Chronic kidney disease (CKD) is a complex disease affecting >10% of the global population, with large between- and within-continent variability reflecting major environmental effects. To identify molecular targets for treatment, genome-wide association study meta-analyses (GWAMAs) of CKD-defining traits have identified hundreds of genetic loci in aggregated populations. However, while GWAMAs estimate the average allelic effect across studies, single population studies may be relevant to unravel specific mechanisms. To assess whether an individual study from a specific population could extend existing knowledge on kidney function genetics, we selected 147 kidney function relevant loci identified by a large European ancestry GWAMA, assessing their association with the glomerular filtration rate estimated from serum creatinine (eGFRcrea) in the Cooperative Health Research In South Tyrol (CHRIS) study (n=10,146), conducted in an Alpine region where thyroid dysfunction is common. We replicated associations with single nucleotide polymorphisms (SNPs) at 11 loci, showing up-to-5.4 times larger effect sizes than in the corresponding GWAMA, not explainable by minor allele frequency differences. Systematic mediation analysis across 70 quantitative traits identified serum magnesium, the activated partial thromboplastin time, and serum urate as partial mediators of the eGFRcrea associations at SHROOM3, SLC34A1, and IGF1R, respectively. Given that free triiodothyronine and thyroxine were effect modifiers across all loci, we conducted SNP-by-thyroid stimulating hormone (TSH) interaction analyses, identifying significant interactions at STC1: SNPs had larger effects on eGFRcrea at higher TSH levels, possibly reflecting stanniocalcin-1 autocrine and paracrine role. Individual population studies can help characterize genetic associations. The interplay between phenotypes at SHROOM3 and SLC34A1 and the role of thyroid function as a genetic effect modifier warrant further investigations.

Background: TTN from delayed clearance of fetal lung fluid (FLF) is common NICU admission among FT infants and require clinical management involving expensive resources,excessive and empiric antibiotics use. The increased risk of TTN among ECS born infants (CS in absence of labor) is a consequence of having excessive FLF with subsequent decreased release of counter regulatory hormones at delivery.

Background Arrhythmogenic Cardiomyopathy (ACM) is a genetic condition hallmarked by ventricular fibro-fatty replacement and arrhythmias. Cardiac mesenchymal stromal cells (C-MSC) differentiate into adipocytes in ACM hearts, through the activation of PPARγ, caused by ACM mutations (e.g. PKP2). The clinical phenotype of ACM is variable for poorly understood reasons. The only recognized cofactor is physical exercise, which is known to increases oxidative stress. An accepted marker of exercise-induced oxidative stress is 13HODE, a component of oxLDL and direct activator of PPARγ. In macrophages, during foam cell formation, 13HODE creates a feed-forward loop increasing both PPARγ and the oxLDL receptor CD36, resulting in fat accumulation. Purpose To investigate oxLDL effects on ACM adipogenesis and to dissect the involved pathways. Methods We analyzed plasmas (n=42) and ventricular tissues (n=4) of ACM patients and matched healthy controls (HC). For in vitro experiments, ACM and HC C-MSC (n=10) have been used, while in vivo experiments have been conducted in heterozygous Pkp2 knock-out mice (Pkp2+/−; n=10). Results We observed higher plasma oxLDL in ACM patients compared to HC (ACM 246.70±55.89 vs HC 102.5±17.95ng/ml; p=0.019). oxLDL levels also discriminate between ACM patients with overt phenotype and their unaffected relatives carriers of the same causative mutations (p=0.03). We observed higher oxidative stress (MDA intensity 40.87±11.76 fold; p=0.015) and CD36 levels (14.72±2.10 fold; p=0.0007) in ACM ventricular tissue, compared to HC. In basal conditions, ACM C-MSC showed greater oxidative stress (MDA intensity 8.83±2.78 fold p=0.017) and higher expression of PPARγ (1.47±0.14 fold; p=0.009) compared to HC C-MSC. The adipogenic stimulation led to a parallel increase of CD36 and lipid accumulation, mainly in ACM C-MSC (slopes statistically different p=0.016). OxLDL and 13HODE administration increased lipid accumulation in ACM C-MSC (ORO staining ACM vs ACM+oxLDL p=0.01; ACM vs ACM+13HODE p=0.014). On the contrary, the antioxidant N-Acetylcysteine (NAC) prevented lipid accumulation in ACM C-MSC (ORO staining ACM+13HODE vs ACM+13HODE+NAC p=0.0009). Through CD36 silencing of ACM C-MSC, we obtained a significantly lower lipid accumulation than non-silenced cells (ORO staining 0.35±0.10 fold; p=0.003). Pkp2+/− mice do not spontaneously accumulate adipocytes in the heart, however Pkp2+/− C-MSC are more prone to lipid accumulation in vitro than WT cells (p=0.007). Accordingly, mice have low plasma oxLDL and cardiac oxidative stress. By increasing plasma cholesterol and oxidative stress through high fat diet, we observed fibro-fatty substitution in Pkp2+/− hearts (p=0.046). Figure 1 Conclusions These findings reveal a modulatory role of oxidized lipids in ACM adipogenesis at a cellular, tissue and clinical level, enlightening novel targets for pharmacological strategies to prevent adipogenic substitution and consequent ACM clinical phenotypes. Acknowledgement/Funding Telethon Foundation; Italian Ministry of Health

Background:The fetal to neonatal transition is accompanied by lung expansion and lung fluid clearance soon after birth. BNP reference values are available mostly for preterm infants. BNP synthesized predominantly in the cardiac ventricle play an important role in the regulation of ECF volume and postnatal circulatory adaptation. Neonates born via ECS are at higher risk for postnatal transitional failure states like TTN. Reference values of BNPs among healthy FT born via ECS (not in labor) have not been reported.