Gene-gene Interaction Analyses for Atrial Fibrillation

Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in a

Sugar-sweetened beverage consumption may modify associations between genetic variants in the CHREBP (carbohydrate responsive element binding protein) locus and HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations

BACKGROUND: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia.METHODS: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63599) and the UK Biobank (N=59220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake.RESULTS: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (beta, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; P<0.0001), but not significantly among the lowest SSB consumers (P=0.81; P-Diff<0.0001). Similar results were observed for 2 additional variants (rs35709627 and rs71556736). For triglyceride, rs55673514 was positively associated with triglyceride concentrations only among the highest SSB consumers (beta, 0.06 [95% CI, 0.02-0.09] In-mg/dL per allele, P=0.001) but not the lowest SSB consumers (P=0.84; P-Diff=0.0005).CONCLUSIONS: Our results identified genetic variants in the CHREBP locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in triglyceride concentrations.Clinical epidemiolog

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings

Oxytocin: Coevolution of human and domesticated animals

The neuropeptide oxytocin (OT) and its homologues are produced in specialized neurons located in Vertebrates exclusively in a deep and evolutionarily old part of the forebrain, the hypothalamus. The axons of OT neurons form the classical hypothalamic-neurohypophyseal tract terminating on blood vessels of the neurohypothysis to release OT into the systemic blood circulation. However, as was recently demonstrated in mammals, collaterals of OT axons concomitantly project to various forebrain regions to modulate the activity of local networks. At the behavioral level, OT facilitates intraspecific social contacts in mammals via various mechanisms ranging from the suppression of neuroendocrine stress responses to the direct OT action on neurons of socially relevant brain regions. Recent reports indicated possible contribution of OT to the formation of the social bond between domesticated mammals (dog, sheep, cattle) and humans. Indeed, social interaction between humans and a domesticated animal resulted in the elevation of peripheral OT levels (in blood, saliva or urine) and, in congruence, exogenous (intranasal) OT application led to more frequent contacts between the owner and the domesticated animal. It has been known for decades that domesticated animals exhibit profound socio-communicative abilities accompanied by suppressed aggression and stress responsiveness. These peculiarities of their behavior and physiology may be influenced by the activity of the central OT system. Therefore, in the present mini-review we focus on the role of OT in the orchestration of distinct forms of social behavior, including the monogamous bond, maternal care, social memory and recognition, aggression, and anxiety. As a conclusion, we propose possible directions for exploration of the OT contribution to empathy between humans and domesticated animals, which was likely established in the course of their co-evolution during last 10.000– 15.000 years

Out-of-the-box and custom implementation of metaheuristics. A case study: The vehicle routing problem with stochastic demand

Metaheuristics are a class of effective algorithms for optimization problems. A basic implementation of a metaheuristic typically requires rather little development effort. With a significantly larger investment in the design, implementation, and fine-tuning, metaheuristics can often produce state-of-the-art results. According to the amount of development effort, we say that an implementation of a metaheuristic is either an out-of-the-box version or a custom one. The possibility of implementing metaheuristics in such a flexible way is one of the major strengths of these algorithms. Nonetheless, it also hides some possible catches. In particular, it should be noticed that results obtained with out-of-the-box implementations cannot be always generalized to custom ones, and vice versa. The goal of this analysis is to stress that these two ways of using metaheuristics are different. As a case study, we focus on the vehicle routing problem with stochastic demand and on five among the most successful metaheuristics-namely, tabu search, simulated annealing, genetic algorithms, iterated local search, and ant colony optimization.We show that the relative performance of these algorithms strongly varies whether one considers out-of-the-box implementations or custom ones, in which the parameters are accurately fine-tuned. Moreover, we underline the relevance of clearly stating the framework in which the results reported in the literature have been obtained. To this aim, we consider also an implementation of the same algorithms as described in the literature. © 2011 Springer-Verlag Berlin Heidelberg.SCOPUS: ar.kinfo:eu-repo/semantics/publishe