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      Variants in the Promoter Region of HLA-DQA1 were Associated with Idiopathic Membranous Nephropathy in a Chinese Han Population

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          Abstract

          Background:

          Idiopathic membranous nephropathy (IMN) is an autoimmune disease and the leading cause of adult nephritic syndrome. HLA-DQA1 had been identified to be associated with IMN in Europeans and the result was replicated in Chinese Han population. In this study, six single nucleotide polymorphisms (SNPs) in the promoter of HLA-DQA1 and other two SNPs with IgA nephropathy were included for the association analysis.

          Methods:

          The SNPs were genotyped in 509 patients and 601 controls by the MassArray iPLEX. The quantification of anti-phospholipase A2 receptor (PLA2R) antibodies in sera of IMN patients was performed by anti-PLA2R ELISA (IgG) kit.

          Results:

          After analysis, four SNPs were significantly associated with IMN, with rs2187668 and rs28383345 as the top two signals ( P = 8.42×10 -5 and 2.48×10 -5, respectively). Even under dominant model, the two SNPs were still significantly associated with IMN ( P = 3.50×10 -3 for rs28383345 and P = 6.55×10 -5 for rs2187668). After conditional study with rs2187668, rs28383345 was the only variant significantly correlated with IMN after Bonferroni correction ( P = 0.016). The minor alleles of the two SNPs were also mutually exclusive in our cohort. This indicated that the two SNPs were independently associated with IMN in Chinese Han population. Levels of anti-PLA2R autoantibodies were correlated with the genotypes of the two SNPs, but not significantly ( P>0.05).

          Conclusions:

          Our results revealed that a novel independent variant in the promoter of HLA-DQA1 was associated with IMN in Chinese Han population. The locus possessed regulatory role according to the data of RegulomeDB. The exact role of the SNPs on the expression of HLA-DQA1 needs further investigation.

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          Most cited references14

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          Pathophysiological advances in membranous nephropathy: time for a shift in patient's care.

          Membranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults. It is the second or third leading cause of end-stage renal disease in patients with primary glomerulonephritis, and is the leading glomerulopathy that recurs after kidney transplantation (occurring in about 40% of patients). Treatment with costly and potentially toxic drugs remains controversial and challenging, partly because of insufficient insight into the pathogenesis of the disease and absence of sensitive biomarkers of disease activity. The disease is caused by the formation of immune deposits on the outer aspect of the glomerular basement membrane, which contain podocyte or planted antigens and circulating antibodies specific to those antigens, resulting in complement activation. In 2002, podocyte neutral endopeptidase was identified as an antigenic target of circulating antibodies in alloimmune neonatal nephropathy, and in 2009, podocyte phospholipase A2 receptor (PLA2R) was reported as an antigenic target in autoimmune adult membranous nephropathy. These major breakthroughs were translated to clinical practice very quickly. Measurement of anti-PLA2R antibodies in serum and detection of PLA2R antigen in glomerular deposits can now be done routinely. Anti-PLA2R antibodies have high specificity (close to 100%), sensitivity (70-80%), and predictive value. PLA2R detection in immune deposits allows for retrospective diagnosis of PLA2R-related membranous nephropathy in archival kidney biopsies. These tests already have a major effect on diagnosis and monitoring of treatment, including after transplantation.
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            Changing spectrum of biopsy-proven primary glomerular diseases over the past 15 years: a single-center study in China.

            The prevalence of chronic kidney disease (CKD) is reported to be 10.8-11.8% of the Chinese population. With economic development and longer life expectancy, the spectrum of CKD etiology has kept changing. Primary glomerular diseases (PGD) are still the most common renal diseases in China. To investigate the changing pattern of PGD in China, we retrospectively analyzed consecutive native renal biopsies performed in our hospital from 1997 to 2011. The patients were grouped according to a 3-year interval, 1997-1999 (period 1), 2000-2002 (period 2), 2003-2005 (period 3), 2006-2008 (period 4), 2009-2011 (period 5), and divided into three age groups (<20, 20-59, and ≥60 years old). 8,909 qualified cases were enrolled in this study. Among 8,909 specimens, 6,337 (71.13%) were diagnosed as PGD, while this prevalence decreased significantly from 77.61% in 1997-1999 to 66.73% in 2006-2008. IgA nephropathy (IgAN) was the most common PGD (36.66%), without any significant difference in the 5 periods (p = 0.185). IgAN was the most common PGD both in patients between the 20- to 59-year-old group (45.58%) and <20-year-old group (19.29%) as well. Membranous nephropathy (MN) was the most frequently found PGD in patients at age ≥60 years (39.64%). The frequency of MN was increased significantly from 6.48% in 1997-1999 to 22.79% in 2009-2011 (p < 0.001). The proportion of elderly patients increased significantly from 3.18% in 1997-1999 to 15.21% in 2009-2011 (p < 0.001). The prevalence of endocapillary proliferative glomerulonephritis (EnPGN) has decreased since 1997. PGD has remained the most common renal disease in China, although with a descending trend. The spectrum of PGD is different in different age groups. The frequency of EnPGN has decreased significantly, while that of MN has increased significantly.
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              Single Nucleotide Polymorphisms in the Phospholipase A 2 Receptor Gene Are Associated with Genetic Susceptibility to Idiopathic Membranous Nephropathy

              Background: The phospholipase A 2 receptor (PLA2R) is a major antigen found in patients with idiopathic membranous nephropathy (MN). The relationship of genetic polymorphisms of PLA2R with the susceptibility and clinical outcomes of this disease is unknown. Methods: We studied 199 patients with idiopathic MN followed up for 3.7 ± 3.2 years. We enrolled 33 patients with secondary MN and 356 subjects with normal blood pressure and no proteinuria. PLA2R single nucleotide polymorphisms (SNPs) were genotyped. Results: The allele frequencies of C in rs35771982 and G in rs3828323 were 73.6 and 73.9%, respectively. Subjects with the CC genotype in rs35771982 had a higher susceptibility to idiopathic MN compared to subjects with other genotypes (odds ratio 2.6; 95% confidence interval 1.8–4.0). Patients with secondary MN were not different from controls with regard to PLA2R genotype. No impact of genetic polymorphisms on renal survival was detected. Conclusion: The findings of this study suggest that PLA2R SNPs might be associated with the risk of developing MN.
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                Author and article information

                Journal
                Chin Med J (Engl)
                Chin. Med. J
                CMJ
                Chinese Medical Journal
                Medknow Publications & Media Pvt Ltd (India )
                0366-6999
                20 July 2017
                : 130
                : 14
                : 1677-1682
                Affiliations
                [1 ]Department of Medical Laboratory, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110011, China
                [2 ]Department of Blood Transfusion, Tangdu Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710038, China
                [3 ]Department of Medical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
                [4 ]Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing 100005, China
                Author notes
                Address for correspondence: Dr. Xiao-Song Qin, Department of Medical Laboratory, Shengjing Hospital of China Medical University, 36# Sanhao Street, Heping District, Shenyang, Liaoning 110004, China E-Mail: qinxs@ 123456sj-hospital.org
                Article
                CMJ-130-1677
                10.4103/0366-6999.209884
                5520554
                28685717
                5b31a0d4-9736-4e7c-86c0-3cfd3332a8b8
                Copyright: © 2017 Chinese Medical Journal

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                : 04 January 2017
                Categories
                Original Article

                autoimmune disease,hla-dqa1,idiopathic membranous nephropathy,promoter,chinese

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