Genetic Identification of Two Novel Loci Associated with... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

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

Dufek, Stephanie1; Cheshire, Chris1; Levine, Adam P.1; Trompeter, Richard S.1; Issler, Naomi1; Stubbs, Matthew1; Mozere, Monika1; Gupta, Sanjana1; Klootwijk, Enriko1; Patel, Vaksha2; Hothi, Daljit2; Waters, Aoife2; Webb, Hazel2; Tullus, Kjell2; Jenkins, Lucy2; Godinho, Lighta2; Levtchenko, Elena3; Wetzels, Jack4; Knoers, Nine5; Teeninga, Nynke6; Nauta, Jeroen6; Shalaby, Mohamed7; Eldesoky, Sherif7; Kari, Jameela A.7; Thalgahagoda, Shenal8; Ranawaka, Randula8; Abeyagunawardena, Asiri8; Adeyemo, Adebowale9; Kristiansen, Mark10; Gbadegesin, Rasheed11; Webb, Nicholas J.12,13; Gale, Daniel P.1; Stanescu, Horia C.1; Kleta, Robert1; Bockenhauer, Detlef1

1Department of Renal Medicine and

10University College London Genomics, Institute of Child Health, University College London, London, United Kingdom;

2Great Ormond Street Hospital, London, United Kingdom;

3University Hospitals Leuven and University of Leuven, Leuven, Belgium;

4Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands;

5Department of Genetics, UMC Groningen, Groningen, The Netherlands;

6Department of Pediatric Nephrology, Erasmus University Medical Centre–Sophia Children’s Hospital, Rotterdam, The Netherlands;

7Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia;

8Department of Paediatrics, University of Peradeniya, Peradeniya, Sri Lanka;

9NHGRI, National Institutes of Health, Bethesda, Maryland;

11Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina; and

12Department of Paediatric Nephrology and

13NIHR Manchester Clinical Research Facility, Manchester Academic Health Science Centre, Royal Manchester Children’s Hospital, Manchester, United Kingdom

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: [email protected] or [email protected]

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Abstract

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.

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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