Individual and epistatic effects of genetic polymorphisms of B-cell co-stimulatory molecules on susceptibility to pemphigus foliaceus.

Following the candidate gene approach we analyzed the CD40L, CD40, BLYS and CD19 genes that participate of B-cell co-stimulation, for association with pemphigus foliaceus (PF), an organ-specific autoimmune disease, characterized by the detachment of epidermal cells from each other (acantholysis) and presence of autoantibodies specific for desmoglein 1 (dsg1), an epidermal cell-adhesion molecule. The disease is endemic in certain regions of Brazil and also is known as fogo selvagem. Complex interactions among environmental and genetic susceptibility factors contribute to the manifestation of this multifactorial disease. The sample included 179 patients and 317 controls. Strong significant association was found with CD40L-726T>C (odds ratio, OR=5.54 and 0.30 for T+ and C+ genotypes, respectively). In addition, there were significant negative associations with CD40 -1T (OR=0.61) and BLYS-871T (OR=0.62) due to the decrease of the frequency of both homo- and heterozygotes in the patient group. No associations were found with variants of CD19 gene. Gene-gene interactions were observed between CD40 and BLYS, and between CD40L and BLYS. So, the dominant protective effects of CD40L-726C and of CD40 -1T only manifest in BLYS-871T+ individuals, and vice versa. We conclude that genetic variability of CD40L, CD40 and BLYS is an important factor for PF pathogenesis.