A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation
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.
Vyšlo v časopise:
A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation. PLoS Genet 8(7): e32767. doi:10.1371/journal.pgen.1002805
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002805
Souhrn
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.
Zdroje
1. HammondGL 2011 Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod 85 431 441
2. HammesAAndreassenTKSpoelgenRRailaJHubnerN 2005 Role of endocytosis in cellular uptake of sex steroids. Cell 122 751 762
3. ThompsonDJHealeyCSBaynesCKalmyrzaevBAhmedS 2008 Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev 17 3490 3498
4. WassellJMichailMSolimanNWardlePG 2011 The value of sex hormone binding globulin (SHBG) in predicting treatment response in polycystic ovary syndrome (PCOS). Clin Lab 57 95 98
5. XitaNTsatsoulisAChatzikyriakidouAGeorgiouI 2003 Association of the (TAAAA)n repeat polymorphism in the sex hormone-binding globulin (SHBG) gene with polycystic ovary syndrome and relation to SHBG serum levels. J Clin Endocrinol Metab 88 5976 5980
6. DingELSongYMansonJEHunterDJLeeCC 2009 Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 361 1152 1163
7. PerryJRWeedonMNLangenbergCJacksonAULyssenkoV 2010 Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet 19 535 544
8. CovielloADZhuangWVLunettaKLBhasinSUlloorJ 2011 Circulating testosterone and SHBG concentrations are heritable in women: the Framingham Heart Study. J Clin Endocrinol Metab 96 E1491 1495
9. MelzerDPerryJRHernandezDCorsiAMStevensK 2008 A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4 e1000072 doi:10.1371/journal.pgen.1000072
10. OhlssonCWallaschofskiHLunettaKLStolkLPerryJR 2011 Genetic determinants of serum testosterone concentrations in men. PLoS Genet 7 e1002313 doi:10.1371/journal.pgen.1002313
11. ChasmanDIPareGMoraSHopewellJCPelosoG 2009 Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet 5 e1000730 doi:10.1371/journal.pgen.1000730
12. HanSYZhouLUpadhyayaALeeSHParkerKL 2001 TFIIAalpha/beta-like factor is encoded by a germ cell-specific gene whose expression is up-regulated with other general transcription factors during spermatogenesis in the mouse. Biol Reprod 64 507 517
13. KudoMOsugaYKobilkaBKHsuehAJ 1996 Transmembrane regions V and VI of the human luteinizing hormone receptor are required for constitutive activation by a mutation in the third intracellular loop. J Biol Chem 271 22470 22478
14. HogeveenKNTalikkaMHammondGL 2001 Human sex hormone-binding globulin promoter activity is influenced by a (TAAAA)n repeat element within an Alu sequence. J Biol Chem 276 36383 36390
15. MartinLJTremblayJJ 2010 Nuclear receptors in Leydig cell gene expression and function. Biol Reprod 83 3 14
16. HuZXiaYGuoXDaiJLiH 2011 A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia. Nat Genet 44 183 186
17. LiXMertens-TalcottSUZhangSKimKBallJ 2010 MicroRNA-27a Indirectly Regulates Estrogen Receptor {alpha} Expression and Hormone Responsiveness in MCF-7 Breast Cancer Cells. Endocrinology 151 2462 2473
18. HarrisonMJTangYHDowhanDH 2010 Protein arginine methyltransferase 6 regulates multiple aspects of gene expression. Nucleic Acids Res 38 2201 2216
19. FranksSGharaniNMcCarthyM 2001 Candidate genes in polycystic ovary syndrome. Hum Reprod Update 7 405 410
20. ChenZJZhaoHHeLShiYQinY 2011 Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 43 55 59
21. CousinPCalemard-MichelLLejeuneHRaverotGYessaadN 2004 Influence of SHBG gene pentanucleotide TAAAA repeat and D327N polymorphism on serum sex hormone-binding globulin concentration in hirsute women. J Clin Endocrinol Metab 89 917 924
22. EhrmannDA 2005 Polycystic ovary syndrome. N Engl J Med 352 1223 1236
23. FranksS 1995 Polycystic ovary syndrome. N Engl J Med 333 853 861
24. AbeTKakyoMTokuiTNakagomiRNishioT 1999 Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem 274 17159 17163
25. LeeJWChoiHSGyurisJBrentRMooreDD 1995 Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol 9 243 254
26. SelvaDMHammondGL 2009 Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha. J Mol Endocrinol 43 19 27
27. JanneMHammondGL 1998 Hepatocyte nuclear factor-4 controls transcription from a TATA-less human sex hormone-binding globulin gene promoter. J Biol Chem 273 34105 34114
28. ReilingEvan 't RietEGroenewoudMJWelschenLMvan HoveEC 2009 Combined effects of single-nucleotide polymorphisms in GCK, GCKR, G6PC2 and MTNR1B on fasting plasma glucose and type 2 diabetes risk. Diabetologia 52 1866 1870
29. QiQWuYLiHLoosRJHuFB 2009 Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population. Diabetologia 52 834 843
30. LingYLiXGuQChenHLuD 2011 Associations of common polymorphisms in GCKR with type 2 diabetes and related traits in a Han Chinese population: a case-control study. BMC Med Genet 12 66
31. TanakaDNagashimaKSasakiMYamadaCFunakoshiS 2011 GCKR mutations in Japanese families with clustered type 2 diabetes. Mol Genet Metab 102 453 460
32. VarboABennMTybjaerg-HansenAGrandePNordestgaardBG 2011 TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population. Arterioscler Thromb Vasc Biol 31 451 457
33. TakeuchiFKatsuyaTChakrewarthySYamamotoKFujiokaA 2010 Common variants at the GCK, GCKR, G6PC2-ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations. Diabetologia 53 299 308
34. OnumaHTabaraYKawamotoRShimizuIKawamuraR 2010 The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population. J Hum Genet 55 600 604
35. HadaritsFKisfaliPMohasMMaaszADugaB 2011 Common functional variants of APOA5 and GCKR accumulate gradually in association with triglyceride increase in metabolic syndrome patients. Mol Biol Rep
36. HuCZhangRWangCYuWLuJ 2010 Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose metabolism and insulin secretion. PLoS ONE 5 e11761 doi:10.1371/journal.pone.0011761
37. KozianDHBarthelACousinEBrunnhoferRAnderkaO 2010 Glucokinase-activating GCKR polymorphisms increase plasma levels of triglycerides and free fatty acids, but do not elevate cardiovascular risk in the Ludwigshafen Risk and Cardiovascular Health Study. Horm Metab Res 42 502 506
38. MohasMKisfaliPJaromiLMaaszAFeherE 2010 GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness? Cardiovasc Diabetol 9 79
39. Orho-MelanderMMelanderOGuiducciCPerez-MartinezPCorellaD 2008 Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57 3112 3121
40. Perez-MartinezPDelgado-ListaJGarcia-RiosAMc MonagleJGulsethHL 2011 Glucokinase regulatory protein genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome. PLoS ONE 6 e20555 doi:10.1371/journal.pone.0020555
41. TamCHMaRCSoWYWangYLamVK 2009 Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents. Diabetes 58 765 769
42. YangZWenJTaoXLuBDuY 2011 Genetic variation in the GCKR gene is associated with non-alcoholic fatty liver disease in Chinese people. Mol Biol Rep 38 1145 1150
43. SeithelAKleinKZangerUMFrommMFKonigJ 2008 Non-synonymous polymorphisms in the human SLCO1B1 gene: an in vitro analysis of SNP c.1929A>C. Mol Genet Genomics 279 149 157
44. BuchSSchafmayerCVolzkeHSeegerMMiquelJF 2010 Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition. Gastroenterology 139 1942 1951 e1942
45. MiyaharaAOkamura-OhoYMiyashitaTHoshikaAYamadaM 2003 Genomic structure and alternative splicing of the insulin receptor tyrosine kinase substrate of 53-kDa protein. J Hum Genet 48 410 414
46. GalliganCLBaigEBykerkVKeystoneECFishEN 2007 Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity. Genes Immun 8 480 491
47. MillardTHDawsonJMacheskyLM 2007 Characterisation of IRTKS, a novel IRSp53/MIM family actin regulator with distinct filament bundling properties. J Cell Sci 120 1663 1672
48. DupuisJLangenbergCProkopenkoISaxenaRSoranzoN 2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42 105 116
49. WangLMuromotoNHayashiHMitaniYUeharaH 1997 Hyperinsulinemia but no diabetes in transgenic mice homozygously expressing the tyrosine kinase-deficient human insulin receptor. Biochem Biophys Res Commun 240 446 451
50. HotamisligilGSBudavariAMurrayDSpiegelmanBM 1994 Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest 94 1543 1549
51. KusariJTakataYHatadaEFreidenbergGKoltermanO 1991 Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles. J Biol Chem 266 5260 5267
52. BlockNEKomoriKRobinsonKADuttonSLLamCF 1991 Diabetes-associated impairment of hepatic insulin receptor tyrosine kinase activity: a study of mechanisms. Endocrinology 128 312 322
53. OdawaraMKadowakiTYamamotoRShibasakiYTobeK 1989 Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor. Science 245 66 68
54. ArnerPPollareTLithellHLivingstonJN 1987 Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 30 437 440
55. SelvaDMHammondGL 2009 Peroxisome-proliferator receptor gamma represses hepatic sex hormone-binding globulin expression. Endocrinology 150 2183 2189
56. AltshulerDHirschhornJNKlannemarkMLindgrenCMVohlMC 2000 The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26 76 80
57. HakonarsonHGrantSF 2011 GWAS and its impact on elucidating the etiology of diabetes. Diabetes Metab Res Rev
58. SelvaDMHogeveenKNInnisSMHammondGL 2007 Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest 117 3979 3987
59. ShihDQBussenMSehayekEAnanthanarayananMShneiderBL 2001 Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet 27 375 382
60. YinLMaHGeXEdwardsPAZhangY 2011 Hepatic hepatocyte nuclear factor 4alpha is essential for maintaining triglyceride and cholesterol homeostasis. Arterioscler Thromb Vasc Biol 31 328 336
61. WilsonW3rdPardo-Manuel de VillenaFLyn-CookBDChatterjeePKBellTA 2004 Characterization of a common deletion polymorphism of the UGT2B17 gene linked to UGT2B15. Genomics 84 707 714
62. TurgeonDCarrierJSLevesqueEHumDWBelangerA 2001 Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members. Endocrinology 142 778 787
63. MenardVEapOHarveyMGuillemetteCLevesqueE 2009 Copy-number variations (CNVs) of the human sex steroid metabolizing genes UGT2B17 and UGT2B28 and their associations with a UGT2B15 functional polymorphism. Hum Mutat 30 1310 1319
64. LevesqueEBeaulieuMGreenMDTephlyTRBelangerA 1997 Isolation and characterization of UGT2B15(Y85): a UDP-glucuronosyltransferase encoded by a polymorphic gene. Pharmacogenetics 7 317 325
65. SwansonCMellstromDLorentzonMVandenputLJakobssonJ 2007 The uridine diphosphate glucuronosyltransferase 2B15 D85Y and 2B17 deletion polymorphisms predict the glucuronidation pattern of androgens and fat mass in men. J Clin Endocrinol Metab 92 4878 4882
66. ChouinardSBarbierOBelangerA 2007 UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 enzymes are major determinants of the androgen response in prostate cancer LNCaP cells. J Biol Chem 282 33466 33474
67. ChouinardSPelletierGBelangerABarbierO 2004 Cellular specific expression of the androgen-conjugating enzymes UGT2B15 and UGT2B17 in the human prostate epithelium. Endocr Res 30 717 725
68. PathiSSJutooruIChadalapakaGSreevalsanSAnandS 2011 GT-094, a NO-NSAID, inhibits colon cancer cell growth by activation of a reactive oxygen species-microRNA-27a: ZBTB10-specificity protein pathway. Mol Cancer Res 9 195 202
69. KumarRManningJSpendloveHEKremmidiotisGMcKirdyR 2006 ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription. Mol Cancer Res 4 655 665
70. KumarRSelthLSchulzRBTayBSNeilsenPM 2011 Genome-wide mapping of ZNF652 promoter binding sites in breast cancer cells. J Cell Biochem
71. KumarRCheneyKMNeilsenPMSchulzRBCallenDF 2010 CBFA2T3-ZNF651, like CBFA2T3-ZNF652, functions as a transcriptional corepressor complex. FEBS Lett 584 859 864
72. CallenDFRicciardelliCButlerMStapletonAStahlJ 2010 Co-expression of the androgen receptor and the transcription factor ZNF652 is related to prostate cancer outcome. Oncol Rep 23 1045 1052
73. BaldassarreGRomanoAArmenanteFRambaldiMPaolettiI 1997 Expression of teratocarcinoma-derived growth factor-1 (TDGF-1) in testis germ cell tumors and its effects on growth and differentiation of embryonal carcinoma cell line NTERA2/D1. Oncogene 15 927 936
74. BurgerHGDudleyECCuiJDennersteinLHopperJL 2000 A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 85 2832 2838
75. SchijfCPvan der MoorenMJDoesburgWHThomasCMRollandR 1993 Differences in serum lipids, lipoproteins, sex hormone binding globulin and testosterone between the follicular and the luteal phase of the menstrual cycle. Acta Endocrinol (Copenh) 129 130 133
76. LinkEParishSArmitageJBowmanLHeathS 2008 SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359 789 799
77. ChambersJCZhangWSehmiJLiXWassMN 2011 Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 43 1131 1138
78. LeeDKKuriharaIJeongJWLydonJPDeMayoFJ 2010 Suppression of ERalpha activity by COUP-TFII is essential for successful implantation and decidualization. Mol Endocrinol 24 930 940
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 7
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