scholarly journals Anti-Mullerian Hormone Protein-Altering Variants Are Associated With Hypertriglyceridemia in the General Population

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A737-A738
Author(s):  
Sydney Chang ◽  
Alan Copperman ◽  
Andrea Elizabeth Dunaif
Keyword(s):  
General Population ◽  
Hemoglobin A1c ◽  
Sequence Data ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
European Ancestry ◽  
Functional Protein ◽  
Antihypertensive Medications ◽  
Health And Nutrition ◽  
Elevated Cholesterol

Abstract We found 17 rare PCOS-specific functional protein-altering variants (PAVs) or mutations in the gene, AMH, that decrease the biologic activity of the encoded protein, anti-Müllerian hormone (AMH), in the heterozygous state. Approximately 3% of European ancestry PCOS cases in our cohort of ~700 were affected. Our preliminary studies found evidence for a metabolic phenotype in both PCOS as well as their male first-degree relatives who were heterozygous carriers of these AMH PAVs. We performed this study to test the hypothesis that AMH mutations are associated with metabolic abnormalities in the general population. The Mount Sinai BioMe Biobank is an electronic health record (EHR)-linked biobank, containing anonymized whole exome sequences from 30,813 participants of diverse ancestries. We interrogated the sequence data to identify individuals with PCOS-related AMH PAVs. IRB-approval was obtained to review the linked EHR. Outcomes were the presence of obesity (BMI ≥ 30 kg/m2), type 2 diabetes (hemoglobin A1C ≥ 6.5%), prediabetes (hemoglobin A1C 5.7% - 6.4%), elevated cholesterol (total cholesterol ≥ 200 mg/dL), hypertriglyceridemia (TG ≥ 150 mg/dL), and hypertension (≥2 blood pressure values ≥140/90, or administration of antihypertensive medications). Control subjects were obtained from the National Health and Nutrition Examination Survey using propensity score matching (for sex, age, and BMI) with a 1:4 case:control ratio. A total of 292 individuals with AMH PAVs were identified, resulting in a combined 0.95% prevalence of AMH PAVs in an unselected population (1.07% in Europeans, 0.28% in African Americans, 0.54% in Hispanics, and 0.07% in Asians). After adjusting for age, BMI, and race/ethnicity, there was a statistically significant increased prevalence of hypertriglyceridemia in both women (OR 7.29, 95% CI 3.77-14.00) and men (OR 10.15, 95% CI 4.68-22.00) with AMH PAVs compared to sex-, age- and BMI-matched controls. There was also a statistically significant increased prevalence of elevated cholesterol in men with AMH PAVs compared to controls (OR 2.48, 95% CI 1.15-5.34). There were no significant differences between individuals with AMH PAVs and matched controls with respect to the other outcomes. These findings suggest that decreased bioactivity of AMH is causally related to dyslipidemia in the general population. TG levels are elevated in both sexes, whereas increases in cholesterol are only seen in men. The mechanisms by which decreases in AMH bioactivity alter circulating lipid levels are of considerable interest since AMH has no known metabolic actions. It is possible that the putative metabolic effects of AMH are mediated by increases in circulating testosterone (T) levels that in turn alter lipid metabolism. Since T levels are not commonly available in EHR, future studies will be needed to investigate this hypothesis as well as to explore metabolic actions of AMH.

scholarly journals Abnormal metabolic phenotype in middle-aged GH-deficient adults despite long-term recombinant human GH replacement

2014 ◽  
Vol 170 (2) ◽  
pp. 263-272 ◽  
Author(s):  
K M J A Claessen ◽  
N M Appelman-Dijkstra ◽  
A M Pereira ◽  
S D Joustra ◽  
R de Mutsert ◽  
...  
Keyword(s):  
General Population ◽  
Metabolic Profile ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Middle Aged ◽  
Aged Patients ◽  
Positive Effects ◽  
The Metabolic Syndrome ◽  
Increased Risk

BackgroundAdult GH deficiency (GHD) is associated with increased cardiovascular mortality. Recombinant human GH (rhGH) replacement has beneficial short-term metabolic effects. Although these positive effects sustain during longer follow-up, the prevalence of the metabolic syndrome (MS) remains increased in comparison with population data not adjusted for the higher mean BMI in GHD adults.ObjectiveTo explore whether middle-aged patients with proposed physiological rhGH replacement have been normalized with respect to MS and its individual components in comparison with the general population, adjusted for age, sex, and BMI.MethodsOne hundred and sixty-one GHD patients (aged 40–70 years) were studied before the start and after 5 years of rhGH replacement, and were compared with 1671 subjects (aged 45–66 years) from the general population (NEO Study).ResultsMS proportion in GHD patients was 41.0% before the start of rhGH suppletion, increasing to 53.4% after 5 years (P=0.007). Despite chronic rhGH replacement, GHD patients had a 1.3-times higher MS proportion than the general population, independently of age, sex, and BMI (95% CI 1.1–1.5, P=0.008). The GHD population showed a different metabolic profile than the general population with similar BMI: an increased risk of hypertriglyceridemia (adjusted prevalence ratio (PR) 2.0, 95% CI 1.7–2.3) and low HDL-C (adjusted PR 1.8, 95% CI 1.5–2.2), but less hyperglycemia (adjusted PR 0.5, 95% CI 0.4–0.7).ConclusionsDespite 5 years of rhGH replacement, GHD patients still have a different metabolic profile and more frequently MS than the general population. These differences were independent of BMI, and resemble the unfavorable metabolic profile of untreated GHD patients, pointing to question the long-term benefits of rhGH replacement.

scholarly journals Impact of Work and Recreational Physical Activity on Prediabetes Condition among U.S. Adults: NHANES 2015–2016

2021 ◽  
Vol 18 (4) ◽  
pp. 1378
Author(s):  
Lenin Pazmino ◽  
Wilmer Esparza ◽  
Arian Ramón Aladro-Gonzalvo ◽  
Edgar León
Keyword(s):  
Physical Activity ◽  
Protective Factor ◽  
Hemoglobin A1c ◽  
Physical Activities ◽  
Recreational Physical Activity ◽  
Physically Active ◽  
Hba1c Test ◽  
Health And Nutrition ◽  
The Impact

More minutes of physical activity (PA) accumulated during a day are associated with a lower risk of diabetes mellitus type 2. However, it is less known if distinct dimensions of PA can produce a different protective effect in the prevention of prediabetes. The aim of this study was to analyze the impact of work and recreational PA on prediabetes among U.S. adults during the period 2015–2016 using the National Health and Nutrition Examination Survey (NHANES) database. Individuals (n = 4481) with hemoglobin A1c (HbA1c) test values of 5.7% to 6.4% were included. A logistic regression multivariate-adjusted analysis was conducted to estimate the association between the odds ratios (ORs) and 95% confidence intervals (CIs) of prediabetes, with work and recreational PA. The prevalence of prediabetes among U.S. adults was lower in physically active individuals both at work (~24%) and recreational (~21%) physical activities compared to individuals who were not physically active (27 to 30%). Individuals lacking practice of recreational PA had a high risk of prediabetes (OR = 1.26, 95% CI: 1.080 to 1.466). PA may be a protective factor for prediabetes conditions depending on gender, age, ethnic group, waist circumference, and thyroid disease.

scholarly journals Hypertension in the United States Fire Service

2021 ◽  
Vol 18 (10) ◽  
pp. 5432
Author(s):  
Saeed U. Khaja ◽  
Kevin C. Mathias ◽  
Emilie D. Bode ◽  
Donald F. Stewart ◽  
Kepra Jack ◽  
...  
Keyword(s):  
Blood Pressure ◽  
General Population ◽  
Age Groups ◽  
Total Sample ◽  
The United States ◽  
Fire Service ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiac Events ◽  
Antihypertensive Medications ◽  
Increased Risk

Hypertension is a major risk factor for atherosclerotic cardiovascular disease and cardiac remodeling and is associated with an increased risk of sudden cardiac events, the leading cause of duty-related death in the fire service. We assessed systemic blood pressures and prevalence of hypertension among US firefighters by decade of life. Medical records of career firefighters (5063 males and 274 females) from four geographically diverse occupational health clinics were assessed. Hypertension was defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg, or taking antihypertensive medication. Results from the firefighter sample were compared to the US general population (2015–2016 and 2017–2018 National Health and Nutrition Examination Surveys). Among the total sample, 69% of firefighters met the criteria for hypertension and 17% were taking antihypertensive medications. Percentages of hypertensive male and female firefighters were 45% and 11% among 20–29 years old, respectively, and increased to 78% and 79% among 50–59 years old, respectively. Compared to the general population, male firefighters had a higher prevalence of hypertension (p < 0.05) across all age groups (11–16% higher). In order to improve firefighter health and protect against sudden incapacitation in this public safety occupational group, increased efforts are necessary to screen for and manage high blood pressure.

scholarly journals Interaction of CREB and PGC-1α Induces Fibronectin Type III Domain-Containing Protein 5 Expression in C2C12 Myotubes

2018 ◽  
Vol 50 (4) ◽  
pp. 1574-1584 ◽  
Author(s):  
Xiu-ying Yang ◽  
Margaret C.L. Tse ◽  
Xiang Hu ◽  
Wei-hua Jia ◽  
Guan-hua Du ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Metabolic Effects ◽  
Hek293 Cells ◽  
Metabolic Phenotype ◽  
C2c12 Myotubes ◽  
Type Iii ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

Background/Aims: Fibronectin type III domain-containing protein 5 (FNDC5), also known as irisin, is a myokine secreted from muscle in response to exercise. However, the molecular mechanisms that regulate FNDC5 expression and the functional significance of irisn in skeletal muscle remain unknown. In this study, we explored the potential pathways that induce FNDC5 expression and delineated the metabolic effects of irisin on skeletal muscle. Methods: C2C12 myotubes were treated with drugs at various concentrations and durations. The expression and activation of genes were measured by real-time polymerase chain reaction (qRT-PCR) and Western blotting. Oxidative phosphorylation was quantified by measuring the oxygen consumption rate (OCR). Results: We found that the exercise-mimicking treatment (cAMP, forskolin and isoproterenol) increased Fndc5 expression in C2C12 myotubes. CREB over-expressed C2C12 myotubes displayed higher Fndc5 expression. CREB over-expression also promoted peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression. PGC-1α-induced Fndc5 expression was blocked when the dominant negative form of CREB (S133A) was present. PGC-1α mutation (S570A) also decreased Fndc5 expression. Immunoprecipitation showed that overexpressed PGC-1α complexed with CREB in HEK293 cells. C2C12 myotubes treated with forskolin also increased endogenous CREB and PGC-1α binding. Functionally, irisin treatment increased mitochondrial respiration, enhanced ATP production, promoted fatty acid oxidation but decreased glycolysis in myotubes. Conclusion: Our observation indicates that cAMP-mediated PGC-1α/CREB interaction triggers Fndc5 expression, which acts as an autocrine/paracrine to shape the metabolic phenotype of myotubes.

GEMPROT: visualization of the impact on the protein of the genetic variants found on each haplotype

2018 ◽  
Vol 35 (14) ◽  
pp. 2492-2494
Author(s):  
Tania Cuppens ◽  
Thomas E Ludwig ◽  
Pascal Trouvé ◽  
Emmanuelle Genin
Keyword(s):  
Genetic Variants ◽  
Protein Sequence ◽  
Sequence Data ◽  
Protein Sequences ◽  
Supplementary Information ◽  
Analysis Tool ◽  
Functional Protein ◽  
Key Players ◽  
On Line ◽  
The Impact

Abstract Summary When analyzing sequence data, genetic variants are considered one by one, taking no account of whether or not they are found in the same individual. However, variant combinations might be key players in some diseases as variants that are neutral on their own can become deleterious when associated together. GEMPROT is a new analysis tool that allows, from a phased vcf file, to visualize the consequences of the genetic variants on the protein. At the level of an individual, the program shows the variants on each of the two protein sequences and the Pfam functional protein domains. When data on several individuals are available, GEMPROT lists the haplotypes found in the sample and can compare the haplotype distributions between different sub-groups of individuals. By offering a global visualization of the gene with the genetic variants present, GEMPROT makes it possible to better understand the impact of combinations of genetic variants on the protein sequence. Availability and implementation GEMPROT is freely available at https://github.com/TaniaCuppens/GEMPROT. An on-line version is also available at http://med-laennec.univ-brest.fr/GEMPROT/. Supplementary information Supplementary data are available at Bioinformatics online.

Epidemiological survey of hemoglobin A1c and liver fibrosis in a general population with non‐alcoholic fatty liver disease

2018 ◽  
Vol 49 (3) ◽  
pp. 296-303 ◽  
Author(s):  
Kenichi Tanaka ◽  
Hirokazu Takahashi ◽  
Hideyuki Hyogo ◽  
Masafumi Ono ◽  
Noriko Oza ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Fibrosis ◽  
General Population ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Hemoglobin A1c ◽  
Epidemiological Survey ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Sensitive detection of DNA contamination in tumor samples via microhaplotypes

2020 ◽  
Author(s):  
Brett Whitty ◽  
John F. Thompson
Keyword(s):  
Sequence Data ◽  
Accurate Determination ◽  
Sensitive Detection ◽  
European Ancestry ◽  
Somatic Variation ◽  
Dna Mixtures ◽  
Accurate Identification ◽  
Sample Contamination ◽  
Dna Contamination ◽  
Low Levels

AbstractBackgroundLow levels of sample contamination can have disastrous effects on the accurate identification of somatic variation in tumor samples. Detection of sample contamination in DNA is generally based on observation of low frequency variants that suggest more than a single source of DNA is present. This strategy works with standard DNA samples but is especially problematic in solid tumor FFPE samples because there can be huge variations in allele frequency (AF) due to massive copy number changes arising from large gains and losses across the genome. The tremendously variable allele frequencies make detection of contamination challenging. A method not based on individual AF is needed for accurate determination of whether a sample is contaminated and to what degree.MethodsWe used microhaplotypes to determine whether sample contamination is present. Microhaplotypes are sets of variants on the same sequencing read that can be unambiguously phased. Instead of measuring AF, the number and frequency of microhaplotypes is determined. Contamination detection becomes based on fundamental genomic properties, linkage disequilibrium (LD) and the diploid nature of human DNA, rather than variant frequencies. We optimized microhaplotype content based on 164 single nucleotide variant sets located in genes already sequenced within a cancer panel. Thus, contamination detection uses existing sequence data and does not require sequencing of any extraneous regions. The content is chosen based on LD data from the 1000 Genomes Project to be ancestry agnostic, providing the same sensitivity for contamination detection with samples from individuals of African, East Asian, and European ancestry.ResultsDetection of contamination at 1% and below is possible using this design. The methods described here can also be extended to other DNA mixtures such as forensic and non-invasive prenatal testing samples where DNA mixes of 1% or less can be similarly detected.ConclusionsThe microhaplotype method allows sensitive detection of DNA contamination in FFPE tumor samples. These methods provide a foundation for examining DNA mixtures in a variety of contexts. With the appropriate panels and high sequencing depth, low levels of secondary DNA can be detected and this can be valuable in a variety of applications.

scholarly journals Nuclear magnetic resonance metabolic fingerprint of bevacizumab in mutant IDH1 glioma cells

2018 ◽  
Vol 52 (4) ◽  
pp. 392-398 ◽  
Author(s):  
Tanja Mesti ◽  
Nadia Bouchemal ◽  
Claire Banissi ◽  
Mohamed N. Triba ◽  
Carole Marbeuf-Gueye ◽  
...  
Keyword(s):  
Tricarboxylic Acid Cycle ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Magic Angle Spinning ◽  
Idh1 Mutation ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Magic Angle ◽  
Metabolic Fingerprint ◽  
U87 Cells

AbstractBackgroundMalignant gliomas are rapidly growing tumours that extensively invade the brain and have bad prognosis. Our study was performed to assess the metabolic effects of bevacizumab on the glioma cells carrying the IDH1 mutation, a mutation, associated with better prognosis and treatment outcome. Bevacizumab is known to inhibit tumour growth by neutralizing the biological activity of vascular endothelial growth factor (VEGF). However, the direct effects of bevacizumab on tumour cells metabolism remain poorly known.Materials and methodsThe immunoassay and MTT assay were used to assess the concentration of secreted VEGF and cell viability after bevacizumab exposure. Metabolomic studies on cells were performed using high resolution magic angle spinning spectroscopy (HRMAS).ResultsmIDH1-U87 cells secreted VEGF (13 ng/mL). Regardless, bevacizumab had no cytotoxic effect, even after a 72h exposure and with doses as high as 1 mg/mL. Yet, HRMAS analysis showed a significant effect of bevacizumab (0.1 mg/mL) on the metabolic phenotype of mIDH1-U87 cells with elevation of 2-hydroxyglutarate and changes in glutamine group metabolites (alanine, glutamate, glycine) and lipids (polyunsaturated fatty acids [PUFA], glycerophosphocholine, and phosphocholine).ConclusionsIn mIDH1-U87 cells, changes in glutamine group metabolites and lipids were identified as metabolic markers of bevacizumab treatment. These data support the possibility of a functional tricarboxylic acid cycle that runs in reductive manner, as a probable mechanism of action of bevacizumab in IDH1 mutated gliomas and propose a new target pathway for effective treatment of malignant gliomas.

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