Journal article
Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome
Journal of the American Society of Nephrology, Vol.29(12), pp.2809-2819
12/2018
DOI: 10.1681/ASN.2018070759
PMID: 30377230
Abstract
Genetic variation in complement genes is a predisposing factor for atypical hemolytic uremic syndrome (aHUS), a life-threatening thrombotic microangiopathy, however interpreting the effects of genetic variants is challenging and often ambiguous.
We analyzed 93 complement and coagulation genes in 400 patients with aHUS, using as controls 600 healthy individuals from Iowa and 63,345 non-Finnish European individuals from the Genome Aggregation Database. After adjusting for population stratification, we then applied the Fisher exact, modified Poisson exact, and optimal unified sequence kernel association tests to assess gene-based variant burden. We also applied a sliding-window analysis to define the frequency range over which variant burden was significant.
We found that patients with aHUS are enriched for ultrarare coding variants in the
,
,
,
,
, and
genes. The majority of the significance is contributed by variants with a minor allele frequency of <0.1%. Disease-related variants tend to occur in specific complement protein domains of FH, CD46, and C3. We observed no enrichment for multiple rare coding variants in gene-gene combinations.
In known aHUS-associated genes, variants with a minor allele frequency >0.1% should not be considered pathogenic unless valid enrichment and/or functional evidence are available.
, which encodes vitronectin, an inhibitor of the terminal complement pathway, is implicated as a novel aHUS-associated gene. Patients with aHUS are not enriched for multiple rare variants in complement genes. In aggregate, these data may help in directing clinical management of aHUS.
Details
- Title: Subtitle
- Genetic Analysis of 400 Patients Refines Understanding and Implicates a New Gene in Atypical Hemolytic Uremic Syndrome
- Creators
- Fengxiao Bu - Molecular Otolaryngology and Renal Research LaboratoriesYuzhou Zhang - Molecular Otolaryngology and Renal Research LaboratoriesKai Wang - College of Public HealthNicolo Ghiringhelli Borsa - Molecular Otolaryngology and Renal Research LaboratoriesMichael B Jones - University of Iowa, OtolaryngologyAmanda O Taylor - Molecular Otolaryngology and Renal Research LaboratoriesErika Takanami - Molecular Otolaryngology and Renal Research LaboratoriesNicole C Meyer - Molecular Otolaryngology and Renal Research LaboratoriesKathy Frees - Molecular Otolaryngology and Renal Research LaboratoriesChristie P Thomas - Division of Nephrology, Department of Internal Medicine, Carver College of Medicine, andCarla Nester - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IowaRichard J H Smith - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of the American Society of Nephrology, Vol.29(12), pp.2809-2819
- DOI
- 10.1681/ASN.2018070759
- PMID
- 30377230
- NLM abbreviation
- J Am Soc Nephrol
- ISSN
- 1046-6673
- eISSN
- 1533-3450
- Publisher
- United States
- Language
- English
- Date published
- 12/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biostatistics; Obstetrics and Gynecology; Nephrology; Otolaryngology; Internal Medicine
- Record Identifier
- 9983986081302771
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