Toll‐like‐Receptor Gene Polymorphisms in Tunisian Endemic Pemphigus Foliaceus

Abstract

Pemphigus foliaceus (PF) is considered to be caused by the combined effects of susceptibility genes and environmental triggers. The polymorphisms of Toll-like receptors (TLRs) genes have been associated with the risk of various autoimmune diseases. The aim of this study was to evaluate the potential association of TLR2-3-4 and 7 gene polymorphisms with Tunisian PF. Fourteen polymorphisms were analyzed in 93 Tunisian PF patients compared to 193 matched healthy controls: rs5743703-rs5743709 and (GT)n repeat (TLR2); rs5743305, rs3775294, and rs3775291 (TLR3), rs4986790 and rs4986791 (TLR4); and rs3853839 (TLR7). Our results showed that the genetic factors varied depending on the epidemiological feature stratification. In fact, in the whole population, no association with the susceptibility to PF was found. The TLR2 GT repeat seems to be closely associated with PF risk in patients originated from the endemic localities (group 3); the GT18 allele and the heterozygous genotype GT18/GT19 seem to confer risk to endemic PF ( P = 0.02 ; OR = 2.3 [1.1-4.9] and P = 0.0002 , OR = 20 [2.5-171], respectively). In contrast, the GT23 repeat could be considered as protector allele ( P = 0.02 , OR = 0.2 [0.06-0.87]). Furthermore, medium GT alleles which induce high promoter activity were also significantly more frequent in patients versus short or long GT repeats ( P = 0.0018 with OR = 3.26 [1.5-7]). On the other hand, the TLR3-rs574305 AA genotype and A allele were significantly more frequent in patients whose age of the onset was above 35 years (group 2) ( P = 0.038 , OR = 1.78 and P = 0.009 , OR = 3.92 , respectively). Besides, the TLR4>rs3775294 A allele was found to be protector only in patients with sporadic features (groups 2 and 4) ( P = 0.03 , OR = 0.57 [0.3-0.9] and P = 0.006 , OR = 0.24 [0.08-0.74], respectively). No statistically significant difference was observed in the genotypic and allelic frequencies of TLR-4 and TLR-7 gene polymorphisms. The present data suggest that TLR2and TLR3 polymorphisms are significantly associated with increased susceptibility to PF in the Tunisian population.

Role of innate immune receptors TLR4 and TLR2 polymorphisms in systemic lupus erythematosus susceptibility

“…Indeed, these mid‐sized GT repeats are the most abundant in every population (Yim et al., 2004). Association of the genotype GT18/GT19 with SLE susceptibility is in line with a recent study conducted in our laboratory, showing that the GT18 allele and the GT18/GT19 genotype are associated with a significant risk to Pemphigus Foliaceus auto‐immune disease ( p = 0.02 and p = 2.3 × 10 −4 , respectively) (Abida et al., 2020).…”

“…PCR reactions were performed in a total volume of 25 μl containing enzymes at 1× buffer, 0.2–0.4 μmol of each primer (Invitrogen, CA, USA), 0.12 mMdNTP (Invitrogen, CA, USA),1 U Taq polymerase (Invitrogen, CA, USA), and 50 ng genomic DNA. The amplified PCR products were digested with specific restriction enzymes at their optimum temperature (Abida et al., 2020; Karananou et al., 2019). Then, the digested products were visualized by electrophoresis on a 3% agarose gel.…”

“…Indeed, TLR2 gene is a commonly studied gene in autoimmune diseases (AID) such as multiple sclerosis (Fujiwara et al., 2018), Pemphigus foliaceus (Abida et al., 2020), atopic dermatitis (Tyurinet al., 2017), vitiligo (Karacaet al., 2013), and type 1 diabetes (Bjornvold et al., 2009).…”

Evaluation of X chromosome inactivation in endemic Tunisian pemphigus foliaceus

“…We examined in detail the 120 informative women (70 HC and 50 PF heterozygotes for AR gene). TLR7 and FOXP3 genotypes were described in our previous data (Abida et al, 2020 ; Ben Jmaa et al, 2017 ). Overall, our results showed that the preferential XCI skewed profile correlated with the heterozygote frequency distribution of those immunity‐related genes in PF patients in comparison to their matched HC (Table 4 ).…”

“…Our previous study reported significant associations of genetic variants of other X‐linked genes like the FOXP3 gene (Xp11.23) with the risk for PF (Ben Jmaa et al, 2017 ). Concerning the TLR7 gene mapped in Xp22.3, we have noted an increase in the TLR7 rs3853839 > GG functional polymorphism in patients with PF compared to HC (Abida et al, 2020 ). Our results showed evidence of increasingly skewed and extremely skewed patterns among heterozygote patients in comparison to their matched HC in AR , TLR7 , and FOXP3 gene polymorphisms were shown.…”