C.N. Ilhan1, R. Lengton1, C.A. Hoekx2, L.B.D. Brinkman2, W.A. Dik3,4, S.A.A. van den Berg1,5, P.C.N. Rensen2, J.A. Visser1, E.F.C van Rossum1, J.E. Oosterman1, M.R. Boon1
1Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands; 2Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands; 3Department of Immunology, Erasmus MC, Rotterdam, the Netherlands; 4Reinier Haga Medical Diagnostics Center, Delft, the Netherlands; 5Department of Clinical Chemistry, Erasmus MC, Rotterdam, the Netherlands. c.ilhan@erasmusmc.nl
Background: South Asians (SA) have a higher risk of developing cardiometabolic diseases than Europids (EUR), partly due to their unfavorable metabolic phenotype resembling hypercortisolism. Yet, studies show that morning plasma cortisol levels in SA are lower compared with EUR. Therefore, we hypothesized that increased glucocorticoid receptor (GR) sensitivity may contribute to their increased risk of cardiometabolic diseases.
Methods: Anthropometrics, plasma and hair glucocorticoids, and corticosteroid-binding globulin (CBG) were determined in healthy lean SA and EUR females (n=12/group). In a subset of the population (n=9/group), GR sensitivity was determined based on dexamethasone-induced up- and downregulation of glucocorticoid target genes in peripheral blood mononuclear cells (PBMCs) and inflammatory markers in monocytes, as well as expression of GR isoforms (GR-α, GR-β, GR-P) in PBMCs.
Results: SA had significantly higher fat percentage than EUR (31.5%±5.9 vs. 24.1%±6.5; p=0.008) despite comparable body mass index, and tended to have a higher waist-to-height ratio. SA had significantly lower plasma cortisol levels than EUR (447.8 µmol/l [324.0–543.5] vs. 638.4 µmol/l [549.9–715.8]; p=0.020), which was not explained by differences in CBG levels, or reflected in long-term hair glucocorticoids. There were no significant ethnic differences in the dexamethasone-induced change in glucocorticoid-target gene expression, or GR isoform expression in PBMCs. In monocytes, SA had a lower dexamethasone-induced fold induction of LOX1 (0.34 [0.22–0.43] vs. 0.43 [0.38–0.54]; p=0.031) and CD163 (2.1 [2.0–2.3] vs. 2.7 [2.3–2.8]; p=0.019), suggesting differential GR sensitivity.
Discussion/conclusion: Our data confirm ethnic differences in anthropometrics between SA and EUR females, and suggest ethnic differences in glucocorticoid regulation and response in monocytes. Future research will focus on including male participants.