Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus.

ABSTRACT

Skin blisters of pemphigus foliaceus (PF) present concomitant deposition of autoantibodies and components of the complement system (CS), whose gene polymorphisms are associated with susceptibility to different autoimmune diseases. To investigate these in PF, we evaluated 992 single-nucleotide polymorphisms (SNPs) of 44 CS genes, genotyped through microarray hybridization in 229 PF patients and 194 controls. After excluding SNPs with minor allele frequency <1%, out of Hardy-Weinberg equilibrium in controls or in strong linkage disequilibrium (r2 ≥ 0.8), 201 SNPs remained for logistic regression. Polymorphisms of 11 genes were associated with PF. MASP1 encodes a crucial serine protease of the lectin pathway (rs13094773 OR = 0.5, p = 0.0316; rs850309 OR = 0.23, p = 0.03; rs3864098 OR = 1.53, p = 0.0383; rs698104 OR = 1.52, p = 0.0424; rs72549154 OR = 0.55, p = 0.0453). C9 (rs187875 OR = 1.46, p = 0.0189; rs700218 OR = 0.12, p = 0.0471) and C8A (rs11206934 OR = 4.02, p = 0.0323) encode proteins of the membrane attack complex (MAC) and C5AR1 (rs10404456 OR = 1.43, p = 0.0155), a potent anaphylatoxin-receptor. Two encode complement regulators MAC-blocking CD59 (rs1047581 OR = 0.62, p = 0.0152) and alternative pathway-blocking CFH (rs34388368 OR = 2.57, p = 0.0195). One encodes opsonin C3 (rs4807895 OR = 2.52, p = 0.0239), whereas four encode receptors for C3 fragments CR1 (haplotype with rs6656401 OR = 1.37, p = 0.0382), CR2 (rs2182911 OR = 0.23, p = 0.0263), ITGAM (CR3, rs12928810 OR = 0.66, p = 0.0435), and ITGAX (CR4, rs11574637 OR = 0.63, p = 0.0056). Associations reinforced former findings, regarding differential gene expression, serum levels, C3, and MAC deposition on lesions. Deregulation of previously barely noticed processes, e.g., the lectin and alternative pathways and opsonization-mediated phagocytosis, also modulate PF susceptibility. The results open new crucial avenues for understanding disease etiology and may improve PF treatment through additional therapeutic targets.