Exp Clin Endocrinol Diabetes 2013; 121 - P97
DOI: 10.1055/s-0033-1336737

Genetic variants of the HLA, vitamin D and glucocorticoid system and their regulatory potential on T-lymphocyte function

Y Moran-Auth 1, M Penna-Martinez 1, K Lasota 1, D Bogdanou 1, E Ramos-Lopez 1, K Badenhoop 1
  • 1University Hospital Frankfurt, Deparment of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, Frankfurt am Main, Germany

Introduction: Vitamin D (alone or in combination with glucocorticoids) is an important immune modulator. Genetic variants of the vitamin D and human leukocyte antigen (HLA) system have been associated with type 1 diabetes (T1D) susceptibility, whereas the role of the glucocorticoid (GC) metabolism is unknown. We investigated whether genetic variants of the HLA, vitamin D and GC system have an influence on the immune response of T-helper (Th) cells.

Methods: Isolated Th cells from 9 healthy controls (HC) and 10 T1D patients were cultured for 72h with phytohemagglutinin (PHA) alone or in combination with calcidiol [25(OH)D3], calcitriol [1,25(OH)2D3], dexamethasone (Dex), 25(OH)D3+Dex and 1,25(OH)2D3+Dex. Furthermore, CYP2R1, CYP27B1, GC receptor (GCR) and 18sRNA expression was measured by Taqman assay and CT-values were defined as 2-[CTtarget-CT18sRNA]. In addition, the CYP2R1 (rs10741657), CYP27B1 (rs10877012) and GCR (rs6198) polymorphisms as well as HLA-haplotypes were genotyped.

Results: Significant down regulation of CYP2R1 was detected in 25(OH)D3+Dex and 1,25(OH)2D3 +Dex stimulated Th cells from T1D with the “AG” CYP2R1 genotype than those with the “GG” genotype (both p = 0.04). Furthermore, by dividing HLA alleles according to high, medium or low risk a significantly reduced CYP2R1 and GCR gene expression was found after cell culture in Th cells from individuals with HLA high or medium risk alleles compared to those with HLA low risk alleles (PHA, 25(OH)D3 and Dex: CYP2R1 and GCR p = 0.01; 1,25(OH)2D3: CYP2R1 p = 5 × 10-3; 1,25(OH)2D3+Dex: CYP2R1 p = 0.01, GCR p = 9 × 10-3; 25(OH)D3+Dex: CYP2R1 p = 6 × 10-3, GCR p = 5 × 10-3).

Conclusion: HLA high risk carriers express less CYP2R1 and GCR than HLA low risk carriers. In addition, the CYP2R1 polymorphism appeared to down-regulate the CYP2R1 expression. In summary, these results provide evidence that genetic variants of the HLA and vitamin D system affect T-lymphocyte gene transcription possible playing a role in T1D development.