Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis.
Vascular endothelial growth factor (VEGF) promotes angiogenesis, and elevated levels are found in plaques of psoriasis. Two VEGF polymorphisms, +405 and -460, are associated with early-onset psoriasis and are close to the functional activator protein-1 site (+419) through which retinoids, an established systemic therapy for psoriasis, can block production of VEGF. We report that peripheral blood mononuclear cells (PBMCs) and epidermal keratinocytes (KC) from patients with psoriasis demonstrate differential, genotype-dependent, regulation of VEGF. For PBMCs, VEGF genotype distinguishes two groups of patients with psoriasis - "high and low VEGF producers" (P < 0.001). In contrast, KC production of VEGF is not genotype dependent. However, the effects of all-trans retinoic acid (RA) on cellular expression of VEGF are determined by both cell type and genotype. RA inhibits KC production of VEGF in a genotype-dependent manner (P < 0.005) whereas RA stimulates PBMCs production irrespective of VEGF genotype (P < 0.001). We also report that the -460 VEGF polymorphism appears to have a clinical pharmacogenetic role in predicting response or non-response of psoriasis to acitretin (P = 0.01). In future, determination of VEGF gene polymorphisms and thus individual patient VEGF "signatures" may be used as a prognostic factor for psoriasis susceptibility/severity and as a means for optimizing treatment response.
Young
Helen S
HS
The Dermatology Centre, The University of Manchester School of Medicine, Hope Hospital, Manchester, UK. helen_s_young@hotmail.com
Summers
Angela M
AM
Read
Ian R
IR
Fairhurst
David A
DA
Plant
Darren J
DJ
Campalani
Emanuela
E
Smith
Catherine H
CH
Barker
Jonathan N W N
JN
Detmar
Michael J
MJ
Brenchley
Paul E C
PE
Griffiths
Christopher E M
CE
D017255:Acitretin / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D011565:Psoriasis / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D012176:Retinoids; D042461:Vascular Endothelial Growth Factor A; D014212:Tretinoin; D017255:Acitretin