👤 Olga Pomares

The DLK1 human gene encodes for the transmembrane EGF-like repeat-containing protein DLK1, which acts as a modulator of adipogenesis. A role for DLK1 in energy metabolism and lipid homeostasis has been suggested and DLK1 gene variants have been related to pubertal development. The aim of this study was to uncover DLK1 SNPs in a cohort of children and analyze their relationship with anthropometric and biochemical variables. Our population-based sample comprises 1237 healthy 6-to-8-year-old Caucasian children. The presence of five DLK1 SNPs (rs1802710, rs876374, rs7155375, rs57098752, and rs7149242) was analyzed by Real-Time PCR, using predesigned TaqMan™ Genotyping Assays. We observed that the SNPs rs1802710 and rs876374 were associated with BMI, and the prevalence of these two SNPs was different in normal-weight children compared to children with obesity. Related to biochemical variables, we found a significant association of the SNPs rs1802710, rs876374, and rs57098752 and their combination with Apo-B plasma concentrations after adjusting by BMI and sex. The SNPs rs1802710 and rs57098752 were also significantly associated with plasma levels of LDL-C and HDL-C, respectively. Our study reveals that DLK1 gene variants may influence both body weight and lipid homeostasis, affecting particularly to the Apo-B biology, in children. DLK1 polymorphisms are associated with BMI and with lipid levels, independently of BMI, early in life. Our data add to the existing literature the evidence that DLK1 gene variants impact on lipid metabolism. The confirmation at the population level that DLK1 genetic variants are associated with anthropometric and lipid variables sustains the role of DLK1 in obesity and related disorders and should lead to further studies aimed at clarifying this effect. Show less

To identify the genetic variants of the vascular endothelial growth factor (VEGF) pathway genes and other genes associated with neovascular age-related macular degeneration (nAMD) as possible predictive biomarkers of a favorable treatment response to aflibercept. A 52-week (with extension phase: 104-week), prospective, open-label, single-arm, multicenter, phase IV trial was conducted in Spain. Patients with nAMD were enrolled. Aflibercept was administered every 8 weeks until week 48 (after 1-monthly loading doses over 3 months). After week 48, the interval between visits for aflibercept administration was extended by 2 weeks per visit to a maximum of 12 weeks if no evidence of disease activity was observed. A total of 338 SNPs in 90 genes associated with nAMD were analyzed. Efficacy was evaluated mainly with best-corrected visual acuity (BCVA), and adverse events (AEs) were reported. Treatment efficacy was defined as an increase in BCVA ≥15 letters versus the baseline visit. Univariate and multivariate logistic regressions were used to associate single-nucleotide polymorphisms (SNPs) and treatment efficacy. 194 nonconsecutive patients were enrolled, 170 completed the 52-week follow-up, and of the 85 patients who started the extension phase, 77 completed this phase. Mean BCVA increased from baseline to weeks 52 and 104 by 9 and 10 letters (p = 0.0001 for both), respectively. The percentages of patients gaining ≥15 letters in weeks 52 and 104 were 33 and 31%, respectively. Multivariate logistic regression showed significant associations of 6 SNPs (in 6 genes) with treatment efficacy: rs12366035 (VEGFB; TT; odds ratio [OR] 217), rs25681 (C5; AA/AG; OR 19.7/8.3), rs17793056 (CX3CR1; CT/CC; OR 8.1/6.2), rs1800775 (CETP; CC; OR 6.6), rs2069845 (IL6; GG/AA; OR 5.6/3.3), and rs13900 (CCL2; CT; OR 4.0). One percent of the patients reported arteriothrombolic events related to aflibercept (cerebrovascular accident) according to the Antiplatelet Trialist Collaboration, and 2% reported serious ocular (retinal pigment epithelial tear, retinal tear, and endophthalmitis) and systemic (cardiac failure, hypersensitivity, and transient ischemic attack) AEs related to aflibercept. Results suggest strong pharmacogenetic associations between one genetic variant of VEGFB (TT, rs12366035) and C5 (AA, rs12366035) genes and the BCVA response after 52-week aflibercept treatment in patients with nAMD. Likewise, the results support the efficacy of aflibercept observed in phase III studies and a good safety profile. Show less