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Combined genetic deficiencies of the classical complement pathway are strongly associated with both systemic lupus erythematosus and primary Sjögren's syndrome

Lundtoft, Christian ; Bengtsson, Anders A. LU ; Jönsen, Andreas LU ; Lundström, Emeli ; Hammenfors, Daniel ; Mandl, Thomas LU ; Truedsson, Lennart LU ; Lindblad‐Toh, Kerstin and Rӧnnblom, Lars (2022) In Arthritis & Rheumatology 74(11). p.1842-1850
Abstract
Objective
Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (pSS) has not been studied systematically. Here we investigated heterozygous C2 deficiency and C4 copy number variation in relation to clinical manifestations in SLE and pSS.
Methods
The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients diagnosed with SLE (n=958) or pSS (n=911), and 2,262 controls using DNA sequencing. Plasma concentration of complement proteins and classical complement function was analysed in a subgroup of... (More)
Objective
Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (pSS) has not been studied systematically. Here we investigated heterozygous C2 deficiency and C4 copy number variation in relation to clinical manifestations in SLE and pSS.
Methods
The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients diagnosed with SLE (n=958) or pSS (n=911), and 2,262 controls using DNA sequencing. Plasma concentration of complement proteins and classical complement function was analysed in a subgroup of patients.
Results
Heterozygous C2 deficiency – when present in combination with a low C4A copy number – substantially increased the risk of SLE (OR=10.2, CI95%: 3.5-37.0) and pSS (OR=13.0, CI95%: 4.5-48.4) when compared to individuals with two C4A copies and normal C2. For patients heterozygous for rs9332736 with one C4A copy, the median age of diagnosis was 7 years and 12 years earlier in SLE and pSS, respectively. Reduced plasma C2 (p=2x10-9) and impaired function of the classical complement pathway (p=0.03) was detected in SLE patients with heterozygous C2 deficiency. Finally, we describe a pSS patient with homozygous C2 deficiency.
Conclusion
We demonstrate that the combination of partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and pSS. Our results emphasise the central role of the complement system in the pathogenesis of both diseases.
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author
; ; ; ; ; ; ; and
contributor
LU
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis & Rheumatology
volume
74
issue
11
pages
1842 - 1850
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:35729719
  • scopus:85139711136
ISSN
2326-5205
DOI
10.1002/art.42270
language
English
LU publication?
yes
id
4bc2558a-e306-4a9d-9176-05b5c1650b4e
date added to LUP
2022-06-22 15:02:42
date last changed
2024-02-19 17:42:05
@article{4bc2558a-e306-4a9d-9176-05b5c1650b4e,
  abstract     = {{Objective<br/>Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (pSS) has not been studied systematically. Here we investigated heterozygous C2 deficiency and C4 copy number variation in relation to clinical manifestations in SLE and pSS.<br/>Methods<br/>The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients diagnosed with SLE (n=958) or pSS (n=911), and 2,262 controls using DNA sequencing. Plasma concentration of complement proteins and classical complement function was analysed in a subgroup of patients.<br/>Results<br/>Heterozygous C2 deficiency – when present in combination with a low C4A copy number – substantially increased the risk of SLE (OR=10.2, CI95%: 3.5-37.0) and pSS (OR=13.0, CI95%: 4.5-48.4) when compared to individuals with two C4A copies and normal C2. For patients heterozygous for rs9332736 with one C4A copy, the median age of diagnosis was 7 years and 12 years earlier in SLE and pSS, respectively. Reduced plasma C2 (p=2x10-9) and impaired function of the classical complement pathway (p=0.03) was detected in SLE patients with heterozygous C2 deficiency. Finally, we describe a pSS patient with homozygous C2 deficiency.<br/>Conclusion<br/>We demonstrate that the combination of partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and pSS. Our results emphasise the central role of the complement system in the pathogenesis of both diseases.<br/>}},
  author       = {{Lundtoft, Christian and Bengtsson, Anders A. and Jönsen, Andreas and Lundström, Emeli and Hammenfors, Daniel and Mandl, Thomas and Truedsson, Lennart and Lindblad‐Toh, Kerstin and Rӧnnblom, Lars}},
  issn         = {{2326-5205}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{11}},
  pages        = {{1842--1850}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis & Rheumatology}},
  title        = {{Combined genetic deficiencies of the classical complement pathway are strongly associated with both systemic lupus erythematosus and primary Sjögren's syndrome}},
  url          = {{http://dx.doi.org/10.1002/art.42270}},
  doi          = {{10.1002/art.42270}},
  volume       = {{74}},
  year         = {{2022}},
}