👤 Nicolas Hense

Mutations in BMP4 have been associated with malformations of the urinary tract in human patients. Genetic studies in mice have shown that these defects are linked to the expression of Bmp4 in the mesenchymal primordium of the ureter, where it acts as a critical signal for coordinated cytodifferentiation of the mesenchymal and epithelial tissues. Here, we used unbiased transcriptional profiling of ureters with genetic depletion of Bmp4 and pharmacological inhibition of BMP4 signaling to decipher the gene regulatory network controlled by BMP4 in the early ureter, focusing on transcription factors as possible drivers of cytodifferentiation. We show that in Bmp4-deficient ureters, expression of Grhl3, Msx2, Pparg, Trp63 and Foxa1 in the epithelial compartment, and of Gata6, Hopx, Id2, Id4, Myocd, Snai1 and Tbx18 in the mesenchymal primordium is reduced. Expression of Msx2, Pparg, Gata6, Id genes, Tbx18 and Snai1 requires direct BMP4 signaling input, whereas reduced expression of the other genes is likely due to secondary changes, including increased retinoic acid signaling. Conditional gene targeting of Smad4 revealed that BMP4-dependent activation of transcription factor genes is mediated in part by SMAD effectors in both ureteral tissues. Thus, our work links BMP4 (signaling) to known transcriptional regulators of ureteral cytodifferentiation and uncovers additional factors that may be relevant to this program. Show less

The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. Case-control association analysis of metabolomics data. Five European cohorts consisting of 2267 AMD patients and 4266 control participants. Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression. Metabolites associated with AMD. We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high-density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD. Show less

Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Pooled analysis of cross-sectional data. Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. AMD features and stage; lipid measurements. HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10 Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered. Show less