The A Allele of the -576G>A Polymorphism of the Transferrin Gene Is Associated with the Increased Risk of Age-Related Macular Degeneration in Smokers

Abstract

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).

Genetic insights into age-related macular degeneration: Controversies addressing risk, causality, and therapeutics

“…(Chowers et al, 2006; Wong et al, 2007) To date, the genetic studies to establish a role of iron metabolism in AMD have been relatively weak. Nearly all of the recent studies of possible associations of transferrin and heme oxygenase-1 and -2 genes have come from a single group (Synowiec et al, 2011; Wysokinski et al, 2011a; Wysokinski et al, 2011b) and replication from larger cohorts has not been done. However, given the critical nature of iron metabolic pathways for the human body, one should not exclude the potential role of these genes in AMD.…”

Transferrin receptor levels and polymorphism of its gene in age-related macular degeneration

“…In the previous papers we reported an association of transferrin gene (TF) variants with AMD risk. Also, we found that the serum level of transferrin was higher among AMD patients than in control group (Wysokinski et al, 2011;Wysokinski et al, 2013). In the present work, we determined the role of sTfR, serum iron concentration and two polymorphisms in the TFRC gene in AMD.…”