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

      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

      Journal of the American Society of Nephrology

      American Society of Nephrology (ASN)

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          Abstract

          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. 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. 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. 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 . 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 references 22

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          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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            The MHC, disease and selection.

            Given large sample sizes, whole genome screens are now able to identify even quite modest contributions of common human genetic variation to disease. These approaches, made possible by the development of high-throughput, dense SNP genotyping, find few associations stronger than those for the human MHC, in multigenic autoimmune conditions. They confirm earlier findings that the major variants affecting susceptibility and resistance to autoimmunity relate to MHC class I and class II genes. It is generally assumed, although there are few good examples, that selection for resistance to infection drives evolution of MHC variation. Many MHC-associated diseases may be the price paid for an effective immune response. Interestingly, the MHC appears to influence susceptibility to conditions unrelated to immunity, including some neuropathologies. The infectious history of the individual, conditioned by their MHC, may exert an indirect effect on these diseases, although there are hints of more direct involvement of MHC molecules in neuronal systems. Here I survey the variety of conditions associated with the MHC in relation to ideas that selection through disease resistance is dependent upon MHC variation, not only at the level of the individual, but also at the level of the population. Copyright © 2011 Elsevier B.V. All rights reserved.
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              Idiopathic nephrotic syndrome in children

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                Author and article information

                Contributors
                (View ORCID Profile)
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                Journal
                Journal of the American Society of Nephrology
                JASN
                American Society of Nephrology (ASN)
                1046-6673
                1533-3450
                July 31 2019
                August 2019
                August 2019
                July 01 2019
                : 30
                : 8
                : 1375-1384
                Article
                10.1681/ASN.2018101054
                6683715
                31263063
                © 2019

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