There are controversies regarding the genetic changes caused by the rs2232365 polymorphism (9;6); however, based on the analysis of gene expression, it is suggested that the polymorphisms alter the expression of FOXP3, predisposing the individual to different clinical and pathological outcomes related to the disease in question. From an immunological point of view, there is a tendency for the T allele to favor an anti-inflammatory profile, while the C allele favors a pro-inflammatory profile.
It seems counterintuitive to associate an anti-inflammatory factor with the risk of tissue aggression; however, these findings corroborate previous studies that suggest that variant T favors the persistence of viral infection in patients with fibrosis (10). With the increase in VL, there is a long-term pro-fibrogenic tendency induced by chronic inflammation and continuous response to healing (11), resulting in the fluctuation of pre-cirrhotic biomarkers (12), such as GGT. The transaminase ratio was stable between genotypes and sexes, indicative of chronic infection, but not relevant for estimating the stage of fibrosis (13). Recent studies by our group show that in liver fibrosis, viral load, in fact, is more associated with the histological profile than liver integrity enzymes (14).
In the multiple logistic regression, the allele T was also associated with advanced fibrosis; however, the decrease in the statistical probability is indicative of other factors influencing liver histopathology. In recent publications, we discard alcoholism as a behavioral factor associated with liver fibrosis (14).
In HTLV-1 infection, the high prevalence of infected women is an epidemiological fact observed in different populations studied (15;16), and is related to the effectiveness of sexual transmission from male to female. With the present study, we suggest that not only transmissivity, but also sex-linked immunogenetic factors can influence susceptibility to HTLV-1 infection. The observed associations suggest that intrinsic mechanisms regulate the action of FOXP3 variants between sexes. Studies show that, in women, epigenetic processes modulate the expression of FOXP3 and alter the susceptibility to diseases (17); the normal development of cells carrying mutant genes is a consequence of mixed chimerism (18), which is suggested in the present study due to the marked frequency of heterozygous women (data not shown). In men, changes in FOXP3 tend to be more relevant due to heredity (19), regulation induced by the Y chromosome (20) and sex hormones (21).
Although there are no studies on the association of the polymorphism with HTLV-1 infection, it is suggested that, in men, the anti-inflammatory tendency induced by the allele T reduces chronic immune hyperactivity, typically seen in the pathogenesis of the infection, reflecting the decrease in the proviral load and the cytokines of cellular immunity (22).The relationship of the polymorphism with the T CD4+ lymphocytes and IL-8 is indicative of the constitution of an atypical pro-inflammatory immune network (23), however, already observed in HTLV-1 infection, mainly in patients with Adult T-cell leukemia (ATL) (24).
In the present study, we did not associate the polymorphism with the clinical and pathological aspects of HTLV-1 infection. However, given the prevalence of asymptomatic patients observed, a cohort study in patients with allele T in this clinical group can clarify whether, in the long term, there will be polarization for a pro-inflammatory profile and changes in the pathogenesis of infection.
Only males were associated with the risk of CAD, however, unrelated to the history of Chlamydia infection. The history of Chlamydia penumonie prevailed and CRP levels fluctuated, but both were not associated with sex and polymorphism. Recent reports confirm that men are generally more likely to develop CAD than women, with the highest death rate in middle age. Women, on the other hand, are at greater risk of stroke, which usually occurs at older ages (25).
We defend the legitimacy of our data based on the FPRP values obtained that support the proposed findings. All values remained noteworthy between 0.25 to 0.001 of prior probability, which, according to Wacholder and collaborators, for polymorphisms whose functional data are suggestive of a possible association (as shown in the literature for rs2232365) is the ideal probability range (26).