Optimized Treatment of Refractory Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia With Alirocumab (OPTIMIZE).

Background Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). In confirmatory trials, proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab substantially lowered LDL-C and reduced cardiovascular morbidity and mortality. However, the routine clinical use of alirocumab in Switzerland has not yet been studied. Methods In this prospective nation-wide cohort study, we aimed to investigate the patient profile and routine clinical efficacy and safety of alirocumab in 207 patients with ASCVD or heterozygous familial hypercholesterolemia and increased LDL-C despite maximally tolerated statin therapy. LDL-C was measured at baseline and after 3-months follow-up. Results Overall, mean age was 63 ± 11 years, 138 (67%) were men, and 168 (81%) had statin intolerance (SI). Patients with SI had a higher baseline LDL-C (4.3 ± 1.4 vs. 3.3 ± 1.4 mmol/l; p < 0.001) and less frequently ASCVD (71% vs. 95%; p = 0.002). After 3 months of treatment with alirocumab, LDL-C was reduced from 4.1 ± 1.5 to 2.0 ± 1.2 mmol/l (50.5%; p < 0.001). Mean absolute and relative reductions in LDL-C were similar in patients with vs. without SI (2.2 ± 1.2 vs. 1.9 ± 1.3 mmol/l; p = 0.24 and 49.0 vs. 56.6%; p = 0.11, respectively). In total, adverse events were recorded in 25 (12%) patients, with no new safety signals. Conclusions In routine clinical practice, alirocumab was predominantly used in patients with SI suggesting that the great majority of patients with insufficient LDL-C control who would be candidates for alirocumab are not receiving this therapeutic option in Switzerland. LDL-C lowering was potent and similar in patients with and without SI, replicating the favorable efficacy-safety profile of alirocumab from randomized trials

The prioritisation of a short list of alien plants for risk analysis within the framework of the Regulation (EU) No. 1143/2014

Thirty-seven alien plant species, pre-identified by horizon scanning exercises were prioritised for pest risk analysis (PRA) using a modified version of the EPPO Prioritisation Process designed to be compliant with the EU Regulation 1143/2014. In Stage 1, species were categorised into one of four lists – a Residual List, EU List of Minor Concern, EU Observation List and the EU List of Invasive Alien Plants. Only those species included in the latter proceeded to the risk management stage where their priority for PRA was assessed. Due to medium or high spread potential coupled with high impacts twenty-two species were included in the EU List of Invasive Alien Plants and proceeded to Stage 2. Four species (Ambrosia trifida, Egeria densa, Fallopia baldschuanica and Oxalis pes-caprae) were assigned to the EU Observation List due to moderate or low impacts. Albizia lebbeck, Clematis terniflora, Euonymus japonicus, Lonicera morrowii, Prunus campanulata and Rubus rosifolius were assigned to the residual list due to a current lack of information on impacts. Similarly, Cornus sericea and Hydrilla verticillata were assigned to the Residual List due to unclear taxonomy and uncertainty in native status, respectively. Chromolaena odorata, Cryptostegia grandiflora and Sphagneticola trilobata were assigned to the Residual List as it is unlikely they will establish in the Union under current climatic conditions. In the risk management stage, Euonymus fortunei, Ligustrum sinense and Lonicera maackii were considered a low priority for PRA as they do not exhibit invasive tendencies despite being widely cultivated in the EU over several decades. Nineteen species were identified as having a high priority for a PRA (Acacia dealbata, Ambrosia confertiflora, Andropogon virginicus, Cardiospermum grandiflorum, Celastrus orbiculatus, Cinnamomum camphora, Cortaderia jubata, Ehrharta calycina, Gymnocoronis spilanthoides, Hakea sericea, Humulus scandens, Hygrophila polysperma, Lespedeza cuneata, Lygodium japonicum, Pennisetum setaceum, Prosopis juliflora, Sapium sebiferum, Pistia stratiotes and Salvinia molesta)

Heritability, determinants and reference values of renal length: a family-based population study

Objectives: In this population-based study, reference values were generated for renal length, and the heritability and factors associated with kidney length were assessed. Methods: Anthropometric parameters and renal ultrasound measurements were assessed in randomly selected nuclear families of European ancestry (Switzerland). The adjusted narrow sense heritability of kidney size parameters was estimated by maximum likelihood assuming multivariate normality after power transformation. Gender-specific reference centiles were generated for renal length according to body height in the subset of non-diabetic non-obese participants with normal renal function. Results: We included 374 men and 419 women (mean ± SD, age 47 ± 18 and 48 ± 17years, BMI 26.2 ± 4 and 24.5 ± 5kg/m2, respectively) from 205 families. Renal length was 11.4 ± 0.8cm in men and 10.7 ± 0.8cm in women; there was no difference between right and left renal length. Body height, weight and estimated glomerular filtration rate (eGFR) were positively associated with renal length, kidney function negatively, age quadratically, whereas gender and hypertension were not. The adjusted heritability estimates of renal length and volume were 47.3 ± 8.5% and 45.5 ± 8.8%, respectively (P < 0.001). Conclusion: The significant heritability of renal length and volume highlights the familial aggregation of this trait, independently of age and body size. Population-based references for renal length provide a useful guide for clinicians. Key Points: • Renal length and volume are heritable traits, independent of age and size. • Based on a European population, gender-specific reference values/percentiles are provided for renal length. • Renal length correlates positively with body length and weight. • There was no difference between right and left renal lengths in this study. • This negates general teaching that the left kidney is larger and longe

PhenoExplorer: An Interactive Web-based Platform for Exploring (Epi)Genome-Wide Associations Using a Swiss Population-based Study

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes

Accounting for a Quantitative Trait Locus for Plasma Triglyceride Levels: Utilization of Variants in Multiple Genes

For decades, research efforts have tried to uncover the underlying genetic basis of human susceptibility to a variety of diseases. Linkage studies have resulted in highly replicated findings and helped identify quantitative trait loci (QTL) for many complex traits; however identification of specific alleles accounting for linkage remains elusive. The purpose of this study was to determine whether with a sufficient number of variants a linkage signal can be fully explained.We used comprehensive fine-mapping using a dense set of single nucleotide polymorphisms (SNPs) across the entire quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma triglyceride levels. Analyses included measured genotype and combined linkage association analyses.Screening this linkage region, we found an over representation of nominally significant associations in five genes (MLL3, DPP6, PAXIP1, HTR5A, INSIG1). However, no single genetic variant was sufficient to account for the linkage. On the other hand, multiple variants capturing the variation in these five genes did account for the linkage at this locus. Permutation analyses suggested that this reduction in LOD score was unlikely to have occurred by chance (p = 0.008).With recent findings, it has become clear that most complex traits are influenced by a large number of genetic variants each contributing only a small percentage to the overall phenotype. We found that with a sufficient number of variants, the linkage can be fully explained. The results from this analysis suggest that perhaps the failure to identify causal variants for linkage peaks may be due to multiple variants under the linkage peak with small individual effect, rather than a single variant of large effect

Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1

Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta = 5.72 × 10(-4)), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10(-16)). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a 'proxy phenotype' of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is ∼1.2 Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis