UVOD: Glukokortikoidni hormoni (GC) ostvaruju svoje efekte vezivanjem za
glukokortikoidni receptor (GR). Adrenokortikotropni hormon (ACTH) reguliše sintezu
GC vezivanjem za ACTH receptor (ACTHR). Prisustvo polimorfizama u genu za GR
(BclI, N363S, ER22/23EK and A3669G) i promotoru ACTHR može uticati na efekte
glukokortikoida i predispoziciju za nastanak unilateralnih adrenalnih incidentaloma.
CILJ RADA: Utvrđivanje mogućeg uticaja funkcionalnih polimorfizama u genima za
GR i ACTHR na predispoziciju za nastanak adrenalnih incidentaloma i osetljivost na GC
i ispitivanje ekspresije GR u tumorskom, peritumorskom i zdravom adrenokortikalnom
tkivu.
METODE: U ispitivanje je bilo uključeno 112 pacijenata i 100 zdravih dobrovoljaca,
koji su podvrgnuti metaboličkom, genetičkom, biohemijskom i antropometrijskom
testiranju. DNK je dobijena iz leukocita periferne krvi. Prisustvo polimorfizama je
detektovano metodama PCR, RFLP i sekvenciranja DNK. Uzorci tkiva su analizirani
imunohistohemijskom metodom.
REZULTATI: Prisustvo dužeg C alela BclI (p<0.001) polimorfizma i kraćeg G alela
A3669G (p<0.001) polimorfizma GR gena su bili nezavisni prediktori adrenalnih
incidentaloma. Pacijenti sa prisutnim C alelom BclI su imali veće tumore (p=0.002), a oni
sa G alelom A3669G više vrednosti postdeksametazonskog kortizola (p=0.025).
Istovremeno prisustvo oba alela je koreliralo sa manjim obimom struka (p=0.002), a
višim baznim i postdeksametazonskog kortizolom (p=0.024). Smanjena ekspresija GRα i
GRβ izoformi zapažena je u tumorskom, a GRα u peritumorskom tkivu. Lokalizacija
GRβ je bila dominantno nukleusna.
ZAKLJUČAK: Prisustvo C alela BclI i G alela A3669G polimorfizmama gena za GR se
nalaze u vezi sa nastankom unilateralnih adrenalnim incidentalomima, a njihovo
zajedničko prisustvo dovodi do smanjene osetljivosti na GC. Stečena intraadenomatozna
glukokortikoidna rezistencija može da dovede do disregulacije produkcije kortizola i
rasta tumora u isto vreme, dok prirodna osetljivost na glukokortikoide najverovatnije
modifikuje ove efekte.INTRODUCTION: Glucocorticoid hormones (GCs) accomplish their effects through
binding to glucocorticoid receptor (GR). Adrenocorticotropic hormone (ACTH) regulates
synthesis of GCs through binding to ACTH receptor (ACTHR). Presence of common GR
gene (BclI, N363S, ER22/23EK and A3669G) and ACTHR promoter polymorphisms can
modulate GCs sensitivity.
OBJECTIVE: The aim of present study was to determine weather functional
polymorphisms in GR and ACTHR genes influence susceptibility for unilateral adrenal
incidentalomas and GC sensitivity, and to investigate GR expression in tumorous,
peritumorous and normal adrenocortical tissue samples.
METHODS: The study included 112 patients with adrenal incidentalomas and 100
population-matched controls. All subjects underwent metabolic, genetic, biochemical and
anthropometric testing. DNA was obtained from peripheral blood leucocytes. The
polymorphisms were detected using PCR, RFLP and DNA sequencing. Tissue samples
were studied by immunohistochemistry.
RESULTS: GR gene variant, C allele of BclI (p<0.001) and G allele of A3669G
(p<0.001) polymorphisms were independent predictors of adrenal incidentalomas.
Patients with present C allele had larger tumors (p=0.002), but those with G allele had
higher postdexamethasone serum cortisol (p=0.025). Both allele carriers had lesser waist
circumference (p=0.002), higher basal (p=0.024) and postdexamethasone cortisol
concentrations. In tumorous tissues GRα and GRβ isoforms had lower expression, but
only GRα in peritumorous tissue. Localization of GRβ was dominantly nuclear.
CONCLUSION: GR gene variants, larger C allele of BclI and minor 3669G allele are
associated with adrenal incidentalomas. Their concurrent presence in patients reduces GC
sensitivity. The acquired tumorous GC resistance probably promote dysregulated cortisol
production and tumor growth, but natural sensitivity to glucocorticoides maybe modifies
these effects