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      Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

      research-article
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      Journal of the American Society of Nephrology : JASN
      American Society of Nephrology
      GWAS, SSNS, HLA, CALHM6, FAM26F

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          Significance Statement

          Although steroid-sensitive nephrotic syndrome (SSNS) is considered an autoimmune disease, its etiology is poorly understood. Genome-wide association studies (GWAS) have provided important insights into other autoimmune diseases, but so far, such studies have reported associations only in the classical HLA region for SSNS. In a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls, the authors found two loci outside the HLA region associated with SSNS at genome-wide significance. The locus with strongest association contains the calcium homeostasis modulator family member 6 gene CALHM6, which has been implicated in the regulation of the immune system. These findings suggest that impaired downregulation of the immune system may be a key mechanism in the pathogenesis of SSNS.

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          Abstract

          Background

          Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.

          Methods

          In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.

          Results

          The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10 −43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10 −17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.

          Conclusions

          Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

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          Most cited references22

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          • Abstract: found
          • Article: not found

          Minimal Change Disease.

          Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.
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            • Record: found
            • Abstract: found
            • Article: not found

            Idiopathic nephrotic syndrome in children

            The incidence of idiopathic nephrotic syndrome (NS) is 1·15-16·9 per 100 000 children, varying by ethnicity and region. The cause remains unknown but the pathogenesis of idiopathic NS is thought to involve immune dysregulation, systemic circulating factors, or inherited structural abnormalities of the podocyte. Genetic risk is more commonly described among children with steroid-resistant disease. The mainstay of therapy is prednisone for the vast majority of patients who are steroid responsive; however, the disease can run a frequently relapsing course, necessitating the need for alternative immunosuppressive agents. Infection and venous thromboembolism are the main complications of NS with also increased risk of acute kidney injury. Prognosis in terms of long-term kidney outcome overall is excellent for steroid-responsive disease, and steroid resistance is an important determinant of future risk of chronic or end-stage kidney disease.
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              • Record: found
              • Abstract: found
              • Article: not found

              Pathogenesis of lipoid nephrosis: a disorder of T-cell function.

              J Shalhoub (1974)
              Clinical observations suggest that lipoid nephrosis is produced by a systemic abnormality of T-cell function resulting in the secretion of a circulating chemical mediator toxic to an immunologically innocent glomerular basement membrane. The lack of evidence of a humoral antibody response, remission induced by measles which modifies cell-mediated immunity, the therapeutic benefits of steroids and cyclophosphamide which also abate cell-mediated responses, and the occurrence of this syndrome in Hodgkin's disease support this hypothesis. The susceptibility of untreated patients to pneumococcal infections may be of primary or secondary pathogenetic importance. Taken together, the data suggest that this syndrome is a clinical expression of a self-limited primary immune-deficiency disease.
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                Author and article information

                Journal
                J Am Soc Nephrol
                J. Am. Soc. Nephrol
                jnephrol
                jnephrol
                ASN
                Journal of the American Society of Nephrology : JASN
                American Society of Nephrology
                1046-6673
                1533-3450
                August 2019
                01 July 2019
                : 30
                : 8
                : 1375-1384
                Affiliations
                [1 ]Department of Renal Medicine and
                [10 ]University College London Genomics, Institute of Child Health, University College London, London, United Kingdom;
                [2 ]Great Ormond Street Hospital, London, United Kingdom;
                [3 ]University Hospitals Leuven and University of Leuven, Leuven, Belgium;
                [4 ]Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands;
                [5 ]Department of Genetics, UMC Groningen, Groningen, The Netherlands;
                [6 ]Department of Pediatric Nephrology, Erasmus University Medical Centre–Sophia Children’s Hospital, Rotterdam, The Netherlands;
                [7 ]Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia;
                [8 ]Department of Paediatrics, University of Peradeniya, Peradeniya, Sri Lanka;
                [9 ]NHGRI, National Institutes of Health, Bethesda, Maryland;
                [11 ]Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina; and
                [12 ]Department of Paediatric Nephrology and
                [13 ]NIHR Manchester Clinical Research Facility, Manchester Academic Health Science Centre, Royal Manchester Children’s Hospital, Manchester, United Kingdom
                Author notes

                S.D., C.C., A.P.L., R.S.T., D.P.G., H.C.S., R.K., and D.B. contributed equally to this work.

                Correspondence: Dr. Robert Kleta or Dr. Detlef Bockenhauer, University College London Department of Renal Medicine, Rowland Hill Street, London NW3 2PF, United Kingdom. Email: r.kleta@ 123456ucl.ac.uk or d.bockenhauer@ 123456ucl.ac.uk
                Author information
                https://orcid.org/0000-0001-5641-6644
                https://orcid.org/0000-0002-9170-1579
                https://orcid.org/0000-0002-0228-8656
                https://orcid.org/0000-0001-5878-941X
                Article
                PMC6683715 PMC6683715 6683715 2018101054
                10.1681/ASN.2018101054
                6683715
                31263063
                dd19325e-c9ba-440b-8dfd-5733c0e38ad5
                Copyright © 2019 by the American Society of Nephrology
                History
                : 28 October 2018
                : 22 April 2019
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 37, Pages: 10
                Funding
                Funded by: Kids Kidney Research https://doi.org/10.13039/501100000405
                Funded by: Kidney Research UK https://doi.org/10.13039/501100000291
                Funded by: King Abdulaziz University https://doi.org/10.13039/501100004054
                Award ID: 432/003/d
                Funded by: National Institutes of Health https://doi.org/10.13039/100000002
                Funded by: National Institutes of Diabetes and Digestive and Kidney Diseases https://doi.org/10.13039/100000062
                Award ID: 5R01DK098135
                Award ID: 5R01DK094987
                Funded by: Doris Duke Charitable Foundation https://doi.org/10.13039/100000862
                Funded by: St. Peter’s Trust for Kidney, Bladder & Prostate Research https://doi.org/10.13039/501100000388
                Funded by: Kidney Research UK https://doi.org/10.13039/501100000291
                Funded by: Rosetrees Trust https://doi.org/10.13039/501100000833
                Funded by: David and Elaine Potter Foundation https://doi.org/10.13039/100014001
                Categories
                Basic Research
                Custom metadata
                August 2019

                CALHM6,FAM26F,HLA,SSNS,GWAS
                CALHM6, FAM26F, HLA, SSNS, GWAS

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