The variant N363S of glucocorticoid receptor in steroid-induced ocular hypertension in Hungarian patients treated with photorefractive keratectomy.

PURPOSE: Variation in sensitivity to glucocorticoids observed in healthy population is influenced by genetic polymorphisms of the glucocorticoid receptor gene (NR3C1). N363S, ER22/23EK, and Bcl I have been previously described as glucocorticoid-sensitivity modulating polymorphisms. We investigated whether these variants may contribute to steroid-induced ocular hypertension and if they play a role as protective or risk factors during exogenous glucocorticoid administration. METHODS: We examined 102 patients who underwent photorefractive keratectomy and received topical steroids (either fluorometholone 0.1% or prednisolone acetate 0.5% alone or combined) as part of postoperative therapy. The choice of steroid depended on course of wound healing and regression. Variations in intraocular pressure (IOP) levels in response to steroid therapy were observed. To genotype DNA, allele-specific PCR amplification was applied for the N363S polymorphism, and PCR-based restriction fragment length polymorphism analysis was performed to examine the Bcl I and the ER22/23EK polymorphisms. We separately analyzed data from three groups of patients: those who received fluorometholone only; those who were initially given fluorometholone then later switched to prednisolone acetate; and those who received prednisolone acetate only. Covariance analysis with forward stepwise variable selection was carried out. RESULTS: In cases where prednisolone acetate was administered, we found a significant correlation between N363S heterozygosity and steroid-induced ocular hypertension. ER22/23EK and Bcl I polymorphisms do not have a major influence on the risk of developing steroid-induced ocular hypertension. CONCLUSIONS: Genotyping of high risk steroid responders may allow an individual therapy to avoid steroid-induced ocular hypertension. The N363S polymorphism may have a clinical significance in the future.

Genetic polymorphisms of vascular endothelial growth factor and angiopoietin 2 in retinopathy of prematurity.

Angiogenic factors such as vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) contribute to development of retinopathy of prematurity (ROP). We aimed to test whether polymorphisms of these factors are associated with ROP. VEGF(-2578) and Ang2(-35) polymorphisms were analyzed with PCR-RFLP method in 200 preterm infants without ROP or with ROP stages 1-5. Our results suggest that there is no association between carrier state of VEGF(-2578) and Ang2(-35) and risk of ROP in preterm infants. The prevalence of VEGF(-2578) "A" allele was lower in preterm boys with severe ROP (stages 4-5) than in those without or with mild ROP (stages 1-3).

Genetic polymorphisms of vascular endothelial growth factor in severe pre-eclampsia.

Several lines of evidence support the hypothesis that vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of pre-eclampsia (PE). VEGF is a key component in the regulation of vascular remodelling and the survival of cytotrophoblasts in the placenta. In this case-control study, we aimed to test whether VEGF genetic polymorphisms are associated with the risk of severe PE. We enrolled 84 nulliparous pregnant women with severe PE (PE group). Their VEGF G(+405)C and VEGF C(-2578)A genotypes were determined by PCR-restriction fragment length polymorphism (PCR-RFLP) from venous blood samples and were compared with the corresponding VEGF genotypes of 96 nulliparous patients with uncomplicated pregnancies (control group). Carriers of the VEGF(+405)G allele occurred less frequently in PE than in the control group [P = 0.039; adjusted odds ratio (aOR) = 0.28, range: 0.08-0.93]. Hypertension and proteinuria were diagnosed earlier (by 1.6 weeks and 1.9 weeks, respectively) in PE patients with VEGF(-2578)A only after adjustment of this association for risk factors of PE. Our results suggest that carriers of VEGF(+405)G allele have a decreased susceptibility to PE and that the progression of PE may be modified by the presence of VEGF(-2578)A allele. Nevertheless, the clinical significance of these findings remains to be determined.

Genetic polymorphisms for vascular endothelial growth factor in perinatal complications.

Low birth weight (LBW) infants have increased susceptibility to perinatal complications. An immature and impaired vascular system may possibly participate in these complications. There is evidence that supports the notion that vascular endothelial growth factor (VEGF), which is an essential regulator of embryonic angiogenesis, plays a central role in the pathogenesis of perinatal complications. We aimed to test whether functional genetic polymorphisms of VEGF are associated with the risk of preterm birth or perinatal morbidity. We enrolled 128 LBW infants (< or = 1500 grams). VEGF T-460C, VEGF C-2578A and VEGF G+405C polymorphisms were determined by real-time PCR or PCR-RFLP, respectively. Their genotypes were compared with VEGF genotypes of 200 healthy, term neonates. The prevalence of the VEGF+405 C allele was higher in LBW infants than in healthy, term neonates (OR [95% CI]: 1.29 [1.01-1.65]). Carrier state for the VEGF -2578A allele was an independent risk factor for enterocolitis necrotisans (NEC) (adjusted OR [95% CI]: 2.77 [1.00-7.65]). The carrier state for the VEGF -2578AA genotype was associated with a decreased risk of acute renal failure (ARF) (adjusted OR [95% CI]: 0.2 [0.05-0.78]). These results suggest that VEGF G+405C polymorphism might be associated with a higher risk of preterm birth and that VEGF C-2578A polymorphism may participate in the development of perinatal complications such as NEC and ARF.

Association of genetic polymorphisms of vascular endothelial growth factor and risk for proliferative retinopathy of prematurity.

The intention of our retrospective study was to determine whether vascular endothelial growth factor (VEGF) genetic polymorphisms are associated with risk for proliferative retinopathy of prematurity (ROP), a condition that is characterized by abnormal retinal neovascularization and can lead to retinal detachment and result in blindness. We enrolled 86 very low birth weight infants (birth weight < or =1500 g) who had been treated with cryo/laser therapy because of the risk for proliferative ROP (treated group). Their VEGF T-460C and G+405C genotypes were determined from dried blood samples and were compared with VEGF genotypes of 115 VLBW infants who were not treated with cryo/laser therapy (untreated group). We found that the allele frequency of VEGF +405C was higher in the treated group than in the untreated group (0.30 versus 0.41; p <0.05). The likelihood of being treated for ROP was higher in heterozygous and homozygous carriers of VEGF +405C alleles [odds ratios adjusted for risk factors of ROP (95% CI): 2.00 (1.02-3.92; p=0.04) and 3.37 (1.17-9.65; p=0.007), respectively]. VEGF -460TT/+405CC haplotype was more prevalent in the treated patients than in the untreated patients (13 of 86 versus 1 of 115; p <0.001), and the association remained significant (p <0.01) even after the adjustment for risk factors of ROP (gestational age, supplemental oxygen therapy, and gender). These findings suggest that the VEGF genotype may be associated with risk for proliferative ROP in VLBW infants.