Single Nucleotide Polymorphisms in the Arginase 1 and 2 Genes Are Differentially Associated with Circulating l-Arginine Concentration in Unsupplemented and l-Arginine–Supplemented Adults

2020 ◽  
Author(s):  
Juliane Hannemann ◽  
Leonard Rendant-Gantzberg ◽  
Julia Zummack ◽  
Jonas Hillig ◽  
Ina Eilermann ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Single Nucleotide Polymorphisms ◽  
Functional Relation ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Supplement Use ◽  
Arginase 1 ◽  
Study Results ◽  
Arginine Concentration

ABSTRACT Background Genetic variation in arginase may underlie variability in whole blood l-arginine concentrations in unsupplemented and l-arginine–supplemented adults. Objectives We aimed to study whether single nucleotide polymorphisms (SNPs) in the arginase 1 (ARG1) and arginase 2 (ARG2) genes are associated with blood l-arginine concentrations in unsupplemented and l-arginine–supplemented individuals. Methods In 374 adults (mean ± SD age: 59.6 ± 14.6 y; 180 males), we analyzed SNPs in the ARG1 (rs2246012 and rs2781667) and ARG2 genes (rs3742879 and rs2759757) and their associations with blood l-arginine concentrations. We analyzed associations of haplotypes for the ARG1 gene and for the ARG1 and ARG2 genes combined with blood l-arginine concentrations in supplement users and unsupplemented participants. Results Of study participants, 120 had low (<42 μmol/L), 133 had medium (42–114 μmol/L), and 121 had high blood l-arginine concentrations (>114 μmol/L); 58 individuals were current l-arginine supplement users. We found a significantly higher prevalence of the minor allele of ARG1 rs2246012 in supplement users with higher blood l-arginine concentrations (P = 0.03). Mean ± SEM l-arginine concentration was 263 ± 9.76 μmol/L in supplement users homozygous for the minor allele of ARG1 rs2246012 (P = 0.004); it was 70.4 ± 25.6 μmol/L in unsupplemented participants homozygous for the minor allele of ARG2 rs3759757 (P = 0.03). The ARG1 haplotype was significantly associated with blood l-arginine concentrations in supplement users (P = 0.046), whereas the combined ARG1/ARG2 haplotype was significantly associated with blood l-arginine concentrations in the cohort as a whole (P = 0.012). Conclusions Genetic variability in the ARG1 and ARG2 genes is associated with blood l-arginine concentrations in humans: ARG1 is associated with blood l-arginine concentrations in l-arginine supplement users, whereas ARG2 is associated with blood l-arginine concentrations in unsupplemented participants. Our study is the first to describe a possible functional relation between ARG1 and ARG2 SNPs and blood l-arginine concentrations; genetic variability in ARG1 may explain variation in blood l-arginine concentrations during supplement use and discrepant study results.

Abstract 14359: Single Nucleotide Polymorphisms in Genes Involved in L-arginine / Dimethylarginine Metabolism Predispose for Pulmonary Hypertension and Acute Mountain Sickness at High Altitude

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Juliane Hannemann ◽  
Julia Zummack ◽  
PATRICIA SIQUES ◽  
JULIO BRITO ◽  
Rainer Boeger
Keyword(s):  
Pulmonary Hypertension ◽  
Relative Risk ◽  
Genetic Variability ◽  
High Altitude ◽  
Acute Mountain Sickness ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Mountain Sickness ◽  
Study Participants

Introduction: Chronic (CH) and chronic-intermittent (CIH) exposure to hypoxia at high altitude causes acute or chronic mountain sickness and elevation of mean pulmonary arterial pressure (mPAP). This is paralleled by increased plasma levels of ADMA, an endogenous inhibitor of NO synthesis. ADMA is cleaved by dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), whilst symmetric dimethylarginine (SDMA) is cleaved by AGXT2. Arginase (ARG1 and ARG2) competes with endothelial NO synthase (NOS3) for L-arginine as substrate. We have shown previously that baseline ADMA (at sea level) determines mPAP after six months of CIH; cut-off values of 25 mm Hg and 30 mm Hg are being used to diagnose high altitude pulmonary hypertension. Hypothesis: We hypothesized that genetic variability in genes coding for core enzymes of ADMA, SDMA, and L-arginine metabolism may predispose individuals for high altitude disease and pulmonary hypertension. Methods: We genotyped 16 common single nucleotide polymorphisms in the NOS3, DDAH1, DDAH2, AGXT2, ARG1 and ARG2 genes of 69 healthy male Chilean subjects. Study participants adhered to a CIH regimen (5d at 3,550m, 2d at sea level) for six months. Metabolites were measured by LC-MS/MS; mPAP was estimated by echocardiography at six months, and altitude acclimatization was assessed by Lake Louise Score and arterial oxygen saturation. Results: Carriers of the minor allele of DDAH1 rs233112 had a higher mean baseline ADMA level (0.76±0.03 vs. 0.67±0.02 μmol/l; p<0.05), whilst the major allele of DDAH2 rs805304 was linked to an exacerbated increase of ADMA in hypoxia (0.10±0.03 vs. 0.04±0.04 μmol/l; p<0.02). Study participants carrying the minor allele of ARG1 rs2781667 had a relative risk of elevated mPAP (>25 mm Hg) of 1.70 (1.56-1.85; p<0.0001), and carriers of the minor allele of NOS3 rs2070744 had a relative risk of elevated mPAP (>30 mm Hg) of 1.58 (1.47-1.69; p<0.0001). The NOS3 and DDAH2 genes were associated with the incidence of acute mountain sickness. Conclusions: We conclude that genetic variability in the L-arginine / ADMA / NO pathway is an important determinant of high altitude pulmonary hypertension and acute mountain sickness. DDAH1 is linked to baseline ADMA, whilst DDAH2 determines the response of ADMA to hypoxia.

scholarly journals OR24-05 Identifying Regulatory Elements Within a Novel Enhancer of FSHB Containing Two PCOS-Associated Single Nucleotide Polymorphisms

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Stephanie C Bohaczuk ◽  
Varykina G Thackray ◽  
Pamela L Mellon
Keyword(s):  
Transcription Factor ◽  
Single Nucleotide Polymorphisms ◽  
Regulatory Elements ◽  
Minor Allele ◽  
Specific Marker ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Alcoholic Fatty Liver ◽  
Conserved Region

Abstract Polycystic ovary syndrome (PCOS) is the most common cause of female infertility, affecting approximately 10 percent of women by Rotterdam criteria, and is comorbid with obesity, type II diabetes, hypertension, and non-alcoholic fatty liver disease. As twin studies reveal that genetics account for approximately 70% of PCOS risk, genome-wide association studies (GWAS) can provide powerful insight into PCOS etiology. PCOS GWAS studies from several populations identified a risk locus containing the FSHB gene, which encodes the beta subunit of follicle-stimulating hormone (FSH). As FSH supplementation can restore ovulation in some PCOS patients, deficient FSH signaling could be a causative factor of anovulation and potentially other facets of PCOS. Two of the lead single nucleotide polymorphisms (SNPs) in association with PCOS, rs11031005 and rs11031006, fall within a highly conserved genomic region in mammals. We hypothesized that the conserved region (~450 base pairs) enhances FSHB transcription, and that one or both PCOS-related SNPs alter its function. We have shown that the conserved region from both human and mouse can act as an enhancer of FSHB in LβT2 cells, an immortalized, mouse-derived, mature pituitary gonadotrope cell line, and that its function is altered by the rs11031006 minor allele through modification of an SF1 consensus site. As elimination of the SF1 site reduced but did not completely abolish the function of the enhancer, we continued our investigation to identify additional regulatory sites. Transient transfection of LβT2 cells revealed a possible role for the rs11031005 SNP in FSHB regulation, with the minor allele decreasing enhancer-mediated FSHB transcription. This effect may be due to decreased binding of an unidentified transcription factor, as gel shift revealed that the rs11031005 minor allele reduced the intensity of a binding complex. Using truncations and sliding deletions, we identified three additional putative transcription factor binding sites with consensus sequences for ZEB1, PTX1, and SMAD. To support a role for the conserved region as an enhancer in native chromatin, we assessed the histone status in LβT2 chromatin. Compared to the proximal Fshb promoter, the enhancer-specific marker, H3K4me1, was enriched near the conserved region. Neither promoter/enhancer markers of active (H3K27Ac) or repressed (H3K27me3) chromatin were enriched near the conserved region, although levels of both modifications were consistent with the Fshb proximal promoter. Overall, our data support the role of this conserved region as a novel regulator of FSHB/Fshb transcription and reveal a possible mechanism to explain the contribution of PCOS-associated SNPs through FSHB regulation.

scholarly journals The Impact of Genetic Variability of CYP1A2, ADORA2A, and AHR on Caffeine Consumption and Response among Adult New Zealanders

Proceedings ◽  
2019 ◽  
Vol 37 (1) ◽  
pp. 30
Author(s):  
Tennent ◽  
Rutherfurd-Markwick ◽  
Ali ◽  
Wham
Keyword(s):  
Cytochrome P450 ◽  
Genetic Variability ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Caffeine Consumption ◽  
Cytochrome P450 1A2 ◽  
Single Nucleotide ◽  
The Impact ◽  
New Zealanders

Three single nucleotide polymorphisms (SNPs) have known links to caffeine consumption,metabolism, and post-consumption effects and responses: cytochrome P450 1A2 (CYP1A2; rs762551) [...]

scholarly journals Διαβητική αμφιβληστροειδοπάθεια σε Έλληνες καυκάσιους πάσχοντες από διαβήτη τύπου 2, συσχέτιση με τον πολυμορφισμό στο γονίδιο του αναστολέα του ενεργοποιητή του πλασμινογόνου 1 (ΡAI 1)

2017 ◽  
Author(s):  
Θωμάς Σοκολάκης
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Odds Ratio ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Pai 1

Ιστορικό: Υπαρχουν συσσωρεύμενα στοιχεία για την ύπαρξη γενετικής ευαισθησίας στην ανάπτυξη διαβητικής αμφιβληστροειδοπάθειας (ΔΑ). Ο ρόλος του αναστολέα του ενεργοποιητή του πλασμινογόνου-1 (PAI-1) στον κινδυνο αναπτυξης ΔΑ παραμένει αμφιλεγόμενος.Σκοπός: Η παρούσα μελέτη σχεδιάστηκε για να διερευνήσει την πιθανή επίδραση των πολυμορφισμών της περιοχής του γονιδίου PAI-1 στον κίνδυνο ανάπτυξης της ΔΑ και στον κίνδυνο ανάπτυξης ΔΑ πρώιμα έναντι καθυστερημένα κατά τη διάρκεια του σακχαρώδους διαβήτη τύπου 2 (ΣΔ2). Μέθοδοι: Συνολικά 138 ασθενείς με ΔΑ, 107 ασθενείς με ΣΔ2 χωρίς ΔΑ και 315 υγιείς μάρτυρες προσλήφθηκαν. Για να καλυφθεί η πλειοψηφία της γενετικής μεταβλητότητας στην εκτεταμένη περιοχή του γονιδίου ΡΑΙ-1, πέντε πολυμορφισμοί μονού νουκλεοτιδίου (single-nucleotide polymorphisms SNPs) από το HapMap χρησιμοποιώντας μια προσέγγιση ανά ζεύγη και r2> 0,8 και μία μικρή συχνότητα αλληλόμορφων (minor allele frequency MAF)> 0,05 εντοπίστηκαν. Χρησιμοποιώντας αναλύσεις λογιστικής παλινδρόμησης, ετικέτες SNPs και απλότυποι δοκιμάστηκαν για ενώσεις με κίνδυνο ανάπτυξης ΔΑ και με κίνδυνο ανάπτυξης ΔΑ νωρίς ή αργά κατά τη διάρκεια του ΣΔ2. Ο γενικευμένος λόγος πιθανότητας (generalized odds ratio ORG) υπολογίστηκε για την εκτίμηση της επίδρασης μεταλλακτικού φορτίου στην ανάπτυξη ΔΑ μεταξύ όλων των συμμετεχόντων. Διενεργήθηκαν διορθώσεις για πολλαπλές συγκρίσεις (p-τιμή <0,01).Αποτελέσματα: Ένα σημαντικό αποτέλεσμα του rs2070682 στον κίνδυνο πρόωρης έναρξης ΔΑ βρέθηκε στο συνκυριαρχο μοντέλο κληρονομικότητας [αναλογία πιθανότητας, OR (95% διάστημα εμπιστοσύνης, CI): 5.04 (1.47-17.28), p = 0.018]. Ωστόσο, αυτή η σχέση οριακά δεν επιβίωσε πολλαπλών διορθώσεων και δοκιμών. Δεν αποκαλύφθηκε καμία άλλη σημαντική συσχέτιση μεταξύ των επισημάνσεων-SNPs και των απλοτύπων ΡΑΙ-1. Επιπλέον, δεν βρέθηκε σημαντική επίδραση του μεταλλακτικού φορτίου της ετικέττας SNPs στον PAI-1 στον κίνδυνο ανάπτυξης ΔΑ στη διαρκεια του ΣΔ2. Συμπεράσματα: Συμπερασματικά, η παρούσα μελέτη δεν παρέχει καμία ισχυρή απόδειξη ότι οι παραλλαγές του γονιδίου PAI-1 εμπλέκονται στον κίνδυνο ανάπτυξης της ΔΑ ή στην ανάπτυξη της ΔΑ κατά τη διάρκεια του ΣΔ2.

scholarly journals Single nucleotide polymorphisms associated with postoperative inadequate analgesia after single-port VATS in Chinese population

2020 ◽  
Author(s):  
Xiufang Xing ◽  
Yongyu Bai ◽  
Kai Sun ◽  
Min Yan
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Pain Perception ◽  
Single Port ◽  
Thoracoscopic Surgery ◽  
Clinical Problem ◽  
Minor Allele ◽  
Chinese Patients ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Increased Risk

Abstract Background: Postoperative inadequate analgesia following video-assisted thoracoscopic surgery (VATS) is a common and significant clinical problem. While genetic polymorphisms may play role in the variability of postoperative analgesia effect, few studies have evaluated the associations between genetic mutations and inadequate analgesia after single-port VATS. Methods: Twenty-eight single nucleotide polymorphisms (SNPs) among 18 selected genes involved in pain perception and modulation were genotyped in 198 Chinese patients undergoing single-port VATS. The primary outcome was the occurrence of inadequate analgesia in the first night and morning after surgery which was defined by a comprehensive postoperative evaluation. Multivariable logistic regression analyses were used to identify the association between genetic variations and postoperative inadequate analgesia. Results: The prevalence of postoperative inadequate analgesia was 45.5% in the present study. After controlling for age and education level, association with inadequate analgesia was observed in four SNPs among three genes encoding voltage-gated sodium channels. Patients with the minor allele of rs33985936 (SCN11A), rs6795970 (SCN10A), and 3312G>T (SCN9A) have an increased risk of suffering from inadequate analgesia. While the patients carrying the minor allele of rs11709492 (SCN11A) have lower risk experiencing inadequate analgesia. Conclusions: We identified that SNPs in SCN9A, SCN10A, and SCN11A play a role in the postoperative inadequate analgesia after single-port VATS. Although future larger and long-term follow up studies are warranted to confirm our findings, the results of the current study may be utilized as predictors for forecasting postoperative analgesic effect for patients receiving this type of surgery.Trial registration: This study was retrospectively registered in the ClinicalTrials.gov Registry (NCT03916120) on April 16, 2019.

scholarly journals DRD2/ANKK1 Taq1A but not COMT single nucleotide polymorphisms contribute to the link between temporal impulsivity and obesity in men

2020 ◽  
Author(s):  
Filip Morys ◽  
Jakob Simmank ◽  
Annette Horstmann
Keyword(s):  
Genetic Variability ◽  
Single Nucleotide Polymorphisms ◽  
The Body ◽  
Nucleotide Polymorphisms ◽  
Cross Sectional ◽  
Single Nucleotide ◽  
Dopaminergic Transmission ◽  
And Gender ◽  
Gender Interactions ◽  
The Brain

AbstractTemporal impulsivity, the tendency to choose a smaller, sooner over a larger, delayed reward, is associated with single nucleotide polymorphisms (SNPs) in COMT and DRD2-related ANKK1 genes, whose products regulate dopaminergic transmission in the brain. Temporal impulsivity is also consistently associated with obesity, sometimes in a genderdependent fashion. Further, there seems to be no direct association between these SNPs and obesity. In this study, we investigated an interaction between BMI, COMT, and DRD2/ANKK1 SNPs, and temporal impulsivity. We tested three plausible models of associations between those variables: (1) genetic variability influencing BMI through temporal impulsivity and gender interactions, (2) genetic variability interacting with temporal impulsivity to influence BMI, (3) interaction of BMI and genetic variability influencing temporal impulsivity. We found evidence for the second model: in men, BMI was dependent on temporal impulsivity and the DRD2/ANKK1 SNP. It shows that increased temporal impulsivity combined with a disadvantageous DRD2/ANKK1 genotype might be a vulnerability factor for the development of obesity. Our study, even though cross-sectional, adds to the body of literature regarding the influence of the dopaminergic system on obesity measures. Our results point to a factor explaining discrepancies in results regarding associations of temporal impulsivity and BMI in women and men.

scholarly journals Single Nucleotide Polymorphisms in TLR4 Affect Susceptibility to Tuberculosis in Mexican Population from the State of Veracruz

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Enrique Ortega ◽  
Sujhey Hernández-Bazán ◽  
Beatriz Sánchez-Hernández ◽  
Ileana Licona-Limón ◽  
Javier Fuentes-Dominguez
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Genetic Model ◽  
Public Health Problem ◽  
Active Tuberculosis ◽  
The State ◽  
Minor Allele ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Tuberculosis Disease ◽  
Active Disease

Tuberculosis is still a global public health problem, with an estimated 10 million new cases and 1.6 million deaths in 2017. Of all humans infected with M. tuberculosis, only 10-15% will develop active tuberculosis disease during their lifetime, and data suggest that along with environmental factors, genetic factors influence susceptibility to develop active disease. Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the initiation and shaping of adaptive immune responses, and several TLRs have been shown to recognize mycobacterial components. In this work, we performed a case-control study to determine if common single nucleotide polymorphisms (SNPs) in genes encoding TLRs 1, 2, 4, 6, and 10 are associated with susceptibility to develop active tuberculosis in population from the state of Veracruz, Mexico. The study included 279 cases and 569 controls. The results show that the frequency of two SNPs in TLR4 was significantly higher in controls than in tuberculosis patients. The minor allele (G) of rs4986790 in TLR4 (D299G) decreased the risk of active tuberculosis in the allelic (A vs. G, OR=0.31, 95%CI=0.09‐0.81, p=0.01) and in the dominant genetic model (AA vs. GG+AG, OR=0.26, 95%CI=0.09‐0.77, p=0.02). Similarly, the minor allele (T) of rs4986791 in TLR4 (T399I) decreased the risk of active disease in the allelic model (C vs. T, OR=0.29, 95%CI=0.10‐0.90, p=0.03). We did not find an association of SNPs in TLR1 (N248S), TLR2 (R753Q), TLR6 (S249P), and TLR10 (A153S and V298I) with tuberculosis disease. These results suggest that in this population, genetic variants of TLR4 affect the susceptibility for suffering active tuberculosis disease.

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