Multifactorial Phenotype Research Articles

Association of rs35767 polymorphism in the IGF1 gene with athletic performance in power and endurance sports: A meta-analysis

BackgroundSport performance is a multifactorial phenotype dependent on the interaction of multiple genetic and non-genetic factors. More than 200 polymorphisms have been associated with athletic performance. The single nucleotide polymorphism (SNP) rs35767, located in the regulatory region of the IGF1 gene, influences its expression and has been associated with sports-related phenotypes. We aimed to perform a meta-analysis to evaluate the association between the rs35767 polymorphism of the IGF1 gene and athletic performance in power and endurance sports. MethodsLiterature has been retrieved from PubMed, Web of Science, Scopus, Embase, and Sport Discus databases until October 2023. This study was designed according to the PRISMA statement. Different models were tested, and heterogeneity was evaluated. ResultsThree studies were included in this meta-analysis. Statistically significant differences were highlighted for the frequency of the minor allele when comparing all athletes and controls (p < 0.001; OR = 1.74; 95 % CI = 1.26–2.40), endurance athletes and controls (p = 0.016; OR = 1.87; 95 % CI = 1.12–3.1) and power sport athletes and controls (p = 0.007; OR = 1.62; 95 % CI = 1.14–2.31). No statistically significant difference was found between the power and endurance groups. According to data analysis, the recessive model is the most suitable genetic model. ConclusionsThis metanalysis supports the role of the minor allele of the rs35767 polymorphism of the IGF1 gene as favoring an athlete's performance in endurance and power sports.

Neurobiology of attention-deficit hyperactivity disorder: historical challenges and emerging frontiers.

Extensive investigations spanning multiple levels of inquiry, from genetic to behavioural studies, have sought to unravel the mechanistic foundations of attention-deficit hyperactivity disorder (ADHD), with the aspiration of developing efficacious treatments for this condition. Despite these efforts, the pathogenesis of ADHD remains elusive. In this Review, we reflect on what has been learned about ADHD while also providing a framework that may serve as a roadmap for future investigations. We emphasize that ADHD is a highly heterogeneous disorder with multiple aetiologies that necessitates a multifactorial dimensional phenotype, rather than a fixed dichotomous conceptualization. We highlight new findings that suggest a more brain-wide, 'global' view of the disorder, rather than the traditional localizationist framework, which asserts that a limited set of brain regions or networks underlie ADHD. Last, we underscore how underpowered studies that have aimed to associate neurobiology with ADHD phenotypes have long precluded the field from making progress. However, a new age of ADHD research with refined phenotypes, advanced methods, creative study designs and adequately powered investigations is beginning to put the field on a good footing. Indeed, the field is at a promising juncture to advance the neurobiological understanding of ADHD and fulfil the promise of clinical utility.

Multi-omics data integration for the identification of biomarkers for bull fertility.

Bull fertility is an important economic trait, and the use of subfertile semen for artificial insemination decreases the global efficiency of the breeding sector. Although the analysis of semen functional parameters can help to identify infertile bulls, no tools are currently available to enable precise predictions and prevent the commercialization of subfertile semen. Because male fertility is a multifactorial phenotype that is dependent on genetic, epigenetic, physiological and environmental factors, we hypothesized that an integrative analysis might help to refine our knowledge and understanding of bull fertility. We combined -omics data (genotypes, sperm DNA methylation at CpGs and sperm small non-coding RNAs) and semen parameters measured on a large cohort of 98 Montbéliarde bulls with contrasting fertility levels. Multiple Factor Analysis was conducted to study the links between the datasets and fertility. Four methodologies were then considered to identify the features linked to bull fertility variation: Logistic Lasso, Random Forest, Gradient Boosting and Neural Networks. Finally, the features selected by these methods were annotated in terms of genes, to conduct functional enrichment analyses. The less relevant features in -omics data were filtered out, and MFA was run on the remaining 12,006 features, including the 11 semen parameters and a balanced proportion of each type of-omics data. The results showed that unlike the semen parameters studied the-omics datasets were related to fertility. Biomarkers related to bull fertility were selected using the four methodologies mentioned above. The most contributory CpGs, SNPs and miRNAs targeted genes were all found to be involved in development. Interestingly, fragments derived from ribosomal RNAs were overrepresented among the selected features, suggesting roles in male fertility. These markers could be used in the future to identify subfertile bulls in order to increase the global efficiency of the breeding sector.

Integrated analysis of inflammatory mRNAs, miRNAs, and lncRNAs elucidates the molecular interactome behind bovine mastitis

Mastitis is known as intramammary inflammation, which has a multifactorial complex phenotype. However, the underlying molecular pathogenesis of mastitis remains poorly understood. In this study, we utilized a combination of RNA-seq and miRNA-seq techniques, along with computational systems biology approaches, to gain a deeper understanding of the molecular interactome involved in mastitis. We retrieved and processed one hundred transcriptomic libraries, consisting of 50 RNA-seq and 50 matched miRNA-seq data, obtained from milk-isolated monocytes of Holstein–Friesian cows, both infected with Streptococcus uberis and non-infected controls. Using the weighted gene co-expression network analysis (WGCNA) approach, we constructed co-expressed RNA-seq-based and miRNA-seq-based modules separately. Module-trait relationship analysis was then performed on the RNA-seq-based modules to identify highly-correlated modules associated with clinical traits of mastitis. Functional enrichment analysis was conducted to understand the functional behavior of these modules. Additionally, we assigned the RNA-seq-based modules to the miRNA-seq-based modules and constructed an integrated regulatory network based on the modules of interest. To enhance the reliability of our findings, we conducted further analyses, including hub RNA detection, protein–protein interaction (PPI) network construction, screening of hub-hub RNAs, and target prediction analysis on the detected modules. We identified a total of 17 RNA-seq-based modules and 3 miRNA-seq-based modules. Among the significant highly-correlated RNA-seq-based modules, six modules showed strong associations with clinical characteristics of mastitis. Functional enrichment analysis revealed that the turquoise module was directly related to inflammation persistence and mastitis development. Furthermore, module assignment analysis demonstrated that the blue miRNA-seq-based module post-transcriptionally regulates the turquoise RNA-seq-based module. We also identified a set of different RNAs, including hub-hub genes, hub-hub TFs (transcription factors), hub-hub lncRNAs (long non-coding RNAs), and hub miRNAs within the modules of interest, indicating their central role in the molecular interactome underlying the pathogenic mechanisms of S. uberis infection. This study provides a comprehensive insight into the molecular crosstalk between immunoregulatory mRNAs, miRNAs, and lncRNAs during S. uberis infection. These findings offer valuable directions for the development of molecular diagnosis and biological therapies for mastitis.

The Association of Variants within Types V and XI Collagen Genes with Knee Joint Laxity Measurements.

Joint laxity is a multifactorial phenotype with a heritable component. Mutations or common polymorphisms within the α1(V) (COL5A1), α1(XI) (COL11A1) and α2(XI) (COL11A2) collagen genes have been reported or proposed to associate with joint hypermobility, range of motion and/or genu recurvatum. The aim of this study was to investigate whether polymorphisms within these collagen-encoding genes are associated with measurements of knee joint laxity and computed ligament length changes within the non-dominant leg. One hundred and six healthy participants were assessed for genu recurvatum (knee hyperextension), anterior-posterior tibial translation, external-internal tibial rotation and ligament length changes during knee rotation of their non-dominant leg. Participants were genotyped for COL5A1 rs12722 (T/C), COL11A1 rs3753841 (C/T), COL11A1 rs1676486 (T/C) and COL11A2 rs1799907 (A/T). The genotype-genotype combination of any two or more of the four COL5A1 rs12722 CC, COL11A1 rs3753841 CC, COL11A1 rs1676486 TT and COL11A2 rs1799907 AA genotypes was associated with decreased active and passive knee hyperextension. These genotype-genotype combinations, including sex (male), increased age and decreased body mass collectively, also contributed to decreased passive knee hyperextension. These findings suggest that COL5A1, COL11A1 and COL11A2 gene-gene interactions are associated with knee hyperextension measurements of the non-dominant leg of healthy individuals.

Investigating the association between COL1A1 and COL3A1 gene variants and knee joint laxity and ligament measurements

BackgroundJoint laxity is a multifactorial phenotype with a heritable component. Type I collagen gene (COL1A1) mutations cause connective tissue disorders with joint hypermobility as a clinical feature, while variants within COL1A1 and type III collagen gene (COL3A1) are associated with musculoskeletal injuries. The aim of this study was to investigate whether COL1A1 and COL3A1 variants are associated with measurements of non-dominant knee joint laxity and computed ligament length changes. Methods106 moderately active uninjured participants were assessed for genu recurvatum, anterior-posterior tibial translation, external-internal tibial rotation and calculated ligament length changes during knee rotation. Participants were genotyped for COL1A1 rs1107946, rs1800012 and COL3A1 rs1800255. FindingsThe COL1A1 rs1107946 GG genotype had significantly larger external rotation [GG: 5.7° (4.9°;6.4°) vs GT: 4.6° (4.2°;5.5°), adjusted P = 0.014], internal rotation [GG: 5.9° (5.3°;6.6°) vs GT: 5.4° (4.7°;6.2°), adjusted P = 0.014], and slack [GG: 18.2° ± 3.2° vs GT: 16.1° ± 3.1°, adjusted P = 0.014]. The GG genotype at both COL1A1 variants had significantly larger active displacement [GG + GG: 6.0 mm (3.8 mm;8.0 mm) vs other genotype combinations: 4.0 mm (2.5 mm;6.0 mm), P < 0.001] and maximum displacement [GG + GG: 8.0 mm (6.9 mm;10.6 mm) vs other genotype combinations: 6.0 mm (5.0 mm;9.0 mm), P = 0.003]. COL1A1 rs1107946 significantly contributed to increased external and internal rotation in multilinear regression models, while both COL1A1 variants, significantly contributed to increased active displacement and slack. Larger medial and lateral cruciate ligament length changes were reported in participants with GG genotypes at both COL1A1 variants. InterpretationThese findings suggest that the COL1A1 variants are associated with knee rotational laxity and changes in ligament length.

Association between Obesity and Metabolic Anomalies in a Population in Eastern Algeria

Obesity is defined by an excess of fat and can be considered as a heterogeneous, multifactorial phenotype, determined by genetic factors, environmental factors, and gene-environment interaction. A high body mass index is an important risk factor in the development of much comorbidity dominated by metabolic disorders and cardiovascular diseases. The objective of this work was to describe the obesity (BMI≥30 kg/m2) and metabolic profile of adults in Constantine. A descriptive cross-sectional survey was conducted and anthropometric and clinical examinations were performed. Biochemical assays (fasting glucose, triglycerides, total cholesterol, HDL and LDL cholesterol) were performed. In total, 1,143 subjects participated, with the sample comprised of 41.3% men and 58.7% women. The mean body mass index was 27.22, and the overall prevalence of obesity in the sample was 30.9%. Abdominal obesity by the International Diabetes Federation (IDF) was present in 68.15% (83.5% women vs. 46.4% men). The incidence of type 2 diabetes was 42% in the obese subjects. The average number of metabolic complications was greater in the obese than non-obese subjects. Binary logistic regression analysis showed that in men the association between hypercholesterolemia, dyslipidemia, and hypertriglyceridemia was the same, regardless of the participants’ BMI. This association increased with BMI in women. With regard to hyperglycemia, the association increased with BMI in men but much more in women. Metabolic abnormalities are more frequent in obese people, increasing their cardiovascular risk, and thus urgent preventive actions need to be taken.

Influence of clinical factors on the protective or deleterious impact of genetic variants in orthodontically induced external root resorption: an observational study

BackgroundPrediction of susceptibility to Orthodontically Induced External Apical Root Resorption (OIEARR) has been hampered by the complex architecture of this multifactorial phenotype. The aim of this study was to analyze the impact of the interaction of multiple variables in the susceptibility to OIEARR.MethodsThe study evaluated 195 patients requiring orthodontic treatment. Nine clinical and treatment variables, single nucleotide polymorphisms (SNPs) from five genes and variables interactions were analyzed as risk factors for OIEARR using a multiple linear regression model.ResultsThe model explained 29% of OIEARR variability (ANOVA: p < 0.01). Duration of treatment was the most important predictor and gender was the second, closely followed by premolar extraction. For genes encoding osteoprotegerin (OPG), the receptor activator of nuclear factor κ B (RANK) and the IL1 receptor antagonist (IL1RN), the effect of analyzed variants changed from protective to deleterious depending on the duration of treatment and the age of the patient.ConclusionsThis work shows that in OIEARR the impact of genetic susceptibility factors is dynamic changing according to clinical variables.

Suicide and Changes in Expression of Neuronal miRNA Predicted by an Algorithm Search through miRNA Databases.

Suicide is multifactorial and polygenic phenotype, affected by environmental and genetic factors. Among epigenetic mechanisms, miRNAs have been studied, but so far no very concise results exist. To overcome limitations of candidate miRNA and whole genome sequencing approaches, we created an in silico analysis algorithm that would help select the best suitable miRNAs that target the most interesting genes associated with suicidality. We used databases/web algorithms DIANA microT, miRDB, miRmap, miRWalk, and TargetScan and candidate genes SLC6A4, HTR1A, BDNF, NR3C1, ZNF714, and NRIP3. Based on a prediction algorithm, we have chosen miRNAs that are targeting regulation of the genes listed, and are at the same time being expressed in the brain. The highest ranking scores were obtained for hsa-miR-4516, hsa-miR-3135b, hsa-miR-124-3p, hsa-miR-129-5p, hsa-miR-27b-3p, hsa-miR-381-3p, hsa-miR-4286. Expression of these miRNAs was tested in the brain tissue of 40 suicide completers and controls, and hsa-miR-4516 and hsa-miR-381-3p showed a trend for statistical significance. We also checked the expression of the target genes of these miRNAs, and for NR3C1 expression was lower in suicide completers compared to controls, which is in accordance with the available literature results. To determine the miRNAs that are most suitable for further suicidality research, more studies, combining in silico analysis and wet lab experiments, should be performed.

Candidate genes associated with athletes' skeletal muscle functions regulation

It is generally recognized that an elite athlete's status is a multifactorial phenotype depending on many environmental and genetic factors. Variations in the sequence of nucleotides in deoxyribonucleic acid (DNA), in particular, single-nucleotide variants (SNVs) act as key internal factors associated with achieving high results in sports. The determination of specific individuals' genetic characteristics allows us to identify athletes who have the greatest genetically determined potential for certain sports that require speed, strength or endurance manifestation. Of course, peculiarities of the structure and function of skeletal muscles are among the most important characteristics in sports results context, in sports associated with the development of power / strength or endurance phenotypes. The composition and function of skeletal muscles are controlled by many different genes, and their SNVs can serve as strength or endurance athletes' status biomarkers. (1) Background: to conduct a thematic review of candidate genes studies and their single-nucleotide variants (SNVs) associated with the functioning of skeletal muscles in athletes. (2) Methods: A search for articles for the period from 2010 to 2020 was conducted in the databases SCOPUS, Web of Science, Google Calendar, Clinical keys, PubMed, e-LIBRARY using keywords and their combinations; (3) Conclusions: The identification of genetic biomarkers associated with muscular system regulation can help neurologists, sports doctors and coaches in developing personalized strategies for selecting children, adolescents and young adults for endurance, strength and speed sports (for example, running short, medium or long distances). Such a personalized approach will increase sports performance and reduce the risk of sports injuries of the musculoskeletal system.

Teaching an old dog new tricks: reactivated developmental signaling pathways regulate ABCB1 and chemoresistance in cancer

Oncogenic multidrug resistance (MDR) is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters. Drug efflux transporters, particularly the MDR P-glycoprotein ABCB1, represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets, but also for inhibiting apoptotic cell death cues, such as removal of proapoptotic signals. Several cell populations exhibiting the MDR phenotype co-exist within a tumor, such as cells forming the bulk tumor cell mass, cancer stem cells, and cancer persister cells. The key to regulation of ABCB1 expression is the cellular transcriptional machinery. Developmental signaling pathways (e.g, Hedgehog, Notch, Wnt/β-catenin, TGFβ, PITX2) are pivotal in governing cell proliferation, survival, differentiation and guiding cell migration during embryogenesis, and their reactivation during carcinogenesis, which is of particular significance for tumor initiation, progression, and metastasis, also leads to the upregulation of ABCB1. These pathways also drive and maintain cancer cell stemness, for which ABCB1 is used as a marker. In this review, the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.

Consortum between mast cell and prostatic lesions-An etiological factor or mere coexistence

Introduction: Prostate cancer exhibits a complex genetic and heterogeneous histological pattern reflecting its multifactorial phenotype. Mast cells mainly known for their role in allergy and anaphylaxis, now regarded as key factor cell in angiogenesis, tissue remodeling and repair, whereas their importance in tumor pathology as either cancer promoter or inhibitor is still debated. Materials and Methods: Study included 100 cases of prostatic lesions with 74 cases of benign prostatic lesions and 26 cases of adenocarcinoma prostate, received in the form of transurethral resection of prostate chips for histopathological examination. The tissues were routinely processed, the paraffin sections stained by hematoxylin and eosin and 1% toluidine blue. Histological diagnosis was made. Mast cell count was done taking a standard of 10 high power fields(x40) and mean were calculated. Distributions of mast cells were noted in stroma, perivascular, periglandular and intraglandular regions. Results: Mast cell count was significantly higher in benign prostatic hyperplasia with mean of 3.6 per high power field whereas absence or low count was found in adenocarcinoma prostate with mean of 1.7 per high power field. Mast cells were located predominantly in stromal region in both BPH and adenocarcinoma prostate; in rest of the areas the numbers were comparable. Conclusion: In this study we observed significant increase in mast cell count in stroma of BPH compared to adenocarcinoma indicating that mast cell density is inversely proportional to malignancy. This suggests high mast cell count favors the prognosis. Keywords: Mast cells, Benign Prostatic Hyperplasia, Adenocarcinoma.

Genomic Determinants of Hypertension With a Focus on Metabolomics and the Gut Microbiome.

Epidemiologic and genomic studies have progressively improved our understanding of the causation of hypertension and the complex relationship with diet and environment. The majority of Mendelian forms of syndromic hypotension and hypertension (HTN) have all been linked to mutations in genes whose encoded proteins regulate salt-water balance in the kidney, supporting the primacy of the kidneys in blood pressure regulation. There are more than 1,477 single nucleotide polymorphisms associated with blood pressure and hypertension and the challenge is establishing a causal role for these variants. Hypertension is a complex multifactorial phenotype and it is likely to be influenced by multiple factors including interactions between diet and lifestyle factors, microbiome, and epigenetics. Given the finite genetic variability that is possible in humans, it is likely that incremental gains from single marker analyses have now plateaued and a greater leap in our understanding of the genetic basis of disease will come from integration of other omics and the interacting environmental factors. In this review, we focus on emerging results from the microbiome and metabolomics and discuss how leveraging these findings may facilitate a deeper understanding of the interrelationships between genomics, diet, and microbial ecology in humans in the causation of essential hypertension.

Polygenic Risk Scores and Physical Activity

Polygenic risk scores (PRS) summarize genome-wide genotype data into a single variable that produces an individual-level risk score for genetic liability. PRS has been used for prediction of chronic diseases and some risk factors. As PRS has been studied less for physical activity (PA), we constructed PRS for PA and studied how much variation in PA can be explained by this PRS in independent population samples. We calculated PRS for self-reported and objectively measured PA using UK Biobank genome-wide association study summary statistics, and analyzed how much of the variation in self-reported (MET-hours per day) and measured (steps and moderate-to-vigorous PA minutes per day) PA could be accounted for by the PRS in the Finnish Twin Cohorts (FTC; N = 759-11,528) and the Northern Finland Birth Cohort 1966 (NFBC1966; N = 3263-4061). Objective measurement of PA was done with wrist-worn accelerometer in UK Biobank and NFBC1966 studies, and with hip-worn accelerometer in the FTC. The PRS accounted from 0.07% to 1.44% of the variation (R) in the self-reported and objectively measured PA volumes (P value range = 0.023 to <0.0001) in the FTC and NFBC1966. For both self-reported and objectively measured PA, individuals in the highest PRS deciles had significantly (11%-28%) higher PA volumes compared with the lowest PRS deciles (P value range = 0.017 to <0.0001). PA is a multifactorial phenotype, and the PRS constructed based on UK Biobank results accounted for statistically significant but overall small proportion of the variation in PA in the Finnish cohorts. Using identical methods to assess PA and including less common and rare variants in the construction of PRS may increase the proportion of PA explained by the PRS.

Asthma and obesity in children: what do we know?

The results of a large number of studies indicate the relationship of obesity and bronchial asthma in children. The review highlights the mechanisms of development of the so-called obese asthma: morphological changes in the respiratory tract, systemic inflammation, adipokine production, impaired glucose and insulin metabolism, genetic and epigenetic factors, changes in the microbiome of the respiratory tract and(or) intestines. The relationship of asthma and obesity can have both a genetic basis and can occur under the influence of a complex of pathogenic factors, and they can be especially important at the “early programming” stage. Obesity increases the risk of asthma development, and in patients with existing asthma due to a number of mechanisms it increases the severity or makes it difficult to achieve control of asthma. Studies showed that patients with obese asthma are distinguished by a more severe course of the disease, poor quality of life and a decreased response to therapy for asthma. Weight loss in children with asthma can lead to an improved well-being of patients, but data on the effectiveness of therapeutic interventions in these children is limited. Comorbidity of asthma and obesity is a complex multifactorial phenotype in children, which requires further study. Being overweight or obese needs to be taken into account as part of asthma treatment in this category of patients.

Genetic Markers Associated with Power Athlete Status.

Athletic performance is a multifactorial phenotype influenced by environmental factors as well as multiple genetic variants. Different genetic elements have a great influence over components of athletic performance such as endurance, strength, power, flexibility, neuromuscular coordination, psychological traits and other features important in sport. The current literature review revealed that to date more than 69 genetic markers have been associated with power athlete status. For the purpose of the present review we have assigned all genetic markers described with reference to power athletes status to seven main groups: 1) markers associated with skeletal muscle structure and function, 2) markers involved in the inflammatory and repair reactions in skeletal muscle during and after exercise, 3) markers involved in blood pressure control, 4) markers involved in modulation of oxygen uptake, 5) markers that are regulators of energy metabolism and cellular homeostasis, 6) markers encoding factors that control gene expression by rearrangement of chromatin fibers and mRNA stability, and 7) markers modulating cellular signaling pathways. All data presented in the current review provide evidence to support the notion that human physical performance may be influenced by genetic profiles, especially in power sports. The current studies still represent only the first steps towards a better understanding of the genetic factors that influence power-related traits, so further analyses are necessary before implementation of research findings into practice.

Toward incorporating genetic risk scores into symptom networks of psychosis.

Psychosis spectrum disorder is a heterogeneous, multifactorial clinical phenotype, known to have a high heritability, only a minor portion of which can be explained by molecular measures of genetic variation. This study proposes that the identification of genetic variation underlying psychotic disorder may have suffered due to issues in the psychometric conceptualization of the phenotype. Here we aim to open a new line of research into the genetics of mental disorders by explicitly incorporating genes into symptom networks. Specifically, we investigate whether links between a polygenic risk score (PRS) for schizophrenia and measures of psychosis proneness can be identified in a network model. We analyzed data from n = 2180 subjects (controls, patients diagnosed with a non-affective psychotic disorder, and the first-degree relatives of the patients). A network structure was computed to examine associations between the 42 symptoms of the Community Assessment of Psychic Experiences (CAPE) and the PRS for schizophrenia. The resulting network shows that the PRS is directly connected to the spectrum of positive and depressive symptoms, with the items conspiracy and no future being more often located on predictive pathways from PRS to other symptoms. To our knowledge, the current exploratory study provides a first application of the network framework to the field of behavior genetics research. This allows for a novel outlook on the investigation of the relations between genome-wide association study-based PRSs and symptoms of mental disorders, by focusing on the dependencies among variables.

Whole-exome sequencing data of suicide victims who had suffered from major depressive disorder

Suicide is one of the leading causes of mortality worldwide; it causes the death of more than one million patients each year. Suicide is a complex, multifactorial phenotype with environmental and genetic factors contributing to the risk of the forthcoming suicide. These factors first generally lead to mental disorders, such as depression, schizophrenia and bipolar disorder, which then become the direct cause of suicide. Here we present a high quality dataset (including processed BAM and VCF files) gained from the high-throughput whole-exome Illumina sequencing of 23 suicide victims – all of whom had suffered from major depressive disorder - and 21 control patients to a depth of at least 40-fold coverage in both cohorts. We identified ~130,000 variants per sample and altogether 442,270 unique variants in the cohort of 44 samples. To our best knowledge, this is the first whole-exome sequencing dataset from suicide victims. We expect that this dataset provides useful information for genomic studies of suicide and depression, and also for the analysis of the Hungarian population.

Clinical and molecular study of a case of severe radio-sensitivity

A case of a patient with a breast intraductal tumor is presented The patient underwent surgical quadrantectomy and axillary lymph node dissection and subsequently received Anthracycline treatment and D radiotherapy following a standard fractionation protocol This case was characterized by the development of grade III dermal toxicity some associated genetic polymorphisms and DNA damage were analyzed We concluded that radiotoxicity is a multifactorial phenotype that should be addressed in a broader context considering not only intrinsic variables but also criteria such as breast size body mass index and concomitant treatments among others

Cystine-thiamin-containing hair-growth formulation modulates the response to UV radiation in an in vitro model for growth-limiting conditions of human keratinocytes

BackgroundUltraviolet radiation (UVR) is known to be harmful to normal human epidermal keratinocytes (NHEKs) of the epidermal skin layer, as well as to hair-follicle-associated keratinocytes. An oral formulation containing l-cystine, thiamin, calcium d-pantothenate, medicinal yeast, keratin and p-aminobenzoic acid (Panto[vi]gar®) has demonstrated clinical efficacy for the treatment of diffuse telogen effluvium; however, its mode of action at the cellular level, and in particular whether protective mechanisms are involved, has yet to be elucidated. ObjectivesTo assess the capacity of ingredients of this oral formulation, both separately and in combination, to modulate the effects of UVR in growth-limited NHEKs in vitro. MethodsNHEKs were incubated in keratinocyte basal medium, keratinocyte basal medium lacking cystine, thiamin, calcium d-pantothenate, folic acid and biotine (minimal growth medium [MGM]) or MGM plus test compound. Test compounds comprised the following four ingredients related to the oral formulation: l-cystine, thiamin, calcium d-pantothenate and folic acid (a proposed metabolite of p-aminobenzoic acid), and a combination of these (Panto[vi]gar®-in vitro correlate; P-IC). The effect of different doses of these compounds on the metabolic activity and proliferation of NHEKs was tested, as well as their influence on the impact of UV light on NHEKs assessed by monitoring metabolic activity, cell number and apoptosis induction. ResultsCompared with basal medium, MGM reduced the proliferation of NHEKs in a time-dependent manner. Reduced proliferation is a characteristic of the multifactorial and complex phenotype associated with diffuse hair loss. l-cystine (50 μM) increased metabolic activity and proliferation 3-fold versus MGM (p < 0.05). Thiamin also had a significant effect (p < 0.05) on proliferation and metabolic activity of NHEKs, but calcium d-pantothenate and folic acid did not when tested individually in this in vitro model. In the presence of P-IC, metabolic activity increased 4-fold and proliferation 3-fold compared with MGM alone (p < 0.05 for both).Following UV irradiation, cells in MGM showed a 72% reduction in metabolic activity, while P-IC-treated cells showed only a 12–18% reduction. The observed prevention of the UV-induced reduction in metabolic activity was not simply due to filtering UVR by the P-IC components, as P-IC-mediated reduction of this effect persisted even when P-IC was washed out during UV irradiation. ConclusionThis study demonstrated that l-cystine and thiamin are essential for proliferation of epidermal keratinocytes and suggests a novel, UV-protective potential of formulations combining l-cystine and thiamin in growth-limited inter-follicular NHEKs in vitro.