Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren's Syndrome.
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Lundtoft Christian, Sjöwall Christopher, Rantapää-Dahlqvist Solbritt, Bengtsson Anders A, Jönsen Andreas, Pucholt Pascal, Wu Yee Ling, Lundström Emeli, Eloranta Maija-Leena, Gunnarsson Iva, Baecklund Eva, Jonsson Roland, Hammenfors Daniel, Forsblad-d'Elia Helena, Eriksson Per, Mandl Thomas, Bucher Sara, Norheim Katrine B, Auglaend Johnsen Svein Joar, Omdal Roald, Kvarnström Marika, Wahren-Herlenius Marie, Truedsson Lennart, Nilsson Bo, Kozyrev Sergey V, Bianchi Matteo, Lindblad-Toh Kerstin, DISSECT consortium, the ImmunoArray consortium, Yu Chack-Yung, Nordmark Gunnel, Sandling Johanna K, Svenungsson Elisabet, Leonard Dag, Rönnblom Lars
Аннотация
METHODS: The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n = 958) or primary SS (n = 911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients.
RESULTS: Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P = 2 × 10-9 ) and impaired function of the classical complement pathway (P = 0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases.
CONCLUSION: We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.