Ancestral Origin of the First Indian Families with Myotonic Dystrophy Type 2

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Interaction between MTHFR 677C>T and periconceptional folic acid supplementation in the risk of Hypospadias

BACKGROUND: Hypospadias is a congenital malformation with both environmental factors and genetic predisposition involved in the pathogenesis. The role of maternal periconceptional folic acid supplement use in the development of hypospadias is unclear. As folate levels may also be influenced by the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, we hypothesize that a gene-environment interaction between this polymorphism and folic acid use is involved in the etiology of hypospadias. METHODS: We conducted a case-control study among 855 hypospadias cases and 713 population-based controls from the AGORA data- and biobank. Folic acid supplement use was derived from maternal questionnaires and infant and maternal DNA was used to determine the MTHFR C677T polymorphism using Taqman assays. We performed separate analyses for different hypospadias phenotypes (anterior/middle/posterior). RESULTS: Hypospadias was neither associated with folic acid use or the MTHFR C677T polymorphism, nor with their interaction. However, we did find an association with middle hypospadias when no supplements were used (odds ratio = 1.6; 95% confidence interval, 1.1-2.4), especially in infants carrying the CT/TT genotype (odds ratio = 2.5; 95% confidence interval, 1.4-4.7). In addition, more infants with these genotypes seemed to have posterior hypospadias, regardless of folic acid use. CONCLUSION: Our study does not suggest a major role for folic acid supplements or the MTHFR C677T polymorphism in the etiology of hypospadias in general, but not using folic acid and/or carrying the MTHFR C677T polymorphism may be associated with middle and posterior hypospadias. Therefore, we stress the importance of studying gene-environment interactions preferably in stratified analyses for different hypospadias phenotypes. Birth Defects Research (Part A) 106:275-284, 2016. (c) 2016 Wiley Periodicals, Inc

DNA methylation associated with persistent ADHD suggests TARBP1 as novel candidate

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Effects of the 34C>T Variant of the AMPD1 Gene on Immune Function, Multi-Organ Dysfunction, and Mortality in Sepsis Patients

Item does not contain fulltextINTRODUCTION: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C>T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. METHODS: The effects of the presence of the 34C>T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n = 285; replication cohort n = 212) and ventilator-associated pneumonia (VAP, n = 117; n = 33) and control patients without infection (n = 101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. RESULTS: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P = 0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P = 0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P = 0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-alpha by LPS-stimulated monocytes was attenuated (P = 0.005), indicative of a more pronounced immunoparalytic state in these patients. CONCLUSIONS: Presence of the AMPD1 34C>T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation

Effects of the 34c<T variant of the AMPD1 gene on immune function, multi-organ dysfunction, and mortality in sepsis patients

Introduction: Adenosine exerts anti-inflammatory and tissue-protective effects during systemic inflammation. While the tissue-protective effects might limit organ damage, its anti-inflammatory properties may induce immunoparalysis and impede bacterial clearance. The common 34C<T loss-of-function variant of AMPD1 (rs17602729) is associated with increased adenosine formation, but effects on immune function and outcome in sepsis patients are unknown. Methods: The effects of the presence of the 34C<T variant on sepsis susceptibility, immune function, multi-organ dysfunction, and mortality in septic patients were studied. Patients suffering from community acquired pneumonia (CAP, initial cohort n=285; replication cohort n=212) and ventilator-associated pneumonia (VAP, n=117; n=33) and control patients without infection (n=101) were enrolled. Genetic distributions of the AMPD1 SNP were CC 76%, CT 22%, and TT 2% in the initial cohort and CC 80%, CT 18%, and TT 2% in the replication cohort. Results: The occurrence of septic CAP, but not septic VAP, was increased for the CT versus CC genotype (OR (95% CI) 2.0 (1.1-3.7); P=0.02) in the initial cohort. The increased risk for the CT versus CC genotype was also observed in the replication cohort but did not reach statistical significance there (P=0.38), resulting in an OR of the total group of 1.7 (95% CI 1.0-3.1), P=0.07. In septic patients carrying the CT genotype, the ex vivo production of TNF-a by LPS-stimulated monocytes was attenuated (P=0.005), indicative of a more pronounced immunoparalytic state in these patients. Conclusions: Presence of the AMPD1 34C<T variant is associated with higher infection susceptibility to CAP, but not to VAP. More pronounced immunoparalysis in these patients mediated by the anti-inflammatory effects of adenosine may account for this observation. © 2015 by the Shock Society

SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin

Background: Despite (neo)adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EPD were assessed using logistic regression models. The datafile (Hurkmans_SumStat_LogReg_DMET_EarlyProgressiveDisaese_CovarMetasSexAge_GRCh37.txt) contains the results of this anaylsis. Conclusions: This study identified a novel locus in SLC7A8 to be associated with EPD in osteosarcoma

SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin

Background: Despite (neo) adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EDP were assessed using logistic regression models and associated variants (p < 0.05) were validated in independent cohorts of 146 (Spain and United Kingdom) and 28 patients (Australia). In the association analyses, EDP was significantly associated with an SLC7A8 locus and was independently validated (meta-analysis validation cohorts: OR 0.19 [0.06-0.55], p = 0.002). The functional relevance of the top hits was explored by immunohistochemistry staining and an in vitro transport models. SLC7A8 encodes for the L-type amino acid transporter 2 (LAT2). Transport assays in HEK293 cells overexpressing LAT2 showed that doxorubicin, but not cisplatin and methotrexate, is a substrate for LAT2 (p < 0.0001). Finally, SLC7A8 mRNA expression analysis and LAT2 immunohistochemistry of osteosarcoma tissue showed that the lack of LAT2 expression is a prognostic factor of poor prognosis and reduced overall survival in patients without metastases (p = 0.0099 and p = 0.14, resp.). Conclusion: This study identified a novel locus in SLC7A8 to be associated with EDP in osteosarcoma. Functional studies indicate LAT2-mediates uptake of doxorubicin, which could give new opportunities to personalize treatment of osteosarcoma patients.Personalised Therapeutic

Converging evidence does not support GIT1 as an ADHD risk gene

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N=19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N=225), and (3) the Brain Imaging Genetics cohort (BIG, N=1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences

SLC7A8 coding for LAT2 is associated with early disease progression in osteosarcoma and transports doxorubicin

Background: Despite (neo)adjuvant chemotherapy with cisplatin, doxorubicin and methotrexate, some patients with primary osteosarcoma progress during first-line systemic treatment and have a poor prognosis. In this study, we investigated whether patients with early disease progression (EDP), are characterized by a distinctive pharmacogenetic profile. Methods and Findings: Germline DNA from 287 Dutch high-grade osteosarcoma patients was genotyped using the DMET Plus array (containing 1,936 genetic markers in 231 drug metabolism and transporter genes). Associations between genetic variants and EPD were assessed using logistic regression models. The datafile (Hurkmans_SumStat_LogReg_DMET_EarlyProgressiveDisaese_CovarMetasSexAge_GRCh37.txt) contains the results of this anaylsis. Conclusions: This study identified a novel locus in SLC7A8 to be associated with EPD in osteosarcoma