Gene Polymorphisms Determining Sex Hormone-Binding Globulin Levels and Endometriosis Risk

Endometriosis is a hormone-dependent disease, in the pathophysiology of which sex hormones (androgens, estrogens, etc.) are involved. The level of bioactive androgens/estrogens (in the free state) in the organism largely depends on sex hormone-binding globulin (SHBG), which binds/transports a significant portion of the androgens/estrogens of the body and, due to this, changes the amount of these hormones in a free state (bioactive), which may be important in the development of endometriosis. The study was devoted to identifying the link between the genetic determinants (single nucleotide polymorphisms [SNPs]) of SHBG (according to predating genome-wide associative studies [GWAS]) and the risk of endometriosis in the Caucasian women of Russia. The study was accomplished on a total sample of 1368 women (395 endometriosis; 973 endometriosis free [controls]). Nine loci with an impact on SHBG level in predating GWAS have been examined. The search for associations of these loci with endometriosis was carried out: both their independent effects and interlocus interactions with an in silico interpretation of the functionality/pathways in which endometriosis-related loci and strongly linked SNPs were involved have been evaluated. Polymorphic locus rs440837 (A > G) ZBTB10 correlated with endometriosis development (recessive genetic model): the SHBG-raising genotype GG rs440837 (A > G) ZBTB10 serves as a risk factor for the disease formation; its presence in the genotype almost doubles the risk of endometriosis (OR = 1.91; 95%CI = 1.13-2.98; p_perm = 0.024; power = 81.13%). The SHBG-impacts of 7 SNPs from 9 analyzed loci such as rs17496332 (A > G) PRMT6, rs780093 (C > T) GCKR, rs10454142 (T > C) PPP1R21, rs3779195 (T > A) BAIAP2L1, rs440837 (A > G) ZBTB10, rs7910927 (G > T) JMJD1C, and rs8023580 (T > C) NR2F2 interacting with each other have been endometriosis-associated. Endometriosis-causal SNP rs440837 (A > G) ZBTB10 and 5 proxy SNPs determine the DNA interaction in the region of 3 genes (RP11-48B3.3, RP11-48B3.4, ZBTB10) with 22 transcription factors and, due to this, affect the processes of development of the endocrine system, gene transcription regulation, TGF-beta signaling pathway, regulation of cell proliferation/differentiation, etc. In conclusion, the results of this study showed the endometriosis risk effect of the SHBG-impact polymorphic variants.