MyVisionTest News Archive
Apr 22, 2011
Iron metabolism gene associated AMD in smokers
A genetic variation of the transferrin gene is associated with increased risk of AMD in smokers.
Oxidative stress is a major environmental risk factor of age-related macular degeneration (AMD) AMD is associated with the increased level of reactive oxygen species (ROS), 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.
It is known that iron ions might be a source of ROS, and an excess of iron may be toxic to cells by the generation of oxidative stress through the iron-catalyzed Fenton reaction, producing highly reactive hydroxyl radicals and other ROS, which are able to damage basic cellular components. The normal aging process may be associated with iron-overload in many tissues. Iron overload and oxidative stress are known to be involved in pathogenesis of various diseases, including heart failure, neurodegenerative disorders, and cancer. Therefore, it seems reasonable that variations in genes encoding proteins of iron metabolism may influence iron homeostasis in many organs, including the eye.
A growing body of evidence suggest that iron and proteins in iron metabolism may be involved in the pathogenesis of AMD. Patients with aceruloplasminemia, a disease associated with iron overload, were reported to have macular atrophy with features of AMD. Maculas derived from AMD-affected patients, both in dry and wet forms, stained for iron, showed an elevated level of chelatable iron in comparison to maculas derived from healthy controls. It has also been shown that iron chelation will protect RPE cells treated with hydrogen peroxide from undergoing apoptosis, suggesting the involvement of iron in oxidative stress-mediated damage.
The plasma protein transferrin (TF) and its receptors 1 and 2 (TFR1 and TFR2) are essential proteins for the uptake of iron by the cell. Each TF molecule can bind two molecules of Fe3+ and after binding, these ferric iron ions can be effectively utilized by the cell. An elevated expression of the TF and TFR2 genes has been reported to be associated with AMD. These data suggest that both TF and TFR2 may be involved in AMD pathogenesis.
Methods and Results
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.
Discussion and Conclusions
This study investigated the association between the -576G>A-TF and 1892C>T-TFR2 polymorphisms and AMD occurrence along with some established risk factors: age, sex, tobacco smoking, and family history. The analysis of risk factors, independent of genotype, showed a strong association with age, sex and family history. Increased age, female gender, and positive family history of AMD were associated with increased risk of the disease.
The investigators did not find any direct association between the genotypes of the -576G>A-TF and 1892C>T-TFR2 polymorphisms and AMD occurrence, either dry, or wet form of the disease. Similarly, combined genotypes of both polymorphisms did not return any significant association. These results indicate that these two polymorphisms are not independent markers of AMD occurrence. A number of other researchers have reported significant synergistic effects of genetic polymorphisms and tobacco smoking on AMD development. In the present study, the stratification of subjects regarding to smoking status revealed an association between the A allele of the -576G>A-TF polymorphism and AMD among smokers.
In summary, the -576G>A polymorphism of the transferrin gene may modulate the risk of AMD associated with tobacco smoking, and it can be considered as a smoking-dependent marker of the disease. These results confirm an important role of iron metabolism in the pathogenesis of AMD.
Read more...
Tohoku J Exp Med. 2011;223(4):253-61. (Free Full Text)
Tags: AMD, iron, genetics, diet
A genetic variation of the transferrin gene is associated with increased risk of AMD in smokers.Oxidative stress is a major environmental risk factor of age-related macular degeneration (AMD) AMD is associated with the increased level of reactive oxygen species (ROS), 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.
A growing body of evidence suggest that iron and proteins in iron metabolism may be involved in the pathogenesis of AMD. Patients with aceruloplasminemia, a disease associated with iron overload, were reported to have macular atrophy with features of AMD. Maculas derived from AMD-affected patients, both in dry and wet forms, stained for iron, showed an elevated level of chelatable iron in comparison to maculas derived from healthy controls. It has also been shown that iron chelation will protect RPE cells treated with hydrogen peroxide from undergoing apoptosis, suggesting the involvement of iron in oxidative stress-mediated damage.
The plasma protein transferrin (TF) and its receptors 1 and 2 (TFR1 and TFR2) are essential proteins for the uptake of iron by the cell. Each TF molecule can bind two molecules of Fe3+ and after binding, these ferric iron ions can be effectively utilized by the cell. An elevated expression of the TF and TFR2 genes has been reported to be associated with AMD. These data suggest that both TF and TFR2 may be involved in AMD pathogenesis.
Methods and Results
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.
Discussion and Conclusions
This study investigated the association between the -576G>A-TF and 1892C>T-TFR2 polymorphisms and AMD occurrence along with some established risk factors: age, sex, tobacco smoking, and family history. The analysis of risk factors, independent of genotype, showed a strong association with age, sex and family history. Increased age, female gender, and positive family history of AMD were associated with increased risk of the disease.
The investigators did not find any direct association between the genotypes of the -576G>A-TF and 1892C>T-TFR2 polymorphisms and AMD occurrence, either dry, or wet form of the disease. Similarly, combined genotypes of both polymorphisms did not return any significant association. These results indicate that these two polymorphisms are not independent markers of AMD occurrence. A number of other researchers have reported significant synergistic effects of genetic polymorphisms and tobacco smoking on AMD development. In the present study, the stratification of subjects regarding to smoking status revealed an association between the A allele of the -576G>A-TF polymorphism and AMD among smokers.
In summary, the -576G>A polymorphism of the transferrin gene may modulate the risk of AMD associated with tobacco smoking, and it can be considered as a smoking-dependent marker of the disease. These results confirm an important role of iron metabolism in the pathogenesis of AMD.
Read more...
Tohoku J Exp Med. 2011;223(4):253-61. (Free Full Text)
