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

Abstract

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 CD40LÀ726T4C (odds ratio, OR ¼ 5.54 and 0.30 for T þ and C þ genotypes, respectively). In addition, there were significant negative associations with CD40 À1T (OR ¼ 0.61) and BLYSÀ871T (OR ¼ 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 CD40LÀ726C and of CD40 À1T only manifest in BLYSÀ871T þ individuals, and vice versa. We conclude that genetic variability of CD40L, CD40 and BLYS is an important factor for PF pathogenesis.

Polymorphisms in the 2q33 and 3q21 chromosome regions including T-cell coreceptor and ligand genes may influence susceptibility to pemphigus foliaceus

“…Trying not to permit weak associations or tendencies to escape from our analysis, nominal p values are reported to allow proper interpretation and to account for the explorative nature of association studies. Moreover, when the same associations are observed in independent samples (in the present study, Euro-and Afro-Brazilians), corrections for multiple testing are unnecessary [17].…”

“…ICOS was found to be highly expressed on germinal center T cells, suggesting involvement in T-B cell interactions [49]. Genetic variation of other molecules participating in T-B cell interactions contributes to differential susceptibility to PF [17]. In addition, the level of ICOS surface expression regulates the magnitude of the in vivo T h 2 response, the immune response prevalent in pemphigus lesional skin, perhaps by influencing T h 2 differentiation [50,51].…”

“…Thus far, the strongest associations were found with HLA class II genes [15,16] and with CD40L [17]. Associations were also seen with IL6, IL4, IL10, PDCD1, CD40 and BLYS [17][18][19], but not with TNF, LTA, DSG1, BAX, TP53, and CD19 polymorphisms [17,20 -22].…”

“…Associations were also seen with IL6, IL4, IL10, PDCD1, CD40 and BLYS [17][18][19], but not with TNF, LTA, DSG1, BAX, TP53, and CD19 polymorphisms [17,20 -22]. Epistasis has been demonstrated between CD40 and BLYS, CD40L, and BLYS, and between DSG1 and HLA class II genes [17,23]. Because much remains to be known about pathogenesis of this disease, analyses of additional genomic regions are necessary.…”

Polymorphisms in genes of the BAFF/APRIL system may constitute risk factors of B‐CLL – a preliminary study on a Polish population

“…What is more, the different impact on disease risk was observed for −871 C>T polymorphism. The T variant have been reported as the risk variant of the familial B-CLL (5) and high risk allele of pSS (3) and contradictory, as a favorable allele for T-cell lymphoma (TCL) patients survival (19) and as associated with lower susceptibility to pemphigus foliaceus (21). Here, we observed differences in the genotype distribution of −871C>T variant between the B-CLL and control groups (P = 0.047), arose because of the underrepresentation of −871CT heterozygotes in the B-CLL group.…”