Iron may be implicated in the generation of oxidative stress by the catalyzing the Haber–Weiss or Fenton reaction. On the other hand, oxidative stress has been implicated in the pathogenesis of age-related macular degeneration (AMD) and heme oxygenase-1 (HO-1), encoded by the HMOX1 gene and heme oxygenase-2 (HO-2), encoded by the HMOX2 gene are important markers of iron-related oxidative stress and its consequences. Therefore, variability of the HMOX1 and HMOX2 genes might be implicated in the pathogenesis of AMD through the modulation of the cellular reaction to oxidative stress. In the present work, we investigated the association between AMD and a G → C transversion at the 19 position in the HMOX1 gene (the 19G>C-HMOX1 polymorphism, rs2071747) and a A → G transition at the −42 + 1444 position in the HMOX2 gene (the −42 + 1444A>G-HMOX2 polymorphism, rs2270363) and its modulation by some environmental factors. 279 patients with AMD and 105 controls were recruited in this study and the polymorphisms were typed by restriction fragment length polymorphism and allele-specific polymerase chain reaction (PCR). We observed an association between the occurrence of dry AMD and the G/A genotype of the −42 + 1444A>G-HMOX2 polymorphism (odds ratio (OR) 2.72), whereas the G/G genotype reduced the risk of dry AMD (OR 0.41). The G/C genotype and the C allele of the 19 G>C-HMOX1 polymorphism and the G/G genotype and the G allele of the −42 + 1444A>G-HMOX2 polymorphism were associated with progression of AMD from dry to wet form (OR 4.83, 5.20, 2.55, 1.69, respectively). On the other hand, the G/G genotype and the G allele of the 19 G>C-HMOX1 polymorphism and the A/G genotype and the A allele of the −42 + 1444A>G-HMOX2 polymorphism protected against AMD progression (OR 0.19, 0.19, 0.34, 0.59, respectively). Therefore, the 19G>C-HMOX1 and the −42 + 1444A>G-HMOX2 polymorphisms may be associated with the occurrence and progression of AMD.Electronic supplementary materialThe online version of this article (doi:10.1007/s11033-011-0955-3) contains supplementary material, which is available to authorized users.

Oxidative stress is thought to play a role in the pathogenesis of age-related macular degeneration (AMD). We determined the extent of oxidative DNA damage and the kinetics of its removal as well as the genotypes of the Ser326Cys polymorphism of the hOGG1 gene in lymphocytes of 30 wet AMD patients and 30 controls. Oxidative DNA damage induced by hydrogen peroxide and its repair were evaluated by the comet assay and DNA repair enzymes. We observed a higher extent of endogenous oxidative DNA damage and a lower efficacy of its repair in AMD patients as compared with the controls. We did not find any correlation between the extent of DNA damage and efficacy of DNA repair with genotypes of the Ser326Cys polymorphism. The results obtained suggest that oxidative DNA damage and inefficient DNA repair can be associated with AMD and the variability of the hOOG1 gene may not contribute to this association.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries, and its pathogenesis is underlined by genetic and environmental factors. Oxidative stress is a major environmental risk factor of AMD; namely, AMD is associated with the increased level of reactive oxygen species, which may be produced in reactions catalyzed by iron present in the retina. Therefore, variability of the genes of iron metabolism may be important in the AMD risk. In the present study, we analyzed the association between AMD and the -576G>A polymorphism of the transferrin gene or the 1892C>T polymorphism of the transferrin receptor 2 (TFR2) gene in 278 patients with AMD and 105 controls. The former polymorphism is located in the promoter region of the transferrin gene and may affect the level of its transcription, while the latter is a synonymous mutation in the exon 16, which may affect the efficiency of translation of TFR2 mRNA. Transferrin and TFR2 are important in iron homeostasis. The A allele of the -576A>G polymorphism was significantly associated with the increased risk of AMD in tobacco smokers, whereas the 1892C>T polymorphism did not influence the risk of AMD related to smoking. Moreover, each polymorphism does not influence the risk of AMD associated with age, sex or the family history of the disease. In conclusion, the A allele of the -576A>G polymorphism of the transferrin gene may increase the risk of AMD in smokers.Keywords: age-related macular degeneration; iron metabolism; transferrin gene; transferrin receptor; genetic polymorphism Tohoku J. Exp. Med., 2011, 223 (4), 253-261. © 2011 Tohoku University Medical Press Age-related macular degeneration (AMD) is the leading cause of vision loss in elderly in developed countries (Gehrs et al. 2006). It is a complex disease affecting the macula, a central part of the retina, leading to the irreversible impairment of central vision (Ding et al. 2009). The frequency of AMD among adults aged more than 75 years exceeds 30% and is expected to increase due to an increasing life expectancy (Liutkeviciene et al. 2010). The early stage of AMD is characterized by druzen formation-a white-yellow deposits in Bruch's membrane under the retinal pigment epithelial (RPE) layer and photoreceptor cells. AMD can develop to one of two advanced forms: dry (atrophic) and wet (exudative, neovascular). Slowly progressing and more common dry AMD is characterized by the presence of an irregular area of depigmentation as a result of the loss of RPE cells and causes a gradual geographic atrophy of the retina. The main feature of wet AMD is choroidal neovascularization with leakage and bleeding, leading to irreversible damage of photoreceptors (Coleman et al. 2008).

SummaryBackgroundAge-related macular degeneration (AMD) is a primary cause of blindness among the elderly in developed countries. The nature of AMD is complex and includes both environmental and hereditary factors. Oxidative stress is thought to be essential in AMD pathogenesis. Iron is suggested to be implicated in the pathogenesis of AMD through the catalysis of the production of reactive oxygen species, which can damage the retina. Heme oxygenase-2 is capable of degradation of heme producing free iron ions, thus, diversity in heme oxygenase-2 gene may contribute to AMD. In the present work we analyzed the association between the c.544G>A polymorphism of the heme oxygenase-2 gene (HMOX2) (rs1051308) and AMD.Material/MethodsThis study enrolled 276 AMD patients and 105 sex- and age-matched controls. Genotyping of the polymorphism was performed with restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) on DNA isolated from peripheral blood.ResultsWe did not find any association between the genotypes of the c.544G>A polymorphism and the occurrence of AMD. This lack of association was independent of potential AMD risk factors: tobacco smoking, sex and age. Moreover, we did not find any association between AMD and smoking in our study population.ConclusionsThe results suggest that the c.544G>A polymorphism of the heme oxygenase-2 gene is not associated with AMD in this Polish subpopulation.