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J Am Soc Nephrol. 2020 Feb;31(2):365-373. doi: 10.1681/ASN.2019040433. Epub 2020 Jan 9.

Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy.

Author information

1
Department of Renal Medicine, University College London, London, United Kingdom.
2
Renal Department, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
3
Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
4
The National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom.
5
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom.
6
National Institute of Health Research BioResource, Cambridge University Hospitals, Cambridge, United Kingdom.
7
Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
8
Children's Renal and Urology Unit, Nottingham Children's Hospital, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
9
Department of Nephrology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
10
Department of Paediatric Nephrology, Great Ormond Street Hospital and University College London Great Ormond Street Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom.
11
Department of Paediatric Nephrology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom.
12
Renal Department, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, United Kingdom.
13
Department of Paediatric Nephrology, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; and.
14
Department of Renal Medicine, University College London, London, United Kingdom; d.gale@ucl.ac.uk.

Abstract

BACKGROUND:

Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN.

METHODS:

We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants.

RESULTS:

Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10-8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10-8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure.

CONCLUSIONS:

We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.

KEYWORDS:

C3 glomerulopathy; Genome-wide association study; Human leukocyte antigen; complement; membranoproliferative glomerulonephritis (MPGN)

PMID:
31919107
PMCID:
PMC7003307
[Available on 2021-02-01]
DOI:
10.1681/ASN.2019040433

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