近日，来自波士顿大学医学院和英国埃克赛特大学的研究者合作研究揭示了影响调节血液中雌激素和睾酮水平的蛋白的遗传标记物。相关研究成果刊登在了国际杂志PLoS Genetics上。文章中，研究者也揭示了其中有些遗传标记物是和肝功能、代谢以及II型糖尿病相关的某些基因直接相关，研究者进而揭示了男性、女性代谢和生殖系统之间的遗传关系。
性激素结合球蛋白（SHBG）是男性和女性血液中携带睾酮和雌激素的关键蛋白质，作为性激素的主要载体，SHBG可以帮助调节骑在不同组织和器官中的效应。通过调节性激素来影响男女性的生殖能力，SHBG而且和许多慢性疾病比如II型糖尿病、乳腺癌及前列腺癌直接相关。
前期研究表明，50%的SHBG突变可由父母遗传而来，但是目前对于影响SHBG水平的特殊基因并不清楚。研究者分析了21，791个男性和女性的基因组来试图寻找影响SHBG水平的基因，同时研究者也确定了来自7046个男性和女性的全基因组相关性的结果。他们发现了12个单核苷酸多态性（SNPs）或者DNA突变序列，和血液中的SHBG水平直接相关。然而这些单核苷酸多态性的结果仅仅在男性中SHBG有16%的突变，在女性中有8%的突变，这就表明，SHBG的水平还受到其它别的因素的影响。
研究结果同样揭示了影响SHBG水平的SNPs和肝功能、肥胖以及II型糖尿病等的基因相关。研究者的研究结果揭示了人类生殖系统和代谢系统之间的关系，并且或许有可能解释在某些代谢疾病如II型糖尿病人中所观察到的性别差异。（生物谷Bioon.com）
编译自：Genetic Markers for Testosterone, Estrogen Level Regulation Identified
doi:10.1371/journal.pgen.1002805
PMC:
PMID:
A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation
Andrea D. Coviello1,2,3#, Robin Haring4#, Melissa Wellons5#, Dhananjay Vaidya6#, Terho Lehtimäki7#, Sarah Keildson8#, Kathryn L. Lunetta9, Chunyan He10,11, Myriam Fornage12, Vasiliki Lagou8,13, Massimo Mangino14, N. Charlotte Onland-Moret15, Brian Chen16, Joel Eriksson17, Melissa Garcia18, Yong Mei Liu19,20, Annemarie Koster21, Kurt Lohman19, Leo-Pekka Lyytikäinen7, Ann-Kristin Petersen22, Jennifer Prescott23,24, Lisette Stolk25,26, Liesbeth Vandenput17, Andrew R. Wood27, Wei Vivian Zhuang9, Aimo Ruokonen28, Anna-Liisa Hartikainen29, Anneli Pouta30, Stefania Bandinelli31, Reiner Biffar32, Georg Brabant33, David G. Cox34,35, Yuhui Chen8, Steven Cummings36, Luigi Ferrucci37, Marc J. Gunter35, Susan E. Hankinson24,38,39, Hannu Martikainen29, Albert Hofman26,40, Georg Homuth41, Thomas Illig42,43, John-Olov Jansson17, Andrew D. Johnson3, David Karasik44, Magnus Karlsson45, Johannes Kettunen46,47, Douglas P. Kiel44, Peter Kraft48, Jingmin Liu49, Östen Ljunggren50, Mattias Lorentzon17, Marcello Maggio51, Marcello R. P. Markus52, Dan Mellström17, Iva Miljkovic53, Daniel Mirel54, Sarah Nelson55, Laure Morin Papunen29, Petra H. M. Peeters15, Inga Prokopenko8,13, Leslie Raffel56, Martin Reincke57, Alex P. Reiner58, Kathryn Rexrode59, Fernando Rivadeneira25,26, Stephen M. Schwartz60, David Siscovick60, Nicole Soranzo14,61, Doris Stöckl62,63, Shelley Tworoger24,39, André G. Uitterlinden25,26,40, Carla H. van Gils15, Ramachandran S. Vasan1,3, H.-Erich Wichmann64,65,66, Guangju Zhai14,67, Shalender Bhasin2, Martin Bidlingmaier57, Stephen J. Chanock68, Immaculata De Vivo23,24, Tamara B. Harris21, David J. Hunter23,24, Mika Kähönen69, Simin Liu70, Pamela Ouyang71, Tim D. Spector14, Yvonne T. van der Schouw15, Jorma Viikari72, Henri Wallaschofski4, Mark I. McCarthy8,73,74, Timothy M. Frayling27, Anna Murray27, Steve Franks75, Marjo-Riitta Järvelin76,77,78,79¶, Frank H. de Jong25¶, Olli Raitakari80¶, Alexander Teumer41¶, Claes Ohlsson17¶, Joanne M. Murabito3,81¶*, John R. B. Perry8,14,27¶*
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.
