Analysis of Four Polymorphisms Located at the Promoter of the Estrogen Receptor Alpha ESR1 Gene in a Population With Gender Incongruence

Abstract

Introduction Gender incongruence defines a state in which individuals feel discrepancy between the sex assigned at birth and their gender. Some of these people make a social transition from male to female (trans women) or from female to male (trans men). By contrast, the word cisgender describes a person whose gender identity is consistent with their sex assigned at birth. Aim To analyze the implication of the estrogen receptor α gene ( ESR1 ) in the genetic basis of gender incongruence. Main Outcome Measures Polymorphisms rs9478245, rs3138774, rs2234693, rs9340799. Method We carried out the analysis of 4 polymorphisms located at the promoter of the ESR1 gene (C1 = rs9478245, C2 = rs3138774, C3 = rs2234693, and C4 = rs9340799) in a population of 273 trans women, 226 trans men, and 537 cis gender controls. For SNP polymorphisms, the allele and genotype frequencies were analyzed by χ 2 test. The strength of the SNP associations with gender incongruence was measured by binary logistic regression. For the STR polymorphism, the mean number of repeats were analyzed by the Mann–Whitney U test. Measurement of linkage disequilibrium and haplotype frequencies were also performed. Results The C2 median repeats were shorter in the trans men population. Genotypes S/S and S/L for the C2 polymorphism were overrepresented in the trans men group ( P = .012 and P = .003 respectively). We also found overtransmission of the A/A genotype (C4) in the trans men population ( P = .017), while the A/G genotype (C4) was subrepresented ( P = .009]. The analyzed polymorphisms were in linkage disequilibrium. In the trans men population, the T(C1)-L(C2)-C(C3)-A(C4) haplotype was overrepresented ( P = .019) while the T(C1)-L(C2)-C(C3)-G(C4) was subrepresented ( P = .005). Conclusion The ESR1 is associated with gender incongruence in the trans men population. Fernández R, Delgado-Zayas E, Ramírez K, et al. Analysis of Four Polymorphisms Located at the Promoter of the Estrogen Receptor Alpha ESR1 Gene in a Population With Gender Incongruence. Sex Med 2020;8:490–500.

MANAGEMENT OF ENDOCRINE DISEASE: Optimal feminizing hormone treatment in transgender people

“…According to Table 1, E1 measurements could be relevant during oral E2 treatment, but this hypothesis remains to be tested. Recently, polymorphisms of the estrogen receptor α gene were associated with gender incongruence in transgender men, whereas no association was found in transgender women (106). In postmenopausal women, variations in the estrogen receptors affected individual variation in treatment effects of E2 (107), and further studies regarding variations in the estrogen receptor are requested in transgender study populations.…”

An Analysis of the Implication of Estrogens and Steroid Receptor Coactivators in the Genetic Basis of Gender Incongruence

“…Most studies about the genetic basis of GI analyzed the implication of some DNA polymorphisms related to ERs, α and β, the AR, the aromatase CYP19A1 or the CYP17A1 [11][12][13][14][15][16][17][18][19][20] as well as the interaction effects (epistasis) among them [15,21]. A summary of the principal studies about the genetic component of GI is shown in Table 1.…”

Epigenetics Is Implicated in the Basis of Gender Incongruence: An Epigenome-Wide Association Analysis

“…Paralleling the brain structural research, studies have been searching for a genetic component of GI. Some authors found variations in the DNA sequence of the androgen (AR) and estrogen (ERs, α and β) ( Henningsson et al, 2005 ; Hare et al, 2009 ; Fernández et al, 2014a , b , 2016 , 2018 , 2020a ; Cortés-Cortés et al, 2017 ; Foreman et al, 2019 ) that could hypothetically modulate the sensitivity of the nuclear steroid receptors. Furthermore, since AR and ER (α and β) are, at the same time, hormonal receptors and transcription factors, the modulation of gene expression via activation of AR and ERs by their ligands and coactivators, could be another presumptive mechanism underlying GI ( Fernández et al, 2021 ; Ramírez et al, 2021 ).…”