Open Access Highly Accessed Research article

Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus

Andreas Jönsen1, Sara C Nilsson2, Emma Ahlqvist3, Elisabet Svenungsson4, Iva Gunnarsson4, Karin G Eriksson5, Anders Bengtsson1, Agneta Zickert4, Maija-Leena Eloranta5, Lennart Truedsson6, Lars Rönnblom5, Gunnel Nordmark5, Gunnar Sturfelt1 and Anna M Blom2*

Author Affiliations

1 Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Kioskgatan 3, SE-221 85 Lund, Sweden

2 Section of Medical Protein Chemistry, Department of Laboratory Medicine Malmö, Lund University, S-205 02 Malmö, Sweden

3 Section of Diabetes and Endocrinology, Department of Clinical Sciences Malmö, Lund University, S-205 02 Malmö, Sweden

4 Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institute, S-171 76 Stockholm, Sweden

5 Section of Rheumatology, Department of Medical Sciences, Uppsala University, SE-751 Uppsala, Sweden

6 Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Sölvegatan 23, 223 62 Lund, Sweden

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Arthritis Research & Therapy 2011, 13:R206  doi:10.1186/ar3539

Published: 15 December 2011

Abstract

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.