Genome Wide Association Identifies Common Variants at the Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin

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Cortisol is a steroid hormone from the adrenal glands that is essential in the response to stress. Most cortisol in blood is bound to corticosteroid binding globulin (CBG). Diseases causing cortisol deficiency (Addison's disease) or excess (Cushing's syndrome) are life-threatening. Variations in plasma cortisol have been associated with cardiovascular and psychiatric diseases and their risk factors. To dissect the genetic contribution to variation in plasma cortisol, we formed the CORtisol NETwork (CORNET) consortium and recruited collaborators with suitable samples from more than 15,000 people. The results reveal that the major genetic influence on plasma cortisol is mediated by variations in the binding capacity of CBG. This is determined by differences in the circulating concentrations of CBG and also in the immunoreactivity of its ‘reactive centre loop’, potentially influencing not only binding affinity for cortisol but also the stability of CBG and hence the tissue delivery of cortisol. These findings provide the first evidence for a common genetic effect on levels of this clinically important hormone, suggest that differences in CBG between individuals are biologically important, and pave the way for further research to dissect causality in the associations of plasma cortisol with common diseases.

Vyšlo v časopise: Genome Wide Association Identifies Common Variants at the Locus Influencing Plasma Cortisol and Corticosteroid Binding Globulin. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004474
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004474

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Zdroje

1. WalkerBR (2007) Glucocorticoids and cardiovascular disease. Eur J Endocrinol 157 : 545–559.

2. PhillipsDIW, BarkerDJP, FallCHD, WhorwoodCB, SecklJR, et al. (1998) Elevated plasma cortisol concentrations: an explanation for the relationship between low birthweight and adult cardiovascular risk factors. J Clin Endocrinol Metab 83 : 757–760.

3. FilipovskyJ, DucimetiereP, EschwegeE, RichardJL, RosselinG, et al. (1996) The relationship of blood pressure with glucose, insulin, heart rate, free fatty acids and plasma cortisol levels according to degree of obesity in middle-aged men. J Hypertens 14 : 229–235.

4. FraserR, IngramMC, AndersonNH, MorrisonC, DaviesE, et al. (1999) Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension 33 : 1364–1368.

5. ReynoldsRM, WalkerBR, PhillipsDIW, SydallHE, AndrewR, et al. (2001) Altered control of cortisol secretion in adult men with low birthweight and cardiovascular risk factors. J Clin Endocrinol Metab 86 : 245–250.

6. LupienSJ, de LeonM, de SantiS, ConvitA, TarshishC, et al. (1998) Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neuroscience 1 : 69–73.

7. HolsboerF (2001) Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 62 : 77–91.

8. BallTM (2006) Cortisol circadian rhythms and stress responses in infants at risk of allergic disease. Neuroimmunomodulation 13 : 294–300.

9. SecklJR, MeaneyMJ (2006) Glucocorticoid “programming” and PTSD risk. Ann N Y Acad Sci 1071 : 351–378.

10. BjorntorpP, HolmG, RosmondR (1999) Hypothalamic arousal, insulin resistance and type 2 diabetes mellitus. Diabetic Med 16 : 373–381.

11. MattssonC, ReynoldsRM, SimonyteK, OlssonT, WalkerBR (2009) Combined receptor antagonist stimulation of the hypothalamic-pituitary-adrenal axis test identifies impaired negative feedback sensitivity to cortisol in obese men. J Clin Endocrinol Metab 94 : 1347–1352.

12. Fernandez-RealJM, GrasaM, CasamitjanaR, RicartW (2000) The insulin resistance syndrome and the binding capacity of cortisol binding globulin (CBG) in men and women. Clin Endocrinol (Oxf) 52 : 93–99.

13. Fernandez-RealJM, PugeatM, GrasaM, BrochM, VendrellJ, et al. (2002) Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. J Clin Endocrinol Metab 87 : 4686–4690.

14. ReynoldsRM, WalkerBR, SyddallHE, AndrewR, WoodPJ, et al. (2005) Is there a gender differences in the associations of low birthweight with adult hypothalamic-pituitary-adrenal axis activity? European Journal of Endocrinology 152 : 249–253.

15. LewisJG, BorowskiKK, ShandBI, GeorgePM, ScottRS (2010) Plasma sex hormone-binding globulin, corticosteroid-binding globulin, cortisol, and free cortisol levels in outpatients attending a lipid disorders clinic: a cross-sectional study of 1137 subjects. Horm Metab Res 42 : 274–279.

16. InglisGC, IngramMC, HollowayCD, SwanL, BirnieD, et al. (1999) Familial pattern of corticosteroids and their metabolism in adult human subjects -⁠ The Scottish adult twin study. J Clin Endocrinol Metab 84 : 4132–4137.

17. BartelsM, de GeusEJC, KirschbaumC, SluyterF, BoomsmaDI (2003) Heritability of daytime cortisol levels in children. Behavior Genetics 33 : 421–433.

18. MormedeP, FouryA, BaratP, CorcuffJB, TereninaE, et al. (2011) Molecular genetics of hypothalamic-pituitary-adrenal axis activity and function. Ann N Y Acad Sci 1220 : 127–136.

19. SmithGD, EbrahimS (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32 : 1–22.

20. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 : 559–575.

21. HenleyDE, LightmanSL (2011) New insights into corticosteroid-binding globulin and glucocorticoid delivery. Neuroscience 180 : 1–8.

22. LiuJZ, McRaeAF, NyholtDR, MedlandSE, WrayNR, et al. (2010) A versatile gene-based test for genome-wide association studies. Am J Hum Genet 87 : 139–145.

23. LewisJG, ElderPA (2011) Corticosteroid-binding globulin reactive centre loop antibodies recognise only the intact natured protein: elastase cleaved and uncleaved CBG may coexist in circulation. J Steroid Biochem Mol Biol 127 : 289–294.

24. Van BaelenH, BrepoelsR, De MoorP (1982) Transcortin Leuven: a variant of human corticosteroid-binding globulin with decreased cortisol-binding affinity. J Biol Chem 257 : 3397–3400.

25. EkeowaUI, GooptuB, BelorgeyD, HagglofP, Karlsson-LiS, et al. (2009) alpha1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies. Clin Sci (Lond) 116 : 837–850.

26. HammondGL, SmithCL, PatersonNAM, SibbaldWJ (1990) A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab 71 : 34–39.

27. BaratP, CorcuffJB, TauberM, MoisanMP (2012) Associations of glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms on fat mass and fat mass distribution in prepubertal obese children. J Physiol Biochem

28. BaratP, DuclosM, GattaB, RogerP, MormedeP, et al. (2005) Corticosteroid binding globulin gene polymorphism influences cortisol driven fat distribution in obese women. Obes Res 13 : 1485–1490.

29. van LeeuwenN, KumstaR, EntringerS, de KloetER, ZitmanFG, et al. (2010) Functional mineralocorticoid receptor (MR) gene variation influences the cortisol awakening response after dexamethasone. Psychoneuroendocrinology 35 : 339–349.

30. DeRijkRH, WustS, MeijerOC, ZennaroMC, FederenkoIS, et al. (2006) A common polymorphism in the mineralocorticoid receptor modulates stress responsiveness. J Clin Endocrinol Metab 91 : 5083–5089.

31. CizzaG, RotherKI (2012) Cortisol binding globulin: more than just a carrier? J Clin Endocrinol Metab 97 : 77–80.

32. HillLA, VassiliadiDA, SimardM, PavlakiA, PerogamvrosI, et al. (2012) Two different corticosteroid-binding globulin variants that lack cortisol-binding activity in a greek woman. J Clin Endocrinol Metab 97 : 4260–4267.

33. PerogamvrosI, UnderhillC, HenleyDE, HadfieldKD, NewmanWG, et al. (2010) Novel corticosteroid-binding globulin variant that lacks steroid binding activity. J Clin Endocrinol Metab 95: E142–E150.

34. LinHY, UnderhillC, LeiJH, Helander-ClaessonA, LeeHY, et al. (2012) High frequency of SERPINA6 polymorphisms that reduce plasma corticosteroid-binding globulin activity in Chinese subjects. J Clin Endocrinol Metab 97: E678–E686.

35. HillLA, VassiliadiDA, SimardM, PavlakiA, PerogamvrosI, et al. (2012) Two different corticosteroid-binding globulin variants that lack cortisol-binding activity in a greek woman. J Clin Endocrinol Metab 97 : 4260–4267.

36. HollidayKL, MacfarlaneGJ, NichollBI, CreedF, ThomsonW, et al. (2010) Genetic variation in neuroendocrine genes associates with somatic symptoms in the general population: results from the EPIFUND study. J Psychosom Res 68 : 469–474.

37. LinHY, UnderhillC, GardillBR, MullerYA, HammondGL (2009) Residues in the human corticosteroid-binding globulin reactive center loop that influence steroid binding before and after elastase cleavage. J Biol Chem 284 : 884–896.

38. PetersenHH, AndreassenTK, BreiderhoffT, BrasenJH, SchulzH, et al. (2006) Hyporesponsiveness to glucocorticoids in mice genetically deficient for the corticosteroid binding globulin. Mol Cell Biol 26 : 7236–7245.

39. MillerVM, PettersonTM, JeavonsEN, LnuAS, RiderDN, et al. (2013) Genetic polymorphisms associated with carotid artery intima-media thickness and coronary artery calcification in women of the Kronos Early Estrogen Prevention Study. Physiol Genomics 45 : 79–88.

40. InouyeM, RipattiS, KettunenJ, LyytikainenLP, OksalaN, et al. (2012) Novel Loci for metabolic networks and multi-tissue expression studies reveal genes for atherosclerosis. PLoS Genet 8: e1002907.

41. WoodAR, PerryJR, TanakaT, HernandezDG, ZhengHF, et al. (2013) Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation. PLoS One 8: e64343.

42. OhlssonC, WallaschofskiH, LunettaKL, StolkL, PerryJR, et al. (2011) Genetic determinants of serum testosterone concentrations in men. PLoS Genet 7: e1002313.

43. ReynoldsRM, FischbacherC, BhopalR, ByrneCD, WhiteM, et al. (2006) Differences in cortisol concentrations in South Asian and European men living in the United Kingdom. Clin Endocrinol (Oxf) 64 : 530–534.

44. MagiR, MorrisAP (2010) GWAMA: software for genome-wide association meta-analysis. BMC Bioinformatics 11 : 288.

45. PruimRJ, WelchRP, SannaS, TeslovichTM, ChinesPS, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26 : 2336–2337.

46. LunaA, NicodemusKK (2007) snp.plotter: an R-based SNP/haplotype association and linkage disequilibrium plotting package. Bioinformatics 23 : 774–776.

47. YangJ, LeeSH, GoddardME, VisscherPM (2011) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88 : 76–82.

48. GroveML, YuB, CochranBJ, HarituniansT, BisJC, et al. (2013) Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. PLoS One 8: e68095.

49. DelaneauO, ZaguryJF, MarchiniJ (2013) Improved whole-chromosome phasing for disease and population genetic studies. Nat Methods 10 : 5–6.

50. HowieBN, DonnellyP, MarchiniJ (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529.

51. AulchenkoYS, RipkeS, IsaacsA, van DuijnCM (2007) GenABEL: an R library for genome-wide association analysis. Bioinformatics 23 : 1294–1296.

52. HammondGL, LahteenmakiPL (1983) A versatile method for the determination of serum cortisol binding globulin and sex hormone binding globulin binding capacities. Clin Chim Acta 132 : 101–110.

53. CoolensJL, VanBH, HeynsW (1987) Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J Steroid Biochem 26 : 197–202.