HLA-C. The generation of these peptides is strongly influenced by endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2)...
January 25, 2019: Journal of the European Academy of Dermatology and Venereology: JEADV
Adeline Ruyssen-Witrand, Cécile Luxembourger, Alain Cantagrel, Delphine Nigon, Pascal Claudepierre, Yannick Degboe, Arnaud Constantin
BACKGROUND: To investigate the association between 12 single nucleotide polymorphisms (SNPs) located on ERAP1 and IL23R with the presence of inflammation on the sacroiliac joint (SIJ) or spinal magnetic resonance imagery (MRI) in an early onset spondyloarthritis (SpA) cohort. METHODS: All the patients included in the DESIR cohort with an axial SpA and available DNA at baseline were enrolled in this study (n = 645 patients) and underwent a clinical examination, CRP assay, SIJ and spinal MRI scans...
January 15, 2019: Arthritis Research & Therapy
Yohei Kirino, Hideaki Nakajima
Patients with Behçet's disease (BD) suffer from episodic ocular and mucocutaneous attacks, resulting in a reduced quality of life. The phenotype of Japanese BD has been changing over the past 20 years, and the rate of HLA-B*51-positive complete type is decreasing while that of intestinal type is increasing. This phenotypical evolution may be related to changes in as-yet-unknown environmental factors, as the immigration influx in Japan is low. Mechanisms discovered by genome-wide association studies include ERAP1-mediated HLA class I antigen bounding pathway, autoinflammation, Th17 cells, natural killer cells, and polarized macrophages, a similar genetic architecture to Crohn's disease, ankylosing spondylitis, and psoriasis...
January 10, 2019: Internal Medicine
Nick Dand, Michael Duckworth, David Baudry, Alice Russell, Charles J Curtis, Sang Hyuck Lee, Ian Evans, Kayleigh J Mason, Ali Alsharqi, Gabrielle Becher, A David Burden, Richard G Goodwin, Kevin McKenna, Ruth Murphy, Gayathri K Perera, Radu Rotarescu, Shyamal Wahie, Andrew Wright, Nick J Reynolds, Richard B Warren, Christopher E M Griffiths, Catherine H Smith, Michael A Simpson, Jonathan N Barker
BACKGROUND: Biologic therapies can be highly effective for the treatment of severe psoriasis but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection could improve patient outcomes and treatment cost-effectiveness. OBJECTIVE: We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the two most commonly prescribed biologics for psoriasis, adalimumab (anti-TNFα) and ustekinumab (anti-IL12/23)...
December 19, 2018: Journal of Allergy and Clinical Immunology
Mahdi Mahmoudi, Amir Ashraf-Ganjouei, Ali Javinani, Farhad Shahram, Akira Meguro, Nobuhisa Mizuki, Nooshin Ahmadzadeh, Saeideh Jafarinejad-Farsangi, Shayan Mostafaei, Hoda Kavosi, Seyedeh Tahereh Faezi, Maassoumeh Akhlaghi, Fereydoun Davatchi
Behçet's Disease (BD) pathogenesis remains unclear, but some genetic loci and environmental factors are proposed to play a role. Here, we investigate the association of the endoplasmic reticulum aminopeptidase-1 (ERAP1) gene variants and HLA-B*51 with BD susceptibility and clinical manifestations in Iranian patients. In the study, 748 BD patients and 776 healthy individuals were included. The MGB-TaqMan Allelic Discrimination method was used to genotype 10 common missense single nucleotide polymorphisms (SNPs) and one intronic SNP in the ERAP1 gene region...
December 4, 2018: Scientific Reports
Yuqing Jiang, Yi Ren, Dong Zhou, Youjia Xu
BACKGROUND: The genetic factor is importantly enrolled in the pathogenesis of ankylosing spondylitis (AS) and haplotype leukocyte antigen (HLA)-B27 is the most well-known. However, only 1% to 5% of B27-positive individuals will develop AS, and it confers only 20% to 30% of the overall genetic risks, indicating more genes other than HLA-B27 may play important roles in AS pathologies. The present study aims to investigate whether the polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) is associated with increased risk of AS susceptibility...
November 2018: Medicine (Baltimore)
José A López de Castro
Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A* 29:02), ankylosing spondylitis (HLA-B* 27), Behçet's disease (HLA-B* 51), and psoriasis (HLA-C* 06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role...
2018: Frontiers in Immunology
Aimee L Hanson, Craig J Morton, Michael W Parker, Darrell Bessette, Tony J Kenna
The oxytocinase subfamily of M1 aminopeptidases plays an important role in processing and trimming of peptides for presentation on major histocompatibility (MHC) Class I molecules. Several large-scale genomic studies have identified association of members of this family of enzymes, most notably ERAP1 and ERAP2, with immune-mediated diseases including ankylosing spondylitis, psoriasis and birdshot chorioretinopathy. Much is now known about the genetics of these enzymes and how genetic variants alter their function, but how these variants contribute to disease remains largely unresolved...
November 9, 2018: Human Immunology
Farhad Babaie, Mehrdad Ebrazeh, Maryam Hemmatzadeh, Fatemeh Sadat Mohammadi, Arezoo Gowhari Shabgah, Mehrzad Hajaliloo, Ali Asghar Ebrahimi, Naghmeh Shirafkan, Gholamreza Azizi, Hamed Mohammadi, Zohreh Babaloo
Background Ankylosing spondylitis (AS) is a debilitating spondyloarthropathy that has been associated with variation in several genes. Human leukocyte antigen (HLA)-B27 constructs an impaired structure, culminating in recognition and activation of immune system. Impaired function of Endoplasmic reticulum aminopeptidase (ERAP) 1, which primes peptides to be loaded in HLA molecules, has strongly been associated with AS proneness. Here, we intended to investigate the possible association of ERAP1 gene single nucleotide polymorphisms (SNPs) with AS susceptibility in Iranian patients...
November 6, 2018: Immunology Letters
Yoshikuni Goto, Takahiro J Nakamura, Kenji Ogawa, Akira Hattori, Masafumi Tsujimoto
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a multi-functional enzyme. In this study, we analyzed its role in lipopolysaccharide-induced inflammatory response in wild-type and ERAP1-knockout mice. Following lipopolysaccharide injection, ERAP1 was secreted into the blood, increasing leucine aminopeptidase activity and NO synthesis therein. Among the amino acids tested, arginine concentration was significantly increased in wild-type mice compared to ERAP1-knockout mice. These results suggest that ERAP1 behaves similar to acute-phase proteins, which are secreted into the blood in response to infectious/inflammatory stimuli and are involved in enhancing NO synthesis as a host defense mechanism...
October 26, 2018: Journal of Biochemistry
Arash Salmaninejad, Mohammad Reza Zamani, Arezoo Gowhari Shabgah, Seyedmojtaba Hosseini, Fatemeh Mollaei, Nayyerehalsadat Hosseini, Amirhossein Sahebkar
Behçet's disease (BD) is a chronic and rare multisystemic disorder defined by autoimmunity and inflammatory characteristics, manifested by ocular lesions, recurrent genital and oral ulcers, skin symptoms and arthritis as well as neurological, intestinal, and vascular involvement. Despite the unknown cause of BD, there is some strong documentation for immunological, genetic, environmental, and infectious factors playing a role in the pathogenesis of BD. While the nature of the genetic variants remains unidentified, many genetic risk factors are considered to contribute to BD susceptibility...
October 20, 2018: Journal of Cellular Physiology
Yanjie Fu, Xiuyan Li, Yuanzheng Chen, Rongpeng Liu, Renheng Wang, Nan Bai
Psoriasis vulgaris (PsV), also known as plaque psoriasis, is a life-threatening autoimmune skin disease. Inflammatory factors may contribute to the development of PsV. Present study aimed to explore the association of endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms (rs26653 and rs27524) with PsV susceptibility in a Chinese Han population. Subgroup analysis was also performed based on the onset of PsV.Present case-control study included 143 patients with PsV and 149 healthy controls. Direct sequencing method was used for genotyping ERAP1 polymorphisms...
October 2018: Medicine (Baltimore)
Jonas J W Kuiper, Jessica van Setten, Matthew Devall, Mircea Cretu-Stancu, Sanne Hiddingh, Roel A Ophoff, Tom O A R Missotten, Mirjam van Velthoven, Anneke I Den Hollander, Carel B Hoyng, Edward James, Emma Reeves, Miguel Cordero-Coma, Alejandro Fonollosa, Alfredo Adán, Javier Martín, Bobby P C Koeleman, Joke H de Boer, Sara L Pulit, Ana Márquez, Timothy R D J Radstake
Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed 'MHC-I (major histocompatibility complex class I)-opathy' family. Genetic studies have pinpointed the endoplasmic reticulum aminopeptidase (ERAP1) and (ERAP2) genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls...
December 15, 2018: Human Molecular Genetics
Kazuma Aoki, Akemi Furuya, Ken Matsumoto, Masafumi Tsujimoto
Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a multifunctional enzyme belonging to the M1 family of aminopeptidases and shown to be associated with various autoimmune diseases. Human ERAP1 protein has two isoforms produced by alternative splicing of the 3' terminal exon, although their functional differences have not yet been fully clarified. In this study, we showed that the isoforms undergo different posttranscriptional regulation mechanisms via their respective 3' untranslated regions. Using a reporter system, we identified several cis-elements that are important for the regulation of alternative splicing...
September 18, 2018: Biochemical and Biophysical Research Communications
Yuliya Pepelyayeva, David P W Rastall, Yasser A Aldhamen, Patrick O'Connell, Sandra Raehtz, Fadel S Alyaqoub, Maja K Blake, Ashley M Raedy, Ariana M Angarita, Abdulraouf M Abbas, Cristiane N Pereira-Hicks, Sarah G Roosa, Laura McCabe, Andrea Amalfitano
Ankylosing spondylitis (AS) is a prototypical sero-negative autoimmune disease that affects millions worldwide. Single nucleotide polymorphisms in the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) gene have been linked to AS via GWAS studies, however, the exact mechanism as to how ERAP1 contributes to pathogenesis of AS is not understood. We undertook µCT imaging and histologic analysis to evaluate bone morphology of the axial skeletons of ERAP1-/- mice and discovered the hallmark skeletal features of AS in these mice, including spinal ankylosis, osteoporosis, and spinal inflammation...
August 20, 2018: Scientific Reports
Emma Reeves, Edward James
Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology; however, they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions...
September 3, 2018: Bioscience Reports
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