IVS1 −397T>C Estrogen ReceptorαPolymorphism Is Associated with Low-Grade Systemic Inflammatory Response in Type 1 Diabetic Girls

Abstract

Purpose. The study aimed to investigate the influence of estrogen receptor α (ER-α) genotypes on inflammatory response and development of microvascular complications in girls with type 1 diabetes. Methods. 152 young regularly menstruating girls with diagnosed type 1 diabetes and 84 young, healthy menstruating girls were recruited. ER-α genotyping was carried out by PCR. Serum concentrations of 17β-estradiol, as well as IL-6, TNF-α, VEGF, and IL-10, were measured. CD4+Foxp3+ TH17 cells were isolated and analyzed by flow cytometry. Results. Type 1 diabetic girls carrying TT genotype were characterized by the lowest serum estradiol level and IL-10 and highest IL-6, TNF-α , and VEGF. The association between the level of certain cytokine and the genetic variant of estrogen receptor α polymorphism was analyzed. Frequencies of CD4+Foxp3+ TH17 cells were also enhanced in TT bearing girls with type 1 diabetes and correlated with the level of analyzed cytokines. In addition, the correlation between serum estradiol level and cytokine concentrations was observed. Conclusions. We propose that TT variant of estrogen receptor α polymorphism may be associated with enhanced inflammatory response, which in turn may lead to acceleration of diabetic retino- and nephropathy in girls with type 1 diabetes. This finding may help the physicians to predict the onset and progression of diabetic microvascular complications.

Grade of inflammation in boys with type 1 diabetes depends on the IVS1 −397T>C estrogen receptor α polymorphism

“…Similarly to our previous paper, regarding IVS1 −397TNC polymorphism (Ryba et al, 2011;Ryba-Stanisławowska et al, 2014), we found that T allele is associated with enhanced inflammatory response in DM1 boys. Our study revealed that boys possessing CC genotype had lower IL-6 and CRP serum level than their counterparts with CT and TT genotype.…”

“…In another study conducted on DM1 adolescent girls, we have discovered that individuals carrying CC genotype were characterized by greater level of CD4+ Foxp3+ Tregs and simultaneous lowest TNF serum level in comparison to patients with CT and TT genotypes (Ryba et al, 2011). Moreover, elevated levels of analyzed proinflammatory factors (Th17 cells, cytokines) in DM1 girls carrying TT genotype promoted enhanced inflammatory response, which may cause diabetic-related microvascular complications (Ryba-Stanisławowska et al, 2014).…”

Estrogen receptor α gene polymorphism and vascular complications in girls with type 1 diabetes mellitus

“…Similarly to previous reports regarding PvuII ER - α gene polymorphism in a smaller group of girls [ 19 , 20 ] and boys [ 21 ] with DM1, researchers have found that CC genotype is associated with weakened inflammatory response. CC genotype bearing girls produced more 17β-estradiol and had lower CRP, IL-6, and TNF-α serum level than their counterparts with CT and TT genotype.…”

“…In our previous study [ 19 ], we have shown that diabetic girls carrying CC genotype were characterized by greater population of CD4 + Foxp3 + Tregs and simultaneous lower TNF serum level in comparison to girls carrying CT or TT genotype. Moreover, elevated levels of analyzed proinflammatory factors (Th17 cells, cytokines) in DM1 girls carrying TT genotype promoted enhanced inflammatory response, which led to development and progression of diabetic microvascular complications [ 20 ]. In another study conducted on DM1 boys, researchers have discovered that individuals carrying CC genotype had lower blood pressure, IL-6, and CRP serum levels.…”

Genetic Mechanisms Leading to Sex Differences Across Common Diseases and Anthropometric Traits

“…Recently, a gene involved in androgen synthesis was associated with RA (Stark et al 2015), and we show that androgen-responsive genes across the genome are enriched for association signal and sex differences. Although estrogen biology has been associated with comorbidities of T1D (Ryba et al 2011;Ryba-Stanisławowska et al 2014;Słomiński et al 2015), our results are the first to suggest a global impact on risk. Interestingly, we observed several examples of an increased proportion of heritability in AR genes in females, and for ER genes in males.…”