Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

Facial-aging mobile apps for smoking prevention in secondary schools in Brazil : appearance-focused interventional study.

Background: Most smokers start smoking during their early adolescence, often with the idea that smoking is glamorous. Interventions that harness the broad availability of mobile phones as well as adolescents' interest in their appearance may be a novel way to improve school-based prevention. A recent study conducted in Germany showed promising results. However, the transfer to other cultural contexts, effects on different genders, and implementability remains unknown. Objective: In this observational study, we aimed to test the perception and implementability of facial-aging apps to prevent smoking in secondary schools in Brazil in accordance with the theory of planned behavior and with respect to different genders. Methods: We used a free facial-aging mobile phone app (?Smokerface?) in three Brazilian secondary schools via a novel method called mirroring. The students? altered three-dimensional selfies on mobile phones or tablets and images were ?mirrored? via a projector in front of their whole grade. Using an anonymous questionnaire, we then measured on a 5-point Likert scale the perceptions of the intervention among 306 Brazilian secondary school students of both genders in the seventh grade (average age 12.97 years). A second questionnaire captured perceptions of medical students who conducted the intervention and its conduction per protocol. Results: The majority of students perceived the intervention as fun (304/306, 99.3%), claimed the intervention motivated them not to smoke (289/306, 94.4%), and stated that they learned new benefits of not smoking (300/306, 98.0%). Only a minority of students disagreed or fully disagreed that they learned new benefits of nonsmoking (4/306, 1.3%) or that they themselves were motivated not to smoke (5/306, 1.6%). All of the protocol was delivered by volunteer medical students. Conclusions: Our data indicate the potential for facial-aging interventions to reduce smoking prevalence in Brazilian secondary schools in accordance with the theory of planned behavior. Volunteer medical students enjoyed the intervention and are capable of complete implementation per protocol

PSEA - Phenotype Set Enrichment Analysis: a new method for analysis of multiple phenotypes

Most genome-wide association studies (GWAS) are restricted to one phenotype, even if multiple related or unrelated phenotypes are available. However, an integrated analysis of multiple phenotypes can provide insight into their shared genetic basis and may improve the power of association studies. We present a new method, called &quot;phenotype set enrichment analysis&quot; (PSEA), which uses ideas of gene set enrichment analysis for the investigation of phenotype sets. PSEA combines statistics of univariate phenotype analyses and tests by permutation. It does not only allow analyzing predefined phenotype sets, but also to identify new phenotype sets. Apart from the application to situations where phenotypes and genotypes are available for each person, the method was adjusted to the analysis of GWAS summary statistics. PSEA was applied to data from the population-based cohort KORA F4 (N = 1,814) using iron-related and blood count traits. By confirming associations previously found in large meta-analyses on these traits, PSEA was shown to be a reliable tool. Many of these associations were not detectable by GWAS on single phenotypes in KORA F4. Therefore, the results suggest that PSEA can be more powerful than a single phenotype GWAS for the identification of association with multiple phenotypes. PSEA is a valuable method for analysis of multiple phenotypes, which can help to understand phenotype networks. Its flexible design enables both the use of prior knowledge and the generation of new knowledge on connection of multiple phenotypes. A software program for PSEA based on GWAS results is available upon request

Novel Genetic Associations with Serum Level Metabolites Identified by Phenotype Set Enrichment Analyses

Availability of standardized metabolite panels and genome-wide single nucleotide polymorphism (SNP) data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate twelve new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways

A Face-Aging Smoking Prevention/Cessation Intervention for Nursery School Students in Germany: An Appearance-Focused Interventional Study

The Education Against Tobacco (EAT) network delivers smoking prevention advice in secondary schools, typically using the mirroring approach (i.e., a selfie altered with a face-aging app and shared with a class). In November 2017, however, the German assembly of EAT opted to expand its remit to include nursing students. To assess the transferability of the existing approach, we implemented it with the self-developed face-aging app Smokerface (=mixed - methods approach) in six nursing schools. Anonymous questionnaires were used to assess the perceptions of 197 students (age 18-40 years; 83.8% female; 26.4% smokers; 23.3% daily smokers) collecting qualitative and quantitative data for our cross-sectional study. Most students perceived the intervention to be fun (73.3%), but a minority disagreed that their own animated selfie (25.9%) or the reaction of their peers (29.5%) had motivated them to stop smoking. The impact on motivation not to smoke was considerably lower than experienced with seventh graders (63.2% vs. 42.0%; notably, more smokers also disagreed (45.1%) than agreed (23.5%) with this statement. Agreement rates on the motivation not to smoke item were higher in females than in males and in year 2-3 than in year 1 students. Potential improvements included greater focus on pathology (29%) and discussing external factors (26%). Overall, the intervention seemed to be appealing for nursing students

Das weltweite Medizinernetzwerk Aufklärung gegen Tabak – Ehrenamtliche Prävention made in Germany

Smoking is the leading preventable cause of premature death in Germany. The network Education Against Tobacco (EAT) is an initiative that was founded in Germany in 2012, in which more than 3500 medical students and physicians engage in volunteer work in about 80medical faculties in 14countries. In this article, the concept, activities, objectives and associated research studies oft he EAT initiative are introduced.On the school level, the initiative addresses 10- to 15-year-old secondary school students. In addition to amultimodal approach, school visits use modern media such as facemorphing apps, which are not only used by students (45,000 per year in 14countries), but by atotal of over 500,000 other people as well. The effectiveness of the school-based intervention is currently being investigated in randomised long-term studies with 20,000 adolescents in Germany. Afirst long-term study demonstrated evidence of aprotective effect regarding the onset of smoking, especially among female students, students having alow level of education and students with amigratory background.The programme educates several hundred prospective physicians at 13 (of 28 participating) German medical faculties each year in science-based elective courses for the well-established smoking cessation counselling of patients and sensitises them to the tobacco epidemic. The approved members engage in dialogue with local members of the German house of representatives as Arzteverband Tabakpravention.EAT motivates the prospective generation of physicians, initially through prevention in school settings, to face the challenge of national tobacco control at the university and federal level