{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T22:14:14Z","timestamp":1772748854839,"version":"3.50.1"},"reference-count":40,"publisher":"The Endocrine Society","issue":"6","license":[{"start":{"date-parts":[[2017,4,11]],"date-time":"2017-04-11T00:00:00Z","timestamp":1491868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,6,1]]},"abstract":"<jats:sec>\n                  <jats:title>Context:<\/jats:title>\n                  <jats:p>Testosterone (T) is a central androgenic hormone, and sex hormone-binding globulin (SHBG) is the major determinant of its bioactivity. There are no acknowledged genetic variants with clear-cut clinical implications, modulating T levels in men.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective:<\/jats:title>\n                  <jats:p>To confirm genetic associations of top loci (SHBG, GCKR, SLCO1B1, and JMJD1C) from genome-wide association (GWA) studies for serum SHBG and T.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design, Patients:<\/jats:title>\n                  <jats:p>Groups differing in general and reproductive parameters: young men (n = 540; 19.3 \u00b1 1.8 years), severe idiopathic male infertility patients (n = 641; 31.6 \u00b1 6.0 years), and male partners of pregnant women (n = 324; 31.9 \u00b1 6.6 years). All patients were recruited at the Andrology Centre, Tartu University Hospital, Estonia.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Main Outcome Measure(s):<\/jats:title>\n                  <jats:p>Genetic associations with reproductive hormones, testicular and sperm parameters (linear regression, additive model); intergroup allele\/genotype distribution comparisons.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results:<\/jats:title>\n                  <jats:p>Associations with serum SHBG levels were robust for SHBG \u221268 G&amp;gt;A [rs1799941; meta-analysis: P = 3.7 \u00d7 10\u221214; allelic effect (standard error) = 4.67 (0.62) nmol\/L], SHBG +1091 C&amp;gt;T [rs727428; P = 7.3 \u00d7 10\u221211; \u22123.74 (0.57)], SHBG Pro185Leu [rs6258; P = 1.2 \u00d7 10\u22124, \u221212.2 (3.17)], and GCKR Pro446Leu [rs1260326; P = 1.5 \u00d7 10\u22124; \u22122.2 (0.59)]. Measured T concentrations correlated with genetically modulated levels of SHBG (r = 0.48 to 0.74, P &amp;lt; 0.0001), guaranteeing stable availability of free T. Among infertile men, SHBG Pro185Leu substitution showed additional downstream effect on luteinizing hormone [P = 5.1 \u00d7 10\u22125; \u22121.66 (0.57) IU\/L] and follicle-stimulating hormone [P = 3.4 \u00d7 10\u22123; \u22122.48 (1.23) IU\/L]. No associations with male reproductive parameters were detected for SHBG Asp327Asn (rs6259), SLCO1B1 Val174Ala (rs4149056), and JMJD1C intronic variant rs7910927.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions:<\/jats:title>\n                  <jats:p>Claims were replicated and additional associations were detected for four of seven tested GWAS top loci. Perspective clinical investigations of these variants are hypotestosteronemia among aging men and pharmacogenetics of hormone replacement therapy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/js.2017-00050","type":"journal-article","created":{"date-parts":[[2017,4,11]],"date-time":"2017-04-11T18:06:53Z","timestamp":1491934013000},"page":"560-576","source":"Crossref","is-referenced-by-count":13,"title":["Genetics of Sex Hormone-Binding Globulin and Testosterone Levels in Fertile and Infertile Men of Reproductive Age"],"prefix":"10.1210","volume":"1","author":[{"given":"Marina","family":"Grigorova","sequence":"first","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia"},{"name":"Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margus","family":"Punab","sequence":"additional","affiliation":[{"name":"Andrology Unit, Tartu University Hospital, 50406 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olev","family":"Poolamets","sequence":"additional","affiliation":[{"name":"Andrology Unit, Tartu University Hospital, 50406 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mart","family":"Adler","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia"},{"name":"Andrology Unit, Tartu University Hospital, 50406 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Vihljajev","sequence":"additional","affiliation":[{"name":"Andrology Unit, Tartu University Hospital, 50406 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maris","family":"Laan","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia"},{"name":"Human Molecular Genetics Research Group, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2017,4,11]]},"reference":[{"issue":"9","key":"2020071622324985600_B1","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1093\/humrep\/den216","article-title":"FSHB promoter polymorphism within evolutionary conserved element is associated with serum FSH level in men","volume":"23","author":"Grigorova","year":"2008","journal-title":"Hum Reprod"},{"key":"2020071622324985600_B2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1210\/jc.2009-1010","article-title":"Increased prevalence of the -211 T allele of follicle stimulating hormone (FSH) beta subunit promoter polymorphism and lower serum FSH in infertile men","volume":"95","author":"Grigorova","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071622324985600_B3","first-page":"1344","article-title":"Toward a pharmacogenetic approach to male infertility: polymorphism of follicle-stimulating hormone beta-subunit promoter.","volume-title":"Fertil Steril","author":"Ferlin","year":"2011"},{"issue":"2","key":"2020071622324985600_B4","first-page":"751","article-title":"Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms","volume":"84","author":"Simoni","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2020071622324985600_B5","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1111\/j.2047-2927.2012.00028.x","article-title":"Study in 1790 Baltic men: FSHR Asn680Ser polymorphism affects total testes volume","volume":"1","author":"Grigorova","year":"2013","journal-title":"Andrology"},{"issue":"2","key":"2020071622324985600_B6","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.fertnstert.2005.02.031","article-title":"Single-nucleotide polymorphisms in the promoter region influence the expression of the human follicle-stimulating hormone receptor","volume":"84","author":"Wunsch","year":"2005","journal-title":"Fertil Steril"},{"issue":"4","key":"2020071622324985600_B7","doi-asserted-by":"crossref","first-page":"e94244","DOI":"10.1371\/journal.pone.0094244","article-title":"Reproductive physiology in young men is cumulatively affected by FSH-action modulating genetic variants: FSHR -29G\/A and c.2039 A\/G, FSHB -211G\/T","volume":"9","author":"Grigorova","year":"2014","journal-title":"PLoS One"},{"issue":"1","key":"2020071622324985600_B8","first-page":"164","article-title":"An immunologically anomalous luteinizing hormone variant in a healthy woman","volume":"74","author":"Pettersson","year":"1992","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2020071622324985600_B9","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/andr.12022","article-title":"Carriers of V-LH among 1593 Baltic men have significantly higher serum LH","volume":"3","author":"Punab","year":"2015","journal-title":"Andrology"},{"issue":"9","key":"2020071622324985600_B10","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.2337\/db09-0031","article-title":"Prediction of metabolic syndrome by low serum testosterone levels in men: results from the study of health in Pomerania","volume":"58","author":"Haring","year":"2009","journal-title":"Diabetes"},{"issue":"4","key":"2020071622324985600_B11","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1210\/jc.2013-2052","article-title":"Late-onset hypogonadism and mortality in aging men","volume":"99","author":"Pye","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2020071622324985600_B12","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1093\/eurheartj\/ehq009","article-title":"Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79","volume":"31","author":"Haring","year":"2010","journal-title":"Eur Heart J"},{"key":"2020071622324985600_B13","doi-asserted-by":"crossref","first-page":"35539","DOI":"10.1038\/srep35539","article-title":"Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis","volume":"6","author":"Laurent","year":"2016","journal-title":"Sci Rep"},{"key":"2020071622324985600_B14","doi-asserted-by":"crossref","first-page":"e1002313","DOI":"10.1371\/journal.pgen.1002313","article-title":"Genetic determinants of serum testosterone concentrations in men","volume":"7","author":"Ohlsson","year":"2011","journal-title":"PLoS Genet"},{"issue":"7","key":"2020071622324985600_B15","doi-asserted-by":"crossref","first-page":"e1002805","DOI":"10.1371\/journal.pgen.1002805","article-title":"A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation","volume":"8","author":"Coviello","year":"2012","journal-title":"PLoS Genet"},{"issue":"23","key":"2020071622324985600_B16","doi-asserted-by":"crossref","first-page":"5222","DOI":"10.1093\/hmg\/dds361","article-title":"Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men","volume":"21","author":"Jin","year":"2012","journal-title":"Hum Mol Genet"},{"issue":"12","key":"2020071622324985600_B17","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1210\/jc.2006-0679","article-title":"SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite levels, and hip bone mineral density","volume":"91","author":"Eriksson","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2020071622324985600_B18","doi-asserted-by":"crossref","first-page":"E719","DOI":"10.1210\/jc.2010-1842","article-title":"Polymorphisms in the SHBG gene influence serum SHBG levels in women with polycystic ovary syndrome","volume":"96","author":"Wickham","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2020071622324985600_B19","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1158\/1055-9965.EPI-08-0734","article-title":"Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women","volume":"17","author":"Thompson","year":"2008","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"2","key":"2020071622324985600_B20","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1210\/jc.2002-021553","article-title":"Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone-binding globulin concentration in hirsute women","volume":"89","author":"Cousin","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2020071622324985600_B21","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.molmed.2015.08.004","article-title":"Modulation of glucokinase regulatory protein: a double-edged sword?","volume":"21","author":"Brouwers","year":"2015","journal-title":"Trends Mol Med"},{"key":"2020071622324985600_B22","first-page":"97","article-title":"Pharmacogenomics of statins: understanding susceptibility to adverse effects","volume":"9","author":"Kitzmiller","year":"2016","journal-title":"Pharm Genomics Pers Med"},{"key":"2020071622324985600_B23","doi-asserted-by":"crossref","first-page":"e0163466","DOI":"10.1371\/journal.pone.0163466","article-title":"JMJD1C exhibits multiple functions in epigenetic regulation during spermatogenesis","volume":"11","author":"Nakajima","year":"2016","journal-title":"PLoS One"},{"key":"2020071622324985600_B24","unstructured":"Punab M. Male Fertility and Its Risk Factors in Estonia [PhD thesis]. Tartu, Estonia: University of Tartu Press; 2007:25\u201328."},{"key":"2020071622324985600_B25","volume-title":"Laboratory Manual for the Examination of the Human Semen and Sperm\u2014Cervical Mucus Interaction","author":"World Health Organization","year":"1999","edition":"4th ed."},{"issue":"1","key":"2020071622324985600_B26","first-page":"18","article-title":"Causes of male infertility: a 9-year prospective monocentre study on 1737 patients with reduced total sperm counts","volume":"32","author":"Punab","year":"2017","journal-title":"Hum Reprod"},{"issue":"4","key":"2020071622324985600_B27","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1046\/j.1365-2605.2000.00240.x","article-title":"Inter-observer variation in the results of the clinical andrological examination including estimation of testicular size","volume":"23","author":"Carlsen","year":"2000","journal-title":"Int J Androl"},{"key":"2020071622324985600_B28","volume-title":"Laboratory Manual for the Examination and Processing of Human Semen","author":"World Health Organization","year":"2010","edition":"5th ed"},{"issue":"10","key":"2020071622324985600_B29","doi-asserted-by":"crossref","first-page":"3666","DOI":"10.1210\/jcem.84.10.6079","article-title":"A critical evaluation of simple methods for the estimation of free testosterone in serum","volume":"84","author":"Vermeulen","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"2020071622324985600_B30","doi-asserted-by":"crossref","first-page":"2680","DOI":"10.1093\/jn\/135.11.2680","article-title":"Polymorphisms in the CYP19 gene may affect the positive correlations between serum and urine phytoestrogen metabolites and plasma androgen concentrations in men","volume":"135","author":"Low","year":"2005","journal-title":"J Nutr"},{"issue":"13","key":"2020071622324985600_B31","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am J Hum Genet"},{"key":"2020071622324985600_B32","first-page":"40","article-title":"Meta: an R package for meta-analysis","volume":"7","author":"Schwarzer","year":"2007","journal-title":"R News"},{"issue":"6","key":"2020071622324985600_B33","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1093\/humrep\/der062","article-title":"Quantitative trait analysis suggests polymorphisms of estrogen-related genes regulate human sperm concentrations and motility","volume":"26","author":"Lee","year":"2011","journal-title":"Hum Reprod"},{"issue":"7","key":"2020071622324985600_B34","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1210\/jc.2015-4106","article-title":"Low free testosterone is associated with hypogonadal signs and symptoms in men with normal total testosterone","volume":"101","author":"Antonio","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2020071622324985600_B35","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.urology.2012.01.068","article-title":"Greater percent-free testosterone is associated with high-grade prostate cancer in men undergoing prostate biopsy","volume":"80","author":"Albisinni","year":"2012","journal-title":"Urology"},{"issue":"11","key":"2020071622324985600_B36","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/nrurol.2015.238","article-title":"The practical management of testosterone deficiency in men","volume":"12","author":"Aversa","year":"2015","journal-title":"Nat Rev Urol"},{"issue":"7307","key":"2020071622324985600_B37","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/nature09270","article-title":"Biological, clinical and population relevance of 95 loci for blood lipids","volume":"466","author":"Teslovich","year":"2010","journal-title":"Nature"},{"issue":"2","key":"2020071622324985600_B38","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/ng.2500","article-title":"Genome-wide association analyses identify 18 new loci associated with serum urate concentrations","volume":"45","author":"Kottgen","year":"2013","journal-title":"Nat Genet"},{"key":"2020071622324985600_B39","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1186\/s12885-016-2373-3","article-title":"SLCO1B1*5 polymorphism (rs4149056) is associated with chemotherapy-induced amenorrhea in premenopausal women with breast cancer: a prospective cohort study","volume":"16","author":"Reimer","year":"2016","journal-title":"BMC Cancer"},{"issue":"12","key":"2020071622324985600_B40","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1038\/nsmb.2702","article-title":"JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks","volume":"20","author":"Watanabe","year":"2013","journal-title":"Nat Struct Mol Biol"}],"container-title":["Journal of the Endocrine Society"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jes\/article-pdf\/1\/6\/560\/17272855\/js.2017-00050.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jes\/article-pdf\/1\/6\/560\/17272855\/js.2017-00050.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T10:56:14Z","timestamp":1594983374000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jes\/article\/1\/6\/560\/3574887"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,11]]},"references-count":40,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2017,6,1]]}},"URL":"https:\/\/doi.org\/10.1210\/js.2017-00050","relation":{},"ISSN":["2472-1972"],"issn-type":[{"value":"2472-1972","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,6,1]]},"published":{"date-parts":[[2017,4,11]]}}}