👤 M Bidlingmaier

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance. Show less

The investigation of expression and functional relevance of G-protein coupled receptors in primary aldosteronism (PA) by molecular and clinical studies. Tissues of 14 aldosterone-producing adenomas (APA), of one unilateral adrenal hyperplasia and of six healthy adult adrenal glands; 12 patients with confirmed PA due to APA; (n=5), idiopathic hyperaldosteronism (n=7) and 8 control subjects (C). The tissues were subjected to a quantitative PCR for determination of mRNA expression levels of AT2R1, GIPR, MC2R, GnRHR, LHR, TRHR, TSHR, glucagon-R, V1aR, V2R, and 5-HT4R. The patients and controls were enrolled in a test protocol consisting of stimulation by posture, mixed meal, ACTH, GnRH, TRH, glucagon, vasopressin, and metoclopramide (MCP). Three patients could be analyzed by both studies. A positive response was defined as an aldosterone increase of more than 50% following stimulation. All the tissues revealed AT2R1, MC2R, AVPR, and 5-HT4R mRNA expression. LHR mRNA was found in normal adrenals and 13 adrenal tumors. By contrast with normal adrenals tumorous adrenal tissue expressed GnRHR mRNA (4/15) and TSHR mRNA (1/15). Both the patients and controls responded to posture, ACTH, glucagon, AVP, and MCP. Specific responses were seen in one patient following TRH and three patients following GnRH stimulation. We provide evidence for peptide hormone responsiveness to various peptide hormones in patients with PA, including GnRH and TRH. A good correlation between clinical and molecular testing could be observed, making an involvement of the receptor expressed in PA possible. Show less