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

Stephanie Dufek, Chris Cheshire, Adam P Levine, Richard S Trompeter, Naomi Issler, Matthew Stubbs, Monika Mozere, Sanjana Gupta, Enriko Klootwijk, Vaksha Patel, Daljit Hothi, Aoife Waters, Hazel Webb, Kjell Tullus, Lucy Jenkins, Lighta Godinho, Elena Levtchenko, Jack Wetzels, Nine Knoers, Nynke TeeningaJeroen Nauta, Mohamed Shalaby, Sherif Eldesoky, Jameela A Kari, Shenal Thalgahagoda, Randula Ranawaka, Asiri Abeyagunawardena, Adebowale Adeyemo, Mark Kristiansen, Rasheed Gbadegesin, Nicholas J Webb, Daniel P Gale, Horia C Stanescu, Robert Kleta, Detlef Bockenhauer

    OnderzoeksoutputAcademicpeer review

    30 Citaten (Scopus)
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    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.

    Originele taal-2English
    Pagina's (van-tot)1375-1384
    Aantal pagina's10
    TijdschriftJournal of the American Society of Nephrology
    Nummer van het tijdschrift8
    StatusPublished - aug.-2019

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