Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

<p><b>Background</b> Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.</p> <p><b>Methods</b> We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.</p> <p><b>Results</b> Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).</p> <p><b>Conclusion</b> Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.</p&gt

Host-guest and guest-guest interactions between xylene isomers confined in the MIL-47(V) pore system

The porous MIL-47 material shows a selective adsorption behavior for para-, ortho-, and meta-isomers of xylenes, making the material a serious candidate for separation applications. The origin of the selectivity lies in the differences in interactions (energetic) and confining (entropic). This paper investigates the xylene-framework interactions and the xylene-xylene interactions with quantum mechanical calculations, using a dispersion-corrected density functional and periodic boundary conditions to describe the crystal. First, the strength and geometrical characteristics of the optimal xylene-xylene interactions are quantified by studying the pure and mixed pairs in gas phase. An extended set of initial structures is created and optimized to sample as many relative orientations and distances as possible. Next, the pairs are brought in the pores of MIL-47. The interaction with the terephthalic linkers and other xylenes increases the stacking energy in gas phase (-31.7 kJ/mol per pair) by roughly a factor four in the fully loaded state (-58.3 kJ/mol per xylene). Our decomposition of the adsorption energy shows various trends in the contributing xylene-xylene interactions. The absence of a significant difference in energetics between the isomers indicates that entropic effects must be mainly responsible for the separation behavior

Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion

The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<∼2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ∼12 000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e.=0.03) for neuroticism and 0.12 (s.e.=0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ∼45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called ‘missing heritability' has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors

Effects of two common polymorphisms in the 3' untranslated regions of estrogen receptor β on mRNA stability and translatability

Estrogen signaling is mediated by estrogen receptors (ERs), ERα and ERβ. Aberrant estrogen signaling is involved in breast cancer development. ERα is one of the key biomarkers for diagnosis and treatment of breast cancer. Unlike ERα, ERβ is still not introduced as a marker for diagnosis and established as a target of therapy. Numerous studies suggest antiproliferative effects of ERβ, however its role remains to be fully explored. Albeit important, ERα is not a perfect marker, and some aspects of ERα function are still unclear. This thesis aims to characterize distinct molecular facets of ER action relevant for breast cancer and provide valuable information for ER-based diagnosis and treatment design. In PAPER I, we analyzed the functionality of two common single nucleotide polymorphisms in the 3’ untranslated regions of ERβ, rs4986938 and rs928554, which have been extensively investigated for association with various diseases. A significant difference in allelic expression was observed for rs4986938 in breast tumor samples from heterozygous individuals. However, no difference in mRNA stability or translatability between the alleles was observed. In PAPER II, we provided a more comprehensive understanding of ERβ function independent of ERα. A global gene expression analysis in a HEK293/ERβ cell model identified a set of ERβ-regulated genes. Gene Ontology (GO) analysis showed that they are involved in cell-cell signaling, morphogenesis and cell proliferation. Moreover, ERβ expression resulted in a significant decrease in cell proliferation. In PAPER III, using the human breast cancer MCF-7/ERβ cell model, we demonstrated, for the first time, the binding of ERα/β heterodimers to various DNA-binding regions in intact chromatin. In PAPER IV, we investigated a potential cross-talk between estrogen signaling and DNA methylation by identifying their common target genes in MCF-7 cells. Gene expression profiling identified around 150 genes regulated by both 17β- estradiol (E2) and a hypomethylating agent 5-aza-2’-deoxycytidine. Based on GO analysis, CpG island prediction analysis and previously reported ER binding regions, we selected six genes for further analysis. We identified BTG3 and FHL2 as direct target genes of both pathways. However, our data did not support a direct molecular interplay of mediators of estrogen and epigenetic signaling at promoters of regulated genes. In PAPER V, we further explored the interactions between estrogen signaling and DNA methylation, with focus on DNA methyltransferases (DNMT1, DNMT3a and DNMT3b). E2, via ERα, up-regulated DNMT1 and down-regulated DNMT3a and DNMT3b mRNA expression. Furthermore, DNMT3b interacted with ERα. siRNA-mediated DNMT3b depletion increased the expression of two genes, CDKN1A and FHL2. We proposed that the molecular mechanism underlying regulation of FHL2 and CDKN1A gene expression involves interplay of DNMT3b and ERα. In conclusion, the studies presented in this thesis contribute to the knowledge of ERβ function, and give additional insight into the cross-talk mechanisms underlying ERα signaling with ERβ and with DNA methylation pathways

Friend versus foe: Neural correlates of prosocial decisions for liked and disliked peers

Although the majority of our social interactions are with people we know, few studies have investigated the neural correlates of sharing valuable resources with familiar others. Using an ecologically valid research paradigm, this functional magnetic resonance imaging study examined the neural correlates of prosocial and selfish behavior in interactions with real-life friends and disliked peers in young adults. Participants (N = 27) distributed coins between themselves and another person, where they could make selfish choices that maximized their own gains or prosocial choices that maximized outcomes of the other. Participants were more prosocial toward friends and more selfish toward disliked peers. Individual prosociality levels toward friends were associated negatively with supplementary motor area and anterior insula activity. Further preliminary analyses showed that prosocial decisions involving friends were associated with heightened activity in the bilateral posterior temporoparietal junction, and selfish decisions involving disliked peers were associated with heightened superior temporal sulcus activity, which are brain regions consistently shown to be involved in mentalizing and perspective taking in prior studies. Further, activation of the putamen was observed during prosocial choices involving friends and selfish choices involving disliked peers. These findings provide insights into the modulation of neural processes that underlie prosocial behavior as a function of a positive or negative relationship with the interaction partner

Stable Genetic Effects on Symptoms of Alcohol Abuse and Dependence from Adolescence into Early Adulthood

Relatively little is known about how genetic influences on alcohol abuse and dependence (AAD) change with age. We examined the change in influence of genetic and environmental factors which explain symptoms of AAD from adolescence into early adulthood. Symptoms of AAD were assessed using the four AAD screening questions of the CAGE inventory. Data were obtained up to six times by self-report questionnaires for 8,398 twins from the Netherlands Twin Register aged between 15 and 32 years. Longitudinal genetic simplex modeling was performed with Mx. Results showed that shared environmental influences were present for age 15–17 (57%) and age 18–20 (18%). Unique environmental influences gained importance over time, contributing 15% of the variance at age 15–17 and 48% at age 30–32. At younger ages, unique environmental influences were largely age-specific, while at later ages, age-specific influences became less important. Genetic influences on AAD symptoms over age could be accounted for by one factor, with the relative influence of this factor differing across ages. Genetic influences increased from 28% at age 15–17 to 58% at age 21–23 and remained high in magnitude thereafter. These results are in line with a developmentally stable hypothesis that predicts that a single set of genetic risk factors acts on symptoms of AAD from adolescence into young adulthood

Treatments for people who use anabolic androgenic steroids: a scoping review.

BACKGROUND: A growing body of evidence suggests that anabolic androgenic steroids (AAS) are used globally by a diverse population with varying motivations. Evidence has increased greatly in recent years to support understanding of this form of substance use and the associated health harms, but there remains little evidence regarding interventions to support cessation and treat the consequences of use. In this scoping review, we identify and describe what is known about interventions that aim to support and achieve cessation of AAS, and treat and prevent associated health problems. METHODS: A comprehensive search strategy was developed in four bibliographic databases, supported by an iterative citation searching process to identify eligible studies. Studies of any psychological or medical treatment interventions delivered in response to non-prescribed use of AAS or an associated harm in any setting were eligible. RESULTS: In total, 109 eligible studies were identified, which included case reports representing a diverse range of disciplines and sources. Studies predominantly focussed on treatments for harms associated with AAS use, with scant evidence on interventions to support cessation of AAS use or responding to dependence. The types of conditions requiring treatment included psychiatric, neuroendocrine, hepatic, kidney, cardiovascular, musculoskeletal and infectious. There was limited evidence of engagement with users or delivery of psychosocial interventions as part of treatment for any condition, and of harm reduction interventions initiated alongside, or following, treatment. Findings were limited throughout by the case report study designs and limited information was provided. CONCLUSION: This scoping review indicates that while a range of case reports describe treatments provided to AAS users, there is scarce evidence on treating dependence, managing withdrawal, or initiating behaviour change in users in any settings. Evidence is urgently required to support the development of effective services for users and of evidence-based guidance and interventions to respond to users in a range of healthcare settings. More consistent reporting in articles of whether engagement or assessment relating to AAS was initiated, and publication within broader health- or drug-related journals, will support development of the evidence base