TY  - JOUR
A1  - Grassmann, Felix
A1  - Fritsche, Lars G.
A1  - Keilhauer, Claudia N.
A1  - Heid, Iris M.
A1  - Weber, Bernhard H. F.
T1  - Modelling the Genetic Risk in Age-Related Macular Degeneration
JF  - PLoS One
N2  - Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available.
KW  - AMD
KW  - complement factor-H
KW  - grading system
KW  - United States
KW  - vitamin C
KW  - prevalence
KW  - variants
KW  - susceptibility
KW  - association
KW  - maculopathy
KW  - variant genotypes
KW  - genetic loci
KW  - macular degeneration
KW  - genetics of disease
KW  - eyes
KW  - cased-control studies
KW  - genotyping
KW  - human genetics
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131315
VL  - 7
IS  - 5
ER  - 
TY  - JOUR
A1  - Gassen, Alwine
A1  - Brechtefeld, Doris
A1  - Schandry, Niklas
A1  - Arteaga-Salas, J. Manuel
A1  - Israel, Lars
A1  - Imhof, Axel
A1  - Janzen, Christian J.
T1  - DOT1A-dependent H3K76 methylation is required for replication regulation in Trypanosoma brucei
JF  - Nucleic Acids Research
N2  - Cell-cycle progression requires careful regulation to ensure accurate propagation of genetic material to the daughter cells. Although many cell-cycle regulators are evolutionarily conserved in the protozoan parasite Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. Here, we analyse the function of the histone methyltransferase DOT1A during cell-cycle progression. Over-expression of DOT1A generates a population of cells with aneuploid nuclei as well as enucleated cells. Detailed analysis shows that DOT1A over-expression causes continuous replication of the nuclear DNA. In contrast, depletion of DOT1A by RNAi abolishes replication but does not prevent karyokinesis. As histone H3K76 methylation has never been associated with replication control in eukaryotes before, we have discovered a novel function of DOT1 enzymes, which might not be unique to trypanosomes.
KW  - variants
KW  - cell-cycle regulation
KW  - blood-stream forms
KW  - african trypanosomes
KW  - mammalian cells
KW  - DNA replication
KW  - DOT1
KW  - protein
KW  - transcription
KW  - cultivation
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131449
VL  - 40
IS  - 20
ER  -