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Elod Kortvely, Anneke I. Den Hollander, Matteo Gorza, Valentina Cipriani, John R. Yates, Caroline Hayward, Alan F. Wright, Sascha Fauser, Carel C. Hoyng, Marius Ueffing; Genetic Association of Glucose Transporter Type 1 Variants with Age-Related Macular Degeneration and its Direct Interaction with Complement Factor H at the Protein Level. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6483.
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Mutations and polymorphic variants in complement factor H (CFH), the main inhibitor of the alternative complement pathway, have been found to be associated with age-related macular degeneration (AMD). In the present study, we sought to identify proteins interacting with CFH that could provide new insights into its (patho)physiological function.
A yeast two-hybrid screen was performed using the non-risk variant of CFH as bait against a human placental cDNA library, in order to identify direct interacting partners. The physiological interaction was confirmed by co-immunoprecipitation followed by mass spectrometry. Glucose transporter type 1 (GLUT1/SLC2A1), a protein identified with both methods as a binding partner of CFH, was selected for further genetic association analysis. Nine tag SNPs were genotyped in three independent cohorts including 1,888 AMD patients and 954 healthy controls.
Using yeast two-hybrid analysis we found that CFH directly binds to GLUT1, the key glucose transporter of the blood-retina barrier. The physical interaction was also confirmed by co-immunoprecipitation experiments combined with mass spectrometry. Further analyses suggest that GLUT1 engages CFH in retinal pigment epithelium cells via its C-terminal exomembrane domains. Genetic association studies detected a significant correlation of GLUT1 polymorphisms (SNP rs3768029) with AMD. Compared to the reference CC-genotype, ORs of 1.339 (95% CI=1.113-1.611, p=0.001) and 1.344 (95% CI=1.067-1.694, p=0.01) were obtained for carriers with CT- and TT-genotypes, respectively.
These results demonstrate a new role for GLUT1 in the localization of CFH to the blood-retina barrier. Polymorphisms in the GLUT1 gene may contribute to AMD risk.
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