La importancia de la genética en el estudio de la hipertrigliceridemia / The importance of genetics in the study of hypertriglyceridemia

La hipertrigliceridemia engloba un conjunto de trastornos lipídicos comunes en la práctica clínica, generalmente definidos como una concentración superior a 150mg/dL en ayunas. Existen diversas clasificaciones de la gravedad de la hipertrigliceridemia en función de sus valores séricos, considerándose por norma general moderada cuando los niveles son inferiores a 500mg/dL y severa cuando son mayores de 1.000mg/dL. Su importancia radica en su asociación con otras alteraciones del perfil lipídico, contribuyendo al aumento del riesgo cardiovascular y de pancreatitis aguda, fundamentalmente con concentraciones superiores a 500mg/dL.(AU)

Hypertriglyceridemia encompasses a set of lipid disorders common in clinical practice, generally defined as a fasting concentration above 150mg/dL. There are various classifications of the severity of hypertriglyceridaemia based on serum values, with levels generally considered moderate when below 500mg/dL and severe when above 1000mg/dL. Its importance lies in its association with other alterations in the lipid profile, contributing to increased cardiovascular risk and increased risk of acute pancreatitis, mainly with concentrations above 500mg/dL.(AU)

Distribution theories for genetic line of least resistance and evolvability measures.

Quantitative genetic theory on multivariate character evolution predicts that a population's response to directional selection is biased toward the major axis of the genetic covariance matrix G-the so-called genetic line of least resistance. Inferences on the genetic constraints in this sense have traditionally been made by measuring the angle of deviation of evolutionary trajectories from the major axis, or more recently by calculating the amount of genetic variance-the Hansen-Houle evolvability-available along the trajectories. However, there have not been clear practical guidelines on how these quantities can be interpreted, especially in a high-dimensional space. This study summarizes pertinent distribution theories for relevant quantities, pointing out that they can be written as ratios of quadratic forms in evolutionary trajectory vectors by taking G as a parameter. For example, a beta distribution with appropriate parameters can be used as a null distribution for squared cosine of the angle of deviation from a major axis or subspace. More general cases can be handled with the probability distribution of ratios of quadratic forms in normal variables. Apart from its use in hypothesis-testing, this latter approach could potentially be used as a heuristic tool for looking into various selection scenarios like directional and/or correlated selection as parameterized with mean and covariance of selection gradients.

Genetic Diversity Assessment in Plants from Reduced Representation Sequencing Data.

Genetic diversity refers to the variety of genetic traits within a population or a species. It is an essential aspect of both plant ecology and plant breeding because it contributes to the adaptability, survival, and resilience of populations in changing environments. This chapter outlines a pipeline for estimating genetic diversity statistics from reduced representation or whole genome sequencing data. The pipeline involves obtaining DNA sequence reads, mapping the corresponding reads to a reference genome, calling variants from the alignments, and generating an unbiased estimation of nucleotide diversity and divergence between populations. The pipeline is suitable for single-end Illumina reads and can be adjusted for paired-end reads. The resulting pipeline provides a comprehensive approach for aligning and analyzing sequencing data to estimate genetic diversity.

Effective dispersal patterns in prairie plant species across human-modified landscapes.

Effective dispersal among plant populations is dependent on vector behaviour, landscape features and availability of adequate habitats. To capture landscape feature effects on dispersal, studies must be conducted at scales reflecting single-generation dispersal events (mesoscale). Many studies are conducted at large scales where genetic differentiation is due to dispersal occurring over multiple generations, making it difficult to interpret the effects of specific landscape features on vector behaviour. Genetic structure at the mesoscale may be determined by ecological and evolutionary processes, such as the consequences of vector behaviour on patterns of gene flow. We used chloroplast haplotypes and nuclear genome SNP surveys to identify landscape features influencing seed and pollen dispersal at a mesoscale within the Rogue River Valley in southern Oregon. We evaluated biotic and abiotic vector behaviour by contrasting two annual species with differing dispersal mechanisms; Achyrachaena mollis (Asteraceae) is a self-pollinating and anemochoric species, and Plectritis congesta (Caprifoliaceae) is biotically pollinated with barochoric seeds. Using landscape genetics methods, we identified features of the study region that conduct or restrict dispersal. We found chloroplast haplotypes were indicative of historic patterns of gene flow prior to human modification of landscapes. Seed dispersal of A. mollis was best supported by models of isolation by distance, while seed-driven gene flow of P. congesta was determined by the distribution of preserved natural spaces and quality habitat. Nuclear genetic structure was driven by both pollen and seed dispersal, and both species responded to contemporary landscape changes, such as urban and agricultural conversion, and habitat availability.

Genomes of historical specimens reveal multiple invasions of LTR retrotransposons in Drosophila melanogaster during the 19th century.

Transposable element invasions have a profound impact on the evolution of genomes and phenotypes. It is thus an important open question how often such TE invasions occur. To address this question, we utilize the genomes of historical specimens, sampled about 200 y ago. We found that the LTR retrotransposons Blood, Opus, and 412 spread in Drosophila melanogaster in the 19th century. These invasions constitute second waves, as degraded fragments were found for all three TEs. The composition of Opus and 412, but not of Blood, shows a pronounced geographic heterogeneity, likely due to founder effects during the invasions. Finally, we identified species from the Drosophila simulans complex as the likely origin of the TEs. We show that in total, seven TE families invaded D. melanogaster during the last 200y, thereby increasing the genome size by up to 1.2Mbp. We suggest that this high rate of TE invasions was likely triggered by human activity. Based on the analysis of strains and specimens sampled at different times, we provide a detailed timeline of TE invasions, making D. melanogaster the first organism where the invasion history of TEs during the last two centuries could be inferred.

Vitamin D constrains inflammation by modulating the expression of key genes on Chr17q12-21.1.

Vitamin D possesses immunomodulatory functions and vitamin D deficiency has been associated with the rise in chronic inflammatory diseases, including asthma (Litonjua and Weiss, 2007). Vitamin D supplementation studies do not provide insight into the molecular genetic mechanisms of vitamin D-mediated immunoregulation. Here, we provide evidence for vitamin D regulation of two human chromosomal loci, Chr17q12-21.1 and Chr17q21.2, reliably associated with autoimmune and chronic inflammatory diseases. We demonstrate increased vitamin D receptor (Vdr) expression in mouse lung CD4+ Th2 cells, differential expression of Chr17q12-21.1 and Chr17q21.2 genes in Th2 cells based on vitamin D status and identify the IL-2/Stat5 pathway as a target of vitamin D signaling. Vitamin D deficiency caused severe lung inflammation after allergen challenge in mice that was prevented by long-term prenatal vitamin D supplementation. Mechanistically, vitamin D induced the expression of the Ikzf3-encoded protein Aiolos to suppress IL-2 signaling and ameliorate cytokine production in Th2 cells. These translational findings demonstrate mechanisms for the immune protective effect of vitamin D in allergic lung inflammation with a strong molecular genetic link to the regulation of both Chr17q12-21.1 and Chr17q21.2 genes and suggest further functional studies and interventional strategies for long-term prevention of asthma and other autoimmune disorders.

Range-wide genetic analysis of an endangered bumble bee (Bombus affinis, Hymenoptera: Apidae) reveals population structure, isolation by distance, and low colony abundance.

Declines in bumble bee species range and abundances are documented across multiple continents and have prompted the need for research to aid species recovery and conservation. The rusty patched bumble bee (Bombus affinis) is the first federally listed bumble bee species in North America. We conducted a range-wide population genetics study of B. affinis from across all extant conservation units to inform conservation efforts. To understand the species' vulnerability and help establish recovery targets, we examined population structure, patterns of genetic diversity, and population differentiation. Additionally, we conducted a site-level analysis of colony abundance to inform prioritizing areas for conservation, translocation, and other recovery actions. We find substantial evidence of population structuring along an east-to-west gradient. Putative populations show evidence of isolation by distance, high inbreeding coefficients, and a range-wide male diploidy rate of ~15%. Our results suggest the Appalachians represent a genetically distinct cluster with high levels of private alleles and substantial differentiation from the rest of the extant range. Site-level analyses suggest low colony abundance estimates for B. affinis compared to similar datasets of stable, co-occurring species. These results lend genetic support to trends from observational studies, suggesting that B. affinis has undergone a recent decline and exhibit substantial spatial structure. The low colony abundances observed here suggest caution in overinterpreting the stability of populations even where B. affinis is reliably detected interannually. These results help delineate informed management units, provide context for the potential risks of translocation programs, and help set clear recovery targets for this and other threatened bumble bee species.

Promoting student interest in plant biology through an inquiry-based module exploring plant circadian rhythm, gene expression, and defense against insects.

We present a weeklong curricular module for high school biology students that promotes knowledge of phytohormones, the circadian clock, and the Central Dogma. The module, which relies on easily accessible items and requires minimal space, integrates a hands-on experiment that guides students through replicating research examining circadian entrainment in postharvest cabbage from groceries. This work found that plants have cyclical, circadian expression of genes that produce phytohormones, and that such cyclical expression influences herbivory by caterpillars. Such cyclical patterns were found in plants both in situ and in postharvest cabbage. This work thus provides an ideal platform to shape student conceptions of circadian rhythms, gene expression, and plant herbivory by having students use light timers to entrain postharvest cabbage to alternating light and dark cycles and then measuring herbivory in these plants. The results should replicate previous work and demonstrate less herbivory when both plant and caterpillar are entrained to the same light and dark cycles since the expression of phytohormones involved in plant defense will be greatest when caterpillars are active. The module then concludes with a discussion of gene regulation and how this influences phytohormones. This module was field tested at four public schools, reaching over 600 students, and we present data demonstrating that the module led to learning gains and likely increases in interest in plant biology and self-efficacy.

Characterization of the genetic determinants of context-specific DNA methylation in primary monocytes.

To better understand inter-individual variation in sensitivity of DNA methylation (DNAm) to immune activity, we characterized effects of inflammatory stimuli on primary monocyte DNAm (n = 190). We find that monocyte DNAm is site-dependently sensitive to lipopolysaccharide (LPS), with LPS-induced demethylation occurring following hydroxymethylation. We identify 7,359 high-confidence immune-modulated CpGs (imCpGs) that differ in genomic localization and transcription factor usage according to whether they represent a gain or loss in DNAm. Demethylated imCpGs are profoundly enriched for enhancers and colocalize to genes enriched for disease associations, especially cancer. DNAm is age associated, and we find that 24-h LPS exposure triggers approximately 6 months of gain in epigenetic age, directly linking epigenetic aging with innate immune activity. By integrating LPS-induced changes in DNAm with genetic variation, we identify 234 imCpGs under local genetic control. Exploring shared causal loci between LPS-induced DNAm responses and human disease traits highlights examples of disease-associated loci that modulate imCpG formation.

Identifying atopic dermatitis risk loci in 1,094,060 individuals with sub analysis of disease severity and onset.

Atopic dermatitis (AD) is a common inflammatory skin disease highly attributable to genetic factors. Here, we report results from a genome-wide meta-analysis of AD in 37,541 cases and 1,056,519 controls with data from the FinnGen project, the Estonian Biobank, the UK Biobank, the EAGLE Consortium, and the BioBank Japan. We detected 77 independent AD-associated loci of which 10 were to our knowledge previously unreported. The associated loci showed enrichment in various immune regulatory processes. We further performed subgroup analyses of mild and severe AD, and of early and late-onset AD, with data from the FinnGen project. 55 of the 79 tested variants in the associated loci showed larger effect estimates for severe than mild AD as determined through administered treatment. The age of onset, as determined by the first hospital visit with AD diagnosis, was lower in patients with particular AD-risk alleles. Our findings add to the knowledge of the genetic background of AD and may underlay the development of new therapeutic strategies.

Management of oral manifestations of a child with Heimler Syndrome-2.

Heimler Syndrome 2 (HS-2) is a rare, autosomal recessive mild form of a peroxisomal biogenesis disorder. Though knowledge regarding the disorder is limited, emerging research has found that sensorineural hearing loss, occasional or late onset pigmentation, amelogenesis imperfecta and nail abnormalities are clinical characteristics representative of HS-2.A school-aged male presented to the dental department with a chief complaint of a lack of enamel on multiple teeth. The patient's medical history was significant for patent ductus arteriosus, bilateral sensorineural hearing loss and biallelic mutation of the PEX6 gene. The clinical exam revealed dental crowding, hypoplasia, hypo-calcification of multiple teeth and enlarged pulp chambers of maxillary molars. This case report details the clinical findings associated with HS-2, the comprehensive dental treatment to be rendered to the patient, and critical information to paediatric dentists and general dentists so that they can make proper referrals to medical specialties.

Genetics impact risk of Alzheimer's disease through mechanisms modulating structural brain morphology in late life.

BACKGROUND: Alzheimer's disease (AD)-related neuropathological changes can occur decades before clinical symptoms. We aimed to investigate whether neurodevelopment and/or neurodegeneration affects the risk of AD, through reducing structural brain reserve and/or increasing brain atrophy, respectively. METHODS: We used bidirectional two-sample Mendelian randomisation to estimate the effects between genetic liability to AD and global and regional cortical thickness, estimated total intracranial volume, volume of subcortical structures and total white matter in 37 680 participants aged 8-81 years across 5 independent cohorts (Adolescent Brain Cognitive Development, Generation R, IMAGEN, Avon Longitudinal Study of Parents and Children and UK Biobank). We also examined the effects of global and regional cortical thickness and subcortical volumes from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium on AD risk in up to 37 741 participants. RESULTS: Our findings show that AD risk alleles have an age-dependent effect on a range of cortical and subcortical brain measures that starts in mid-life, in non-clinical populations. Evidence for such effects across childhood and young adulthood is weak. Some of the identified structures are not typically implicated in AD, such as those in the striatum (eg, thalamus), with consistent effects from childhood to late adulthood. There was little evidence to suggest brain morphology alters AD risk. CONCLUSIONS: Genetic liability to AD is likely to affect risk of AD primarily through mechanisms affecting indicators of brain morphology in later life, rather than structural brain reserve. Future studies with repeated measures are required for a better understanding and certainty of the mechanisms at play.

Alzheimer's disease prevention: Apolipoprotein e4 moderates the effect of physical activity on brain beta-amyloid deposition in healthy older adults.

OBJECTIVES: To investigate if higher baseline physical activity levels are associated with less ß-amyloid burden and whether the ApoE4 genotype moderates this association cross-sectionally and longitudinally. DESIGN: Prospective cohort study. METHODS: 204 cognitively normal older adults (74.5 ±â€¯6.6 years; 26 % ApoE4-carrier) were analyzed. Baseline physical activity was measured using the Minnesota Physical Activity Questionnaire. Brain ß-amyloid burden was measured with positron emission tomography using 11C-labeled Pittsburgh compound. A subsample of 128 participants underwent longitudinal positron emission tomography (2.0 ±â€¯0.9 scans over 5 ±â€¯3 years). Statistical analysis was run according to physical activity (high/low group) and the ApoE4 genotype (carrier/noncarrier). RESULTS: The ApoE4 genotype moderated the relationship between physical activity and ß-amyloid, such that low physical activity had a greater impact on ß-amyloid deposition in ApoE4-carriers than noncarriers. This ApoE4 × physical activity effect on brain ß-amyloid deposition was also observed when all available ß-amyloid scan timepoints were included in the model. ß-amyloid deposition increased over time (p < 0.001), and ApoE4-carriers had disproportionately greater ß-amyloid accumulation than ApoE4-noncarriers. The lower physical activity group had marginally greater ß-amyloid accumulation than the higher physical activity group (p = 0.099), but there was no significant ApoE4 effect on ß-amyloid accumulation. CONCLUSIONS: Low physical activity in combination with the ApoE4-carrier genotype is associated with increased ß-amyloid burden, suggesting that ApoE4 moderates the effect of physical activity on ß-amyloid load. However, this effect was insufficient for baseline physical activity to modulate the change in ß-amyloid accumulation over time.

Molecular mechanisms underlying structural plasticity of electroconvulsive therapy in major depressive disorder.

Although previous studies reported structural changes associated with electroconvulsive therapy (ECT) in major depressive disorder (MDD), the underlying molecular basis of ECT remains largely unknown. Here, we combined two independent structural MRI datasets of MDD patients receiving ECT and transcriptomic gene expression data from Allen Human Brain Atlas to reveal the molecular basis of ECT for MDD. We performed partial least square regression to explore whether/how gray matter volume (GMV) alterations were associated with gene expression level. Functional enrichment analysis was conducted using Metascape to explore ontological pathways of the associated genes. Finally, these genes were further assigned to seven cell types to determine which cell types contribute most to the structural changes in MDD patients after ECT. We found significantly increased GMV in bilateral hippocampus in MDD patients after ECT. Transcriptome-neuroimaging association analyses showed that expression levels of 726 genes were positively correlated with the increased GMV in MDD after ECT. These genes were mainly involved in synaptic signaling, calcium ion binding and cell-cell signaling, and mostly belonged to excitatory and inhibitory neurons. Moreover, we found that the MDD risk genes of CNR1, HTR1A, MAOA, PDE1A, and SST as well as ECT related genes of BDNF, DRD2, APOE, P2RX7, and TBC1D14 showed significantly positive associations with increased GMV. Overall, our findings provide biological and molecular mechanisms underlying structural plasticity induced by ECT in MDD and the identified genes may facilitate future therapy for MDD.

Evaluation of an Updated Gene Panel as a Diagnostic Tool for Both Male and Female Infertility.

In recent years, an increasing number of genes associated with male and female infertility have been identified. The genetics of infertility is no longer limited to the analysis of karyotypes or specific genes, and it is now possible to analyse several dozen infertility genes simultaneously. Here, we present the diagnostic activity over the past two years including 140 patients (63 women and 77 men). Targeted sequencing revealed causative variants in 17 patients, representing an overall diagnostic rate of 12.1%, with prevalence rates in females and males of 11% and 13%, respectively. The gene-disease relationship (GDR) was re-evaluated for genes due to the addition of new patients and/or variants in the actual study. Five genes changed categories: two female genes (MEIOB and TBPL2) moved from limited to moderate; two male genes (SOHLH1 and GALNTL5) moved from no evidence to strong and from limited to moderate; and SEPTIN12, which was unable to classify male infertility, was reclassified as limited. Many infertility genes have yet to be identified. With the increasing integration of genetics in reproductive medicine, the scope of intervention extends to include other family members, in addition to individual patients or couples. Genetic counselling consultations and appropriate staffing will need to be established in fertility centres. Trial registration number: Not applicable.

Association of uncertain significance genetic variants with myocardial mechanics and morphometrics in patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Careful interpretation of the relation between phenotype changes of the heart and gene variants detected in dilated cardiomyopathy (DCM) is important for patient care and monitoring. OBJECTIVE: We sought to assess the association between cardiac-related genes and whole-heart myocardial mechanics or morphometrics in nonischemic dilated cardiomyopathy (NIDCM). METHODS: It was a prospective study consisting of patients with NIDCM. All patients were referred for genetic testing and a genetic analysis was performed using Illumina NextSeq 550 and a commercial gene capture panel of 233 genes (Systems Genomics, Cardiac-GeneSGKit®). It was analyzed whether there are significant differences in clinical, two-dimensional (2D) echocardiographic, and magnetic resonance imaging (MRI) parameters between patients with the genes variants and those without. 2D echocardiography and MRI were used to analyze myocardial mechanics and morphometrics. RESULTS: The study group consisted of 95 patients with NIDCM and the average age was 49.7 ± 10.5. All echocardiographic and MRI parameters of myocardial mechanics (left ventricular ejection fraction 28.4 ± 8.7 and 30.7 ± 11.2, respectively) were reduced and all values of cardiac chambers were increased (left ventricular end-diastolic diameter 64.5 ± 5.9 mm and 69.5 ± 10.7 mm, respectively) in this group. It was noticed that most cases of whole-heart myocardial mechanics and morphometrics differences between patients with and without gene variants were in the genes GATAD1, LOX, RASA1, KRAS, and KRIT1. These genes have not been previously linked to DCM. It has emerged that KRAS and KRIT1 genes were associated with worse whole-heart mechanics and enlargement of all heart chambers. GATAD1, LOX, and RASA1 genes variants showed an association with better cardiac function and morphometrics parameters. It might be that these variants alone do not influence disease development enough to be selective in human evolution. CONCLUSIONS: Combined variants in previously unreported genes related to DCM might play a significant role in affecting clinical, morphometrics, or myocardial mechanics parameters.

A 30-nation investigation of lay heritability beliefs.

Lay beliefs about human trait heritability are consequential for cooperation and social cohesion, yet there has been no global characterisation of these beliefs. Participants from 30 countries (N = 6128) reported heritability beliefs for intelligence, personality, body weight and criminality, and transnational factors that could influence these beliefs were explored using public nation-level data. Globally, mean lay beliefs differ from published heritability (h2) estimated by twin studies, with a worldwide majority overestimating the heritability of personality and intelligence, and underestimating body weight and criminality. Criminality was seen as substantially less attributable to genes than other traits. People from countries with high infant mortality tended to ascribe greater heritability for most traits, relative to people from low infant mortality countries. This study provides the first systematic foray into worldwide lay heritability beliefs. Future research must incorporate diverse global perspectives to further contextualise and extend upon these findings.

Translation, cross-cultural adaptation, and preliminary validation of a patient-reported outcome measure for genetic counseling outcomes in Sweden.

Genetic counseling is key for understanding the consequences of hereditary and genetic diseases and, therefore, crucial for patients, their families, and healthcare providers. Genetic counseling facilitates individuals' comprehension, decision-making, and adaptation to hereditary diseases. This study focuses on the Swedish adaptation of the Genetic Counseling Outcome Scale-24 (GCOS-24), an internationally validated, patient-reported outcome measure (PROM) for quantifying patient empowerment in genetic counseling. This study aimed to translate and cross-culturally adapt the GCOS-24 to measure patient-reported outcome from genetic counseling in Sweden. The adaptation process was meticulously conducted, adhering to international guidelines, with cross-cultural adaptation, translation, and back translation, to ensure semantic, conceptual, and idiomatic equivalence with the original English version. Face validity and understandability was assured using qualitative cognitive interviews conducted with patient representatives, and by a committee of experts in the field. The psychometric properties of the Swedish version of GCOS-24 (GCOS-24swe) were evaluated using a robust sample of 374 patients. These individuals received genetic counseling by telephone or video, necessitated by the constraints of the COVID-19 pandemic. Participants responded to GCOS-24swe both before and after genetic counseling. The GCOS-24swe demonstrated face validity, good internal consistency (Cronbach's alpha = 0.86), significant responsiveness (Cohen's d = 0.65, p < 0.001), and good construct validity. The study's findings underscore the GCOS-24swe's potential as an effective instrument in both clinical practice and research within Sweden. It offers a valuable means for assessing patient empowerment, a key goal of genetic counseling. Additional psychometric assessment of test-retest reliability and interpretability would further enhance the utility of GCOS-24swe.