Home >Current Issue

Volume: 6, Issue: 5, Sep-Oct, 2018
DOI: 10.7324/JABB.2018.60501

Research Article

Comprehensive analysis of damage associated SNPs of Sex Hormone Binding Globulin gene

Richa Bhatnager, Mehak Dangi, Amita Suneja Dang

  Author Affiliations


Sex hormone-binding globulin (SHBG) controls the bioavailability of androgens, and its association has been found in a number of disorders such as hyperandrogenism, obesity, diabetes, and cancer. Many human singlenucleotide polymorphisms (SNPs) that are now recognized provide an opportunity to understand the association between genotype and phenotype. In our analysis, we found P185L (rs6258) substitution possess damaging effect on protein structure. ConSurf analysis predicted P185L is conserved and exposed in protein structure. Secondary and tertiary structure of mutated protein was predicted by PSIPRED and Swiss Modeller which were by superimposed using UCSF Chimera to predict their side-chain modification. FT site server predicted amino acid residues that are involved in ligand-binding site of SHBG protein and none of the substitution was involved in ligand-binding site. Six SNPs associated with untranslated region affect the miRNA seed region, thereby affect gene regulation. Ten SNPs associated with splice site were found to alter slicing signal by our study, hence affect the mRNA processing and resulted in faulty polypeptide. Alteration in SHBG polypeptide affects its affinity toward androgen binding and its physiological level as well. These SNPs are still uncharacterized; hence providing a baseline for validation of their association with the susceptibility of diseases and develop personalized therapeutics.


Sex hormone-binding globulin, Androgens, Untranslated regions, Splice site, Non-synonymous singlenucleotide polymorphism.

Citation: Bhatnager R, Dangi M, Dang AS. Comprehensive analysis of damage associated single nucleotide polymorphisms of sex hormone binding globulin gene. J App Biol Biotech. 2018; Online First.

Copyright: Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.


1. Aydın B, Winters SJ. Sex hormone-binding globulin in children and adolescents. Journal of clinical research in pediatric endocrinology. 2016;8(1):1. https://doi.org/10.4274/jcrpe.2764

2. P’etra PH, Namkung PC, Senear DF, McCrae DA, Rousslang KW, Teller DC, Ross JBA. Molecular characterization of the sex steroid binding protein (SBP) of plasma. Re-examination of rabbit SBP and comparison with the human, macaque and baboon proteins. J. Steroid Biochem. 1986; 25:191–200. https://doi.org/10.1016/0022-4731(86)90416-4

3. Hammond GL, Underbill DA, Rykse HM, Smith CL. The human sex hormone-binding globulin gene contains exons for androgen-binding protein and two other testicular messenger RNAs. Molecular Endocrinology. 1989 ;3(11):1869-76. https://doi.org/10.1210/mend-3-11-1869

4. Berube D, Seralini GE, Gagne R, Hammond GL. Localization of the human sex hormone-binding globulin gene (SHBG) to the short arm of chromosome 17 (17p12→ p13). Cytogenetic and Genome Research. 1990;54(1-2):65-7. https://doi.org/10.1159/000132958

5. Rosner W, aden DP, khan MS. Hormonal influences on the secretion of steroid-binding proteins by a human hepatoma-derived cell line. The Journal of Clinical Endocrinology & Metabolism. 1984;59(4):806-8. https://doi.org/10.1210/jcem-59-4-806

6. Plymate SR, matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. The Journal of Clinical Endocrinology & Metabolism. 1988;67(3):460-4. https://doi.org/10.1210/jcem-67-3-460

7. Edmunds SE, Stubbs AP, Santos AA, Wilkinson ML. Estrogen and androgen regulation of sex hormone binding globulin secretion by a human liver cell line. The Journal of steroid biochemistry and molecular biology. 1990;37(5):733-9. https://doi.org/10.1016/0960-0760(90)90358-R

8. Cibula D, Skrha J, Hill M, Fanta M, Haakova L, Vrbikova J, Zivny J. Prediction of insulin sensitivity in nonobese women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2002;87(12):5821-5. https://doi.org/10.1210/jc.2002-020586

9. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931-45. https://doi.org/10.1038/nature03001

10. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931-45. https://doi.org/10.1038/nature03001

11. Dabhi B, Mistry KN. In silico analysis of single nucleotide polymorphism (SNP) in human TNF-\a gene. Meta gene. 2014;2:586-95. https://doi.org/10.1016/j.mgene.2014.07.005

12. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TD, Lewis H, Schafer AJ, Chatterjee VK. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature.1999;402(6764):880-3. https://doi.org/10.1038/47254

13. Chasman D, Adams RM. Predicting the functional consequences of non-synonymous single nucleotide polymorphisms: structure-based assessment of amino acid variation. Journal of molecular biology. 2001;307(2):683-706. https://doi.org/10.1006/jmbi.2001.4510

14. Lander ES. The new genomics: global views of biology. Science. 1996;274(5287):536. https://doi.org/10.1126/science.274.5287.536

15. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. New England Journal of Medicine. 1994;331(16):1056-61. https://doi.org/10.1056/NEJM199410203311604

16. Bhagwat M. Searching NCBI's dbSNP database. Current protocols in bioinformatics. 2010:1-9. https://doi.org/10.1002/0471250953.bi0119s32

17. Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic acids research. 2003;31(13):3812-4. https://doi.org/10.1093/nar/gkg509

18. Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PloS one. 2012;7(10):e46688. https://doi.org/10.1371/journal.pone.0046688

19. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nature methods. 2010;7(4):248-9. https://doi.org/10.1038/nmeth0410-248

20. Bao L, Zhou M, Cui Y. nsSNPAnalyzer: identifying disease-associated nonsynonymous single nucleotide polymorphisms. Nucleic acids research. 2005;33(2):W480-2. https://doi.org/10.1093/nar/gki372

21. Capriotti E, Fariselli P, Casadio R. I-Mutant2. 0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic acids research. 2005;33(2):W306-10.

22. Finn RD, Coggill P, Eberhardt RY, Eddy SR, Mistry J, Mitchell AL, Potter SC, Punta M, Qureshi M, Sangrador-Vegas A. The Pfam protein families database: towards a more sustainable future. Nucleic Acids Research. 2016; 44:D279–D285. https://doi.org/10.1093/nar/gkv1344

23. Delorenzi M, Speed T. An HMM model for coiled-coil domains and a comparison with PSSM-based predictions. Bioinformatics. 2002;18(4):617-25. https://doi.org/10.1093/bioinformatics/18.4.617

24. Sickmeier M, Hamilton JA, LeGall T, Vacic V, Cortese MS, Tantos A, Szabo B, Tompa P, Chen J, Uversky VN, Obradovic Z. DisProt: the database of disordered proteins. Nucleic acids research. 2006;35(1):D786-93.

25. Pickrell JK, Marioni JC, Pai AA, Degner JF, Engelhardt BE, Nkadori E, Veyrieras JB, Stephens M, Gilad Y, Pritchard JK. Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature. 2010;464(7289):768-72. https://doi.org/10.1038/nature08872

26. Desmet FO, Hamroun D, Lalande M, Collod-B\éroud G, Claustres M, B\éroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic acids research. 2009;37(9):e67-. https://doi.org/10.1093/nar/gkp215

27. Anderson DC. Sex‐hormone‐binding globulin. Clinical endocrinology. 1974;3(1):69-96. https://doi.org/10.1111/j.1365-2265.1974.tb03298.x

28. Evans DJ, Hoffmann RG, Kalkhoff RK, Kissebah AH. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. The Journal of Clinical Endocrinology & Metabolism. 1983;57(2):304-10. https://doi.org/10.1210/jcem-57-2-304

29. Raison J, Bonithon-Kopp C, Egloff M, Ducimetiere P, Guy-Grand B. Hormonal influences on the relationships between body fatness, body fat distribution, lipids, lipoproteins, glucose and blood pressure in French working women. Atherosclerosis. 1990;85(2-3):185-92. https://doi.org/10.1016/0021-9150(90)90110-5

30. Haffner SM, Katz MS, Dunn JF. Increased upper body and overall adiposity is associated with decreased sex hormone binding globulin in postmenopausal women. International journal of obesity. 1991;15(7):471-8.

31. Lapidus L, Lindstedt G, Lundberg PA, Bengtsson C, Gredmark T. Concentrations of sex-hormone binding globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women. Clinical chemistry. 1986;32(1):146-52.

32. Lindstedt G, Lundberg PA, Lapidus L, Lundgren H, Bengtsson C, Björntorp P. Low sex-hormone-binding globulin concentration as independent risk factor for development of NIDDM: 12-yr follow-up of population study of women in Gothenburg, Sweden. Diabetes. 1991;40(1):123-8. https://doi.org/10.2337/diab.40.1.123

33. Soler JT, Folsom AR, Kaye SA, Prineas RJ. Associations of abdominal adiposity, fasting insulin, sex hormone binding globulin, and estrone with lipids and lipoproteins in post-menopausal women. Atherosclerosis. 1989;79(1):21-7. https://doi.org/10.1016/0021-9150(89)90029-4

34. Pugeat M, Moulin P, Cousin P, Fimbel S, Nicolas MH, Crave JC, Lejeune H. Interrelations between sex hormone-binding globulin (SHBG), plasma lipoproteins and cardiovascular risk. The Journal of steroid biochemistry and molecular biology. 1995;53(1):567-72. https://doi.org/10.1016/0960-0760(95)00102-6

35. Ohlsson C, Wallaschofski H, Lunetta KL, Stolk L, Perry JR, Koster A, Petersen AK, Eriksson J, Lehtim\äki T, Huhtaniemi IT, Hammond GL. Genetic determinants of serum testosterone concentrations in men. PLoS genetics. 2011;7(10):e1002313. https://doi.org/10.1371/journal.pgen.1002313

Article Metrics

Similar Articles