Polymorphism in the Drug Transporter Gene ABCB1 as a Potential Disease Modifier in Cortisol-Producing Adrenal Adenomas

Abstract

Introduction Endogenous hypercortisolism presents with variable phenotypes. Etiological factors accounting for the level of hypercortisolism or varying severity of associated comorbidities are lacking. Recently, the adrenal ATP-binding cassette B1 (ABCB1) gene was identified as a modulator of glucocorticoid secretion.

Objective To evaluate the effect of ABCB1 polymorphism rs2032582 on steroid metabolome and clinical phenotypes in patients with endogenous hypercortisolism.

Methods In this cross-sectional cohort study, 137 patients prospectively enrolled in the German Cushing’s registry were included (41 with ACTH-producing pituitary adenoma, 21 with cortisol-producing adrenal adenoma, and 75 with excluded hypercortisolism). In all patients, ABCB1 polymorphism was analyzed using a TaqMan genotyping assay, glucocorticoid metabolite excretion in 24-hour urine samples was analyzed by gas chromatography-mass spectrometry, and the clinical phenotype was assessed systematically.

Results In patients with cortisol-producing adrenal adenomas, but not in patients with ACTH-producing pituitary adenomas, homozygous major allele GG of ABCB1 polymorphism rs2032582 was associated with higher overall cortisol metabolite secretion (median 13515 [IQR 10347; 25669] µg/24h vs. 9645 [6146; 10732] µg/24h in minor homo- and heterozygotes, p=0.036) and elevated major cortisol metabolites αTHF, THF and THE (9339 [6929; 17789] µg/24h vs. 6288 [4184; 7455] µg/24h, p=0.045). Moreover, these patients showed higher mean arterial pressure (116 [111; 131] mmHg in major homozygotes vs. 105 [96; 112] mmHg in minor homo- and heterozygotes, p=0.036).

Conclusion The genotype of drug transporter gene ABCB1 rs2032582 polymorphism is associated with the degree of cortisol metabolite secretion in cortisol-producing adrenal adenomas and could, therefore, represent a modifier of disease severity in this context.

Keywords

cortisol - hypercortisolism - steroids - ABCB1 - Cushing’s syndrome

Publication History

Received: 24 April 2024

Accepted after revision: 28 August 2024

Article published online:
18 September 2024

• References

• 1 Dekkers OM, Horvath-Puho E, Jorgensen JO. et al. Multisystem morbidity and mortality in Cushing’s syndrome: A cohort study. J Clin Endocrinol Metab 2013; 98: 2277-2284
• 2 Pecori Giraldi F, Moro M, Cavagnini F. et al. Gender-related differences in the presentation and course of Cushing’s disease. J Clin Endocrinol Metab 2003; 88: 1554-1558
• 3 Zilio M, Barbot M, Ceccato F. et al. Diagnosis and complications of Cushing’s disease: Gender-related differences. Clin Endocrinol (Oxf) 2014; 80: 403-410
• 4 Detomas M, Deutschbein T, Tamburello M. et al. Erythropoiesis in Cushing syndrome: Sex-related and subtype-specific differences. Results from a monocentric study. J Endocrinol Invest 2024; 47: 101-113
• 5 Ragnarsson O, Glad CA, Bergthorsdottir R. et al. Body composition and bone mineral density in women with Cushing’s syndrome in remission and the association with common genetic variants influencing glucocorticoid sensitivity. Eur J Endocrinol 2015; 172: 1-10
• 6 Valassi E, Aulinas A, Glad CA. et al. A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing’s syndrome. Clin Endocrinol (Oxf) 2017; 87: 433-439
• 7 Lopez JP, Brivio E, Santambrogio A. et al. Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation. Sci Adv 2021; 7: eabe4497
• 8 Hodges LM, Markova SM, Chinn LW. et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 2011; 21: 152-161
• 9 Meijer OC, de Lange EC, Breimer DD. et al. Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 1998; 139: 1789-1793
• 10 Gramer I, Karakus E, Hartmann MF. et al. Urinary cortisol metabolites are reduced in MDR1 mutant dogs in a pilot targeted GC-MS urinary steroid hormone metabolome analysis. J Vet Pharmacol Ther 2022; 45: 265-272
• 11 Kimchi-Sarfaty C, Oh JM, Kim IW. et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 2007; 315: 525-528
• 12 Lovas K, Gjesdal CG, Christensen M. et al. Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: Effects on bone. Eur J Endocrinol 2009; 160: 993-1002
• 13 Meijer OC, Karssen AM, de Kloet ER. Cell- and tIssue-specific effects of corticosteroids in relation to glucocorticoid resistance: Examples from the brain. J Endocrinol 2003; 178: 13-18
• 14 Bruckl TM, Uhr M. ABCB1 genotyping in the treatment of depression. Pharmacogenomics 2016; 17: 2039-2069
• 15 Brant SR, Panhuysen CI, Nicolae D. et al. MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet 2003; 73: 1282-1292
• 16 Devine K, Villalobos E, Kyle CJ. et al. The ATP-binding cassette proteins ABCB1 and ABCC1 as modulators of glucocorticoid action. Nat Rev Endocrinol 2023; 19: 112-124
• 17 Berr CM, Di Dalmazi G, Osswald A. et al. Time to recovery of adrenal function after curative surgery for Cushing’s syndrome depends on etiology. J Clin Endocrinol Metab 2015; 100: 1300-1308
• 18 Osswald A, Deutschbein T, Berr CM. et al. Surviving ectopic Cushing’s syndrome: Quality of life, cardiovascular and metabolic outcomes in comparison to Cushing’s disease during long-term follow-up. Eur J Endocrinol 2018; 179: 109-116
• 19 Vogel F, Braun LT, Rubinstein G. et al. Persisting muscle dysfunction in Cushing’s syndrome despite biochemical remission. J Clin Endocrinol Metab 2020; 105: e4490-e4498
• 20 Fleseriu M, Auchus R, Bancos I. et al. Consensus on diagnosis and management of Cushing’s disease: A guideline update. Lancet Diabetes Endocrinol 2021; 9: 847-875
• 21 Braun LT, Osswald A, Zopp S. et al. Delineating endogenous Cushing’s syndrome by GC-MS urinary steroid metabotyping. EBioMedicine 2024; 99: 104907
• 22 Gandhi K, Adhikari P, Basu A. et al. Association between a 11beta-hydroxysteroid dehydrogenase type 1 gene polymorphism and metabolic syndrome in a South Indian population. Metab Syndr Relat Disord 2013; 11: 397-402
• 23 Feldman K, Szappanos A, Butz H. et al. The rs4844880 polymorphism in the promoter region of the HSD11B1 gene associates with bone mineral density in healthy and postmenopausal osteoporotic women. Steroids 2012; 77: 1345-1351
• 24 Hammond GL. Plasma steroid-binding proteins: Primary gatekeepers of steroid hormone action. J Endocrinol 2016; 230: R13-R25
• 25 Braun LT, Vogel F, Zopp S. et al. Diurnal salivary cortisol profiles in patients with Cushing’s syndrome. Exp Clin Endocrinol Diabetes 2022; 130: 434-438