Sex Hormone-Binding Globulin and Risk of Coronary Heart Disease in Men and Women

Overview

Journal Clin Chem

Publisher Oxford University Press

Specialty Biochemistry

Date 2023 Jan 26

PMID 36702572

Authors

Jie Li

Lingling Zheng

Kei Hang Katie Chan

Xia Zou

Jihui Zhang

Jundong Liu

Qingwei Zhong

Tracy E Madsen

Wen-Chih Wu

JoAnn E Manson

Xueqing Yu

Simin Liu

Affiliations

Soon will be listed here.

Abstract

Background: The role of sex hormone-binding globulin (SHBG) levels in clinical risk stratification and intervention for coronary heart disease (CHD) remains uncertain. We aimed to examine whether circulating levels of SHBG are predictive of CHD risk in men and women.

Methods: We investigated the association between SHBG and the risk of incident CHD in 128 322 men and 135 103 women free of CHD at baseline in the prospective United Kingdom Biobank (UKB) cohort. The unconfounded associations were estimated using Mendelian randomization (MR) analysis. We further conducted a meta-analysis to integrate currently available prospective evidence. CHD events included nonfatal and fatal myocardial infarction and coronary revascularization.

Results: In the UKB, during a median of 11.7 follow-up years, 10 405 men and 4512 women developed CHD. Serum levels of SHBG were monotonically associated with a decreased risk of CHD in both men (adjusted hazard ratio [HR] per log nmol/L increase in SHBG: 0.88 [0.83-0.94]) and women (HR: 0.89 [0.83-0.96]). MR-based analyses suggested causality and a dose-response relationship of SHBG with CHD risk. A cumulative meta-analysis including 216 417 men and 138 282 women from 11 studies showed that higher levels of SHBG were prospectively associated with decreased CHD risk in men comparing the highest with the lowest quartile: pooled relative risk (RR) 0.81 (0.74-0.89) and women (pooled RR: 0.86 [0.78-0.94]).

Conclusions: Higher circulating SHBG levels were directly and independently predictive of lower CHD risk in both men and women. The utility of SHBG for CHD risk stratification and prediction warrants further study.

Citing Articles

Association between alcohol consumption and incidence of dementia in current drinkers: linear and non-linear mendelian randomization analysis.

Zheng L, Liao W, Luo S, Li B, Liu D, Yun Q EClinicalMedicine. 2024; 76:102810.

PMID: 39290634 PMC: 11405827. DOI: 10.1016/j.eclinm.2024.102810.

Causal validation of the relationship between 35 blood and urine biomarkers and hyperthyroidism: a bidirectional Mendelian randomization study and meta-analysis.

Xu W, Wu J, Chen D, Zhang R, Yang Y Front Endocrinol (Lausanne). 2024; 15:1430798.

PMID: 39188917 PMC: 11345139. DOI: 10.3389/fendo.2024.1430798.

Causal relationship analysis between 35 blood/urine metabolites and gastroesophageal reflux disease: A Mendelian randomization combined meta-analysis study.

Chen D, Xu W, Wen Y, Tan X, Liu J Medicine (Baltimore). 2024; 103(32):e39248.

PMID: 39121258 PMC: 11315488. DOI: 10.1097/MD.0000000000039248.

Association between sex hormone binding globulin and metabolic syndrome in US adults: insights from National Health and Nutrition Examination Survey (NHANES) 2013-2016.

Yang Y, Wang J, Huang Y, Liu Y, Liu S, Liu H Diabetol Metab Syndr. 2024; 16(1):170.

PMID: 39026336 PMC: 11256583. DOI: 10.1186/s13098-024-01398-6.

The association between immune cells and breast cancer: insights from Mendelian randomization and meta-analysis.

Xu W, Zhang T, Zhu Z, Yang Y Int J Surg. 2024; 111(1):230-241.

PMID: 38935111 PMC: 11745723. DOI: 10.1097/JS9.0000000000001840.

References

Davey Smith G, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman S, Elwood P . Cortisol, testosterone, and coronary heart disease: prospective evidence from the Caerphilly study. Circulation. 2005; 112(3):332-40. DOI: 10.1161/CIRCULATIONAHA.104.489088. View

Ruth K, Day F, Tyrrell J, Thompson D, Wood A, Mahajan A . Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med. 2020; 26(2):252-258. PMC: 7025895. DOI: 10.1038/s41591-020-0751-5. View

Joffe H, Ridker P, Manson J, Cook N, Buring J, Rexrode K . Sex hormone-binding globulin and serum testosterone are inversely associated with C-reactive protein levels in postmenopausal women at high risk for cardiovascular disease. Ann Epidemiol. 2005; 16(2):105-12. DOI: 10.1016/j.annepidem.2005.07.055. View

Luo S, Au Yeung S, Zhao J, Burgess S, Schooling C . Association of genetically predicted testosterone with thromboembolism, heart failure, and myocardial infarction: mendelian randomisation study in UK Biobank. BMJ. 2019; 364:l476. PMC: 6402044. DOI: 10.1136/bmj.l476. View

Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson M . High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011; 58(16):1674-81. DOI: 10.1016/j.jacc.2011.07.019. View

Joseph D . Structure, function, and regulation of androgen-binding protein/sex hormone-binding globulin. Vitam Horm. 1994; 49:197-280. DOI: 10.1016/s0083-6729(08)61148-6. View

Wang A, Gerstein H, Lee S, Hess S, Pare G, Ryden L . Testosterone and sex hormone-binding globulin in dysglycemic women at high cardiovascular risk: A report from the Outcome Reduction with an Initial Glargine Intervention trial. Diab Vasc Dis Res. 2021; 18(2):14791641211002475. PMC: 8481727. DOI: 10.1177/14791641211002475. View

Simons P, Valkenburg O, Stehouwer C, Brouwers M . Sex hormone-binding globulin: biomarker and hepatokine?. Trends Endocrinol Metab. 2021; 32(8):544-553. DOI: 10.1016/j.tem.2021.05.002. View

Krupenko S, Krupenko N, Danzo B . Interaction of sex hormone-binding globulin with plasma membranes from the rat epididymis and other tissues. J Steroid Biochem Mol Biol. 1994; 51(1-2):115-24. DOI: 10.1016/0960-0760(94)90122-8. View

10.

Boef A, Dekkers O, le Cessie S . Mendelian randomization studies: a review of the approaches used and the quality of reporting. Int J Epidemiol. 2015; 44(2):496-511. DOI: 10.1093/ije/dyv071. View

11.

Chen B, Brennan K, Goto A, Song Y, Aziz N, You N . Sex hormone-binding globulin and risk of clinical diabetes in American black, Hispanic, and Asian/Pacific Islander postmenopausal women. Clin Chem. 2012; 58(10):1457-66. PMC: 4088986. DOI: 10.1373/clinchem.2012.193086. View

12.

Yeap B, Alfonso H, Chubb S, Hankey G, Handelsman D, Golledge J . In older men, higher plasma testosterone or dihydrotestosterone is an independent predictor for reduced incidence of stroke but not myocardial infarction. J Clin Endocrinol Metab. 2014; 99(12):4565-73. DOI: 10.1210/jc.2014-2664. View

13.

Dashti H, Daghlas I, Lane J, Huang Y, Udler M, Wang H . Genetic determinants of daytime napping and effects on cardiometabolic health. Nat Commun. 2021; 12(1):900. PMC: 7876146. DOI: 10.1038/s41467-020-20585-3. View

14.

Gyawali P, Martin S, Heilbronn L, Vincent A, Jenkins A, Januszewski A . Higher Serum Sex Hormone-Binding Globulin Levels Are Associated With Incident Cardiovascular Disease in Men. J Clin Endocrinol Metab. 2019; 104(12):6301-6315. DOI: 10.1210/jc.2019-01317. View

15.

Pugeat M, Moulin P, Cousin P, Fimbel S, Nicolas M, Crave J . Interrelations between sex hormone-binding globulin (SHBG), plasma lipoproteins and cardiovascular risk. J Steroid Biochem Mol Biol. 1995; 53(1-6):567-72. DOI: 10.1016/0960-0760(95)00102-6. View

16.

Nakhla A, Khan M, Rosner W . Biologically active steroids activate receptor-bound human sex hormone-binding globulin to cause LNCaP cells to accumulate adenosine 3',5'-monophosphate. J Clin Endocrinol Metab. 1990; 71(2):398-404. DOI: 10.1210/jcem-71-2-398. View

17.

Vikan T, Schirmer H, Njolstad I, Svartberg J . Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Eur J Endocrinol. 2009; 161(3):435-42. DOI: 10.1530/EJE-09-0284. View

18.

Dunn J, Nisula B, Rodbard D . Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981; 53(1):58-68. DOI: 10.1210/jcem-53-1-58. View

19.

Menke A, Guallar E, Rohrmann S, Nelson W, Rifai N, Kanarek N . Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol. 2010; 171(5):583-92. PMC: 6596446. DOI: 10.1093/aje/kwp415. View

20.

Yeap B, Marriott R, Antonio L, Raj S, Dwivedi G, Reid C . Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men. Ann Intern Med. 2021; 175(2):159-170. DOI: 10.7326/M21-0551. View