Association of estrogen and aromatase gene polymorphisms with systemic lupus erythematosus

Abstract

Experimental and animal studies suggested that estrogens play an important role in the development of systemic lupus erythematosus (SLE) through a variety of mechanisms involved in the regulation of the immune system. The objective of this study was to investigate the association between genetic variations in estrogen metabolic pathway genes, including estrogen receptor α (ESR1), estrogen receptor β (ESR2), and aromatase (CYP19A1), and risk of SLE. We performed a genetic study of SLE among 46 medical record-confirmed female SLE cases and 102 female controls participating in an Internet-based case–control study of SLE. Polymorphisms analysed included: ESR1 PvuII, XbaI, and GT repeat; ESR2 RsaI, AluI, and CA repeat; and CYP19A1 RsaI, SfaN1, and TTTA repeat. We found significant association of the ESR1 PvuII (PP vs. pp, odds ratio (OR): 3.1, 95% confidence interval (CI): 1.1–9.3) and XbaI (XX vs. xx, adjusted OR: 3.4, 95% CI: 1.1–10.5) with SLE. Carrying the PPXX genotype conferred the highest risk (PPXX vs. ppxx, OR: 4.6, 95% CI: 1.3–15.9). We also found an association of SLE with the ESR2 CA repeat (SS vs. LL, OR: 2.8, 95% CI: 1.0–8.0). Our results support a role of estrogen in pathogenesis of SLE and suggested that genetic variants in the estrogen receptor genes might influence susceptibility.

Association between ERα polymorphisms and systemic lupus erythematosus: susceptibility and in silico analysis

“…In addition, they observed higher risk of SLE in individuals with combined PP/XX (CC/GG) genotypes. 20 In a meta-analysis performed by Cai et al, the combination of ERa PvuII CC/CT genotypes was associated with SLE susceptibility (especially among Asians). Although they observed no significant association between the ERa XbaI polymorphism and SLE in the overall analysis, a marginally significant association was reported between the combination of GG/ GA genotypes and SLE in Asians.…”

“…17,18 The relation between ERa PvuII and XbaI polymorphisms and the expression of Th1 and Th2 cytokine such as interleukin-10(IL-10), interleukin-4 (IL-4), interleukin-2 (IL-2) and interferon (IFN)-c and SLE have been shown. 19 Although several studies aimed to assay the relation between the ERa polymorphisms and SLE 20,21 , the results were inconsistent. Therefore, the current study was performed to investigate the association between the ERa XbaI and PvuII polymorphisms with SLE susceptibility in the southeast of Iran.…”

“…5 Higher incidence of SLE among women in reproductive years has introduced estrogens as the probable mediators of SLE. 6 Some studies have not revealed significant difference in plasma estradiol levels between women with SLE and control women. 7 Evidence provided by Kanda et al shows that estrogen increases the anti-double-stranded DNA (anti-dsDNA) antibody production in peripheral blood mononuclear cells (PBMCs) 8 and it has been shown that estrogen decreases in vitro apoptosis in PBMCs of SLE patients.…”

Association between estrogen receptor‐α gene polymorphisms and dermatomyositis in Bulgarian patients

“…Estrogen acts through two nuclear receptors: estrogen receptor‐α (ER‐α), coded by ESR1 , and estrogen receptor‐β (ER‐β), coded by ESR2 . The PvuII P (C) and XbaI X (G) variants were found to lead to enhanced ER‐α activity and elevated serum estradiol production . Until now, there has been no study of the association of ESR1 XbaI x/X and PvuII p/P polymorphisms in DM.…”

Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis

“…Recently, Wang et al showed that polymorphisms in ER genes were associated with SLE, providing a mechanism for how estrogen metabolites could increase the risk for SLE in women [149]. Estrogen has been found to increase autoAbs and IC deposition in animal models of lupus [144,150].…”