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Published on: June 8, 2022
Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with
Andreas Jönsen1, Sara C Nilsson, Emma Ahlqvist
1Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Kioskgatan 3, SE-221 85 Lund, Sweden.
Insights
Mutations in complement inhibitor genes CFH and CD46 do not cause lupus nephritis but may accelerate its onset. These findings offer insights into lupus nephritis pathogenesis and potential therapeutic targets.
Area of Science:
- Immunology
- Genetics
- Nephrology
Background:
- Inherited complement deficiencies are linked to systemic lupus erythematosus (SLE).
- Complement inhibitor deficiencies are associated with atypical hemolytic uremic syndrome (aHUS).
Purpose of the Study:
- To investigate the role of mutations in complement inhibitor genes CD46 and CFH in SLE patients with nephritis.
- To determine if these mutations predispose to SLE or nephritis, or influence disease onset.
Main Methods:
- Exome sequencing of CD46 and CFH genes in Swedish SLE patients with nephritis (n=196).
- Analysis of identified mutations and polymorphisms in SLE patients without nephritis (n=326) and healthy controls (n=523).
Main Results:
- Nonsynonymous heterozygous CFH mutations were found in 6.1% of nephritis patients versus 4.0-5.4% in others.
- Two nonsynonymous heterozygous CD46 mutations were identified in SLE patients, not controls.
- Mutations in CD46 and CFH did not predispose to SLE or nephritis but were linked to earlier nephritis onset.
Conclusions:
- Frequent mutations in CFH and CD46 are not associated with SLE nephritis, unlike in aHUS.
- CD46 and CFH mutations may act as modifying factors, potentially causing earlier onset of nephritis in SLE patients.
Introduction:
Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS).
Methods:
The exons of complement inhibitor genes CD46 and CFH (factor H) were fully sequenced using the Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and in healthy controls (n = 523).
Results:
We found nonsynonymous, heterozygous mutations in CFH in 6.1% patients with nephritis, in comparison with 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two nonsynonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients versus 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in noncoding regions of CD46, which were previously implicated in aHUS.
Conclusions:
SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.
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