Grade of inflammation in boys with type 1 diabetes depends on the IVS1 −397T>C estrogen receptor α polymorphism
Introduction
The etiology and progression of type 1 diabetes mellitus (DM1) are associated with genetic and environmental factors. Within genetic determinants, which influence autoimmunity the most, are polymorphisms of certain genes. Numerous genetic polymorphisms influence susceptibility to type 1 diabetes development. These genetic varieties may also affect severity of established disease (Gregersen & Behrens, 2006). Another factor that affects autoimmunity is gender. Female sex is described as more prone to the development of autoimmune diseases (Quintero, Amador-Patarroyo, Montoya-Ortiz, Rojas-Villarraga, & Anaya, 2012). This phenomenon may be partially explained by the influence of sex hormones on the activity of immune system (Zandman-Goddard, Peeva, & Shoenfeld, 2007).
The effect of estrogens is elicited by binding-mediated activation of estrogen receptors (ER-α and ER-β). The response of tissues to estrogens is determined by allelic variants of the ER-α encoding gene. That is why many associations between estrogen receptors variants and hormone-related clinical effects have been distinguished (Figtree, Noonan, Hindi, & Collins, 2009).
The most common and widely studied variations are the PvuII (IVS1 −397T>C, rs2234693) and XbaI single nucleotide polymorphismsm (SNP) localized in the first intron of the ER-α gene. In a case of PvuII SNP the T→C transition, associated with loss of the PvuII restriction site (CC genotype), creates binding site for transcription factor from Myb family. In vitro analyzes have proven that B-myb increases transcription of a reporter construct by ten times. Associations between PvuII or XbaI polymorphisms and certain clinical conditions have been verified. These studies concern: risk of cardiovascular disease development (Herrington et al., 2002b, Myśliwska et al., 2009), osteoporosis (Albagha et al., 2001, Becherini et al., 2009), cancer (Haiman et al., 1999, Weiderpass et al., 2000), increased blood pressure (Ellis, Infantino, & Harrap, 2004), spontaneous abortion (Anousha et al., 2013), multiple sclerosis (Niino, Kikuchi, Fukazawa, Yabe, & Tashiro, 2000), depression (Ryan & Ancelin, 2012), Alzheimer's disease (Boada et al., 2012), diabetes type 2 and obesity (Albagha et al., 2001), as well as type 1 diabetes (Ryba et al., 2011, Ryba-Stanisławowska et al., 2014).
Our previous studies unveiled connections between inflammatory response and the polymorphic variants of the ER-α gene. We have proven that the possession of IVS1 −397 TT genotype leads to enhanced inflammatory response in females with an established coronary artery disease. The proinflammatory profile was displayed by greater production of TNF and IL-6 (Myśliwska et al., 2009). 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).
ER-α gene polymorphisms have been connected with particular clinical conditions in men or adolescent boys, including the risk of developing prostate cancer (Chae, Huang, Strickland, Hoffman, & Helzlsouer, 2009), decreased bone density (Lorentzon, Lorentzon, Bäckström, & Nordström, 1999), the risk of cardiovascular disease (Kjaergaard et al., 2007, Kunnas et al., 2000), spermatogenic defects (Meng, Mu, & Wang, 2013), as well as diabetes type 2 (Linnér et al., 2013, Speer et al., 2001).
Because the ER is a ligand-activated transcription factor (Safe, 2001), ER-α gene polymorphisms may exert different effects in childhood, according to prevalent levels of estradiol, which rise during puberty. As far as we know, studies analyzing the association between ER-α polymorphisms and immune/inflammatory response have not been conducted in DM1 boys. Therefore, in the present study, we examine associations between the IVS1 −397T>C polymorphism and indicators of inflammatory response as well as diabetic complications in DM1 boys.
Section snippets
Subjects
The study group consisted of 108 young boys with diagnosed type 1 diabetes who were recruited from the Chair and Clinics of Paediatrics, Diabetology and Endocrinology, Medical University of Gdańsk. Mean age of patients was 12.8 ± 4 years. Type 1 diabetes was determined according to the criteria of the American Diabetes Association (2010). Patients with simultaneous autoimmune, chronic, and acute, inflammatory diseases were excluded from the study. The level of C-peptide was below 0.5 ng/mL in all
The IVS1 −397T>C estrogen receptor α genotype distribution
The frequencies of IVS1 −397T>C genotypes in DM1 group were as follows: CC, 28.7%; CT, 48.1%; TT, 23.2%. These frequencies were conformed to the Hardy–Weinberg equilibrium (p = 0.72). The genotype distributions in the group of healthy boys were: CC, 21.9%; CT,– 54.7%; TT, 23.4%, and they also conformed to the Hardy–Weinberg principle (p = 0.45). Comparison of frequencies of PvuII genotypes between the DM1 patients and healthy group revealed lack of significant differences (p = 0.57; χ2 Pearson test).
The IVS1 −397T>C ER-α gene polymorphism and clinical characteristics of patients
Discussion
Estrogens are important steroid hormones that regulate many organs in men and women. This effect of estrogens is mediated by activation of ERs, which are expressed in many tissues, including reproductive and immune systems. Prepubertal children are highly responsive to actions of sex steroids. In prepubertal boys normal plasma level of estradiol is very low, below the detection limit of the classical immunoassays. Therefore, even a small variation would result in a major change in the activity
Acknowledgments
This work was supported by The State Committee for Scientific Research ST28 (Medical University of Gdańsk).
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Conflict of Interest: The authors declare that they have no conflict of interest.