Interaction between Genetic Control of Vascular Endothelial Growth Factor Production and Retinoid Responsiveness in Psoriasis

Abstract

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.

Genetic Influences on Pharmacological Interventions in Psoriasis

“…Patients with VEGF polymorphism genotype -460 TT were almost two times more likely to fail acitretin therapy than to respond [26]. There was also a significant amount of responders to acitretin therapy who were a -460 TC genotype (P=0.01) [26]. This study requires a larger cohort of patients to confirm these conclusions.…”

“…Patients with type 1 early onset plaque psoriasis (which is defined as an onset of disease prior to the age of 40) and acitretin use were recruited (n=106) [26]. Patients with VEGF polymorphism genotype -460 TT were almost two times more likely to fail acitretin therapy than to respond [26]. There was also a significant amount of responders to acitretin therapy who were a -460 TC genotype (P=0.01) [26].…”

“…In a study by Young et al, VEGF polymorphisms and various factors of psoriasis pathogenesis and response to acitretin were examined. Patients with type 1 early onset plaque psoriasis (which is defined as an onset of disease prior to the age of 40) and acitretin use were recruited (n=106) [26]. Patients with VEGF polymorphism genotype -460 TT were almost two times more likely to fail acitretin therapy than to respond [26].…”

Clinical evaluation of AKBBA in the management of psoriasis

“…It is the only mitogen to specifically act on endothelial cells and stimulate the elongation, network formation, and branching of nonproliferating endothelial cells in cultures deprived of oxygen and nutrients. High levels of VEGF have been found in the synovial joints of Psoriatic arthritis (9), and psoriatic plaques (10). A correlation has been seen between the PASI score and VEGF (11).…”

Pharmacogenetics of Psoriasis Treatment

“…Angiogenesis, especially inappropriate vascular expansion, is indeed a common pathogenic component of psoriasis. Two polymorphisms within VEGF, rs2010963 and rs833061, have been implicated in diseases with strong angiogenic background [31]. Beside the inluence on treatment response, they may also inluence the time of onset of the disease [32,33].…”