Role of adenylate cyclase 9 in the pharmacogenomic response to dalcetrapib clinical paradigm and molecular mechanisms in precision cardiovascular medicine

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.Cardiolog

Electron microscopic demonstration of centrifugal nerve fibers in the human optic nerve

Electron microscopic views of centrifugal nerve fibers in the optic nerve stump of a 56-year-old man are presented. These nerve fibers had survived for 16 days after removal of the corresponding eyeball and exhibited terminal swellings pointing in a distal direction and indicating axoplasmic flow towards the removed eye. The centrifugal nerves in this adult lack any evidence of attempted regeneration that has earlier been observed under similar conditions in the optic nerve stump of a child. Zentrifugale (antidrome, efferente) Nervenfasern sind hier zum ersten Mal mit dem Elektronenmikroskop im menschlichen Sehnerven dargestellt worden. Diese Nervenfasern wurden in dem Sehnervenstumpf eines 56jährigen Mannes 16 Tage nach der Entfernung des dazugehörigen Auges gefunden. Endschwellungen dieser Nervenfasern waren distal ausgerichtet und deuteten damit einen Axoplasmafluß in Richtung des entfernten Auges an. Während deutliche Regenerationsversuche an den distalen Enden unterbrochener zentrifugaler Nervenfasern im Sehnervenstumpf eines Kindes früher beobachtet worden sind, fanden sich im Sehnerven dieses Erwachsenen keinerlei Zeichen von Regeneration der zentrifugalen Fasern.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47369/1/417_2004_Article_BF00414787.pd

FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials

Objective To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials. Design Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials. Data sources Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015. Eligibility criteria for study selection Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity. Results We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category. Conclusions We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions. Systematic review registration PROSPERO CRD42015015969

Randomized clinical trials on the effects of dietary fat and carbohydrate on plasma lipoproteins and cardiovascular disease

A review.Several dietary approaches have decreased cardiovascular events in randomized clin.trials.Replacing satd.fat with polyunsatd.fat prevented coronary events in men and the Mediterranean diets and fatty fish improved survival.None of these tri