GATM locus does not replicate in rhabdomyolysis study.
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ABSTRACT:
SUBMITTER: Floyd JS
PROVIDER: S-EPMC4230441 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
Publications
GATM locus does not replicate in rhabdomyolysis study.
Floyd James S JS Bis Joshua C JC Brody Jennifer A JA Heckbert Susan R SR Rice Kenneth K Psaty Bruce M BM
Nature 20140901 7518
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Project description:Statin-induced myopathy (SIM) is the most common reason for discontinuation of statin therapy. A polymorphism affecting the gene encoding glycine amidinotransferase (GATM rs9806699 G > A) was previously associated with reduced risk for SIM. Our objective was to replicate the GATM association in a large, multicenter SIM case-control study. Mild and severe SIM cases and age- and gender-matched controls were enrolled. Participants were genotyped, and associations were tested (n = 715) using chi-square and logistic regression with consideration for SIM severity and exclusion of subjects with potentially confounding comedications. The minor allele (A) frequencies of GATM rs9806699 in the controls (n = 106), mild SIM (n = 324), and severe SIM (n = 285) cases were 0.26, 0.28, and 0.29, respectively (p = 0.447). The unadjusted odds ratio for the A allele for any SIM (mild or severe) was 1.14 (0.82-1.61; p = 0.437), which remained nonsignificant in all models. Our results do not replicate the association between GATM rs9806699 and SIM.
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Project description:Reliability of Sequencing in determine drug resistance in M.tuberculosis
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Project description:The ten most statistically significant estimated glomerular filtration rate (eGFRcrea)-associated loci from genome-wide association studies (GWAs) are tested for associations with chronic kidney disease (CKD) in 208 patients, including dialysis-independent CKD and dialysis-dependent end-stage renal disease (kidney failure). The allele A of intergenic SNP rs2453533 (near GATM) is more frequent in dialysis-independent CKD patients (n = 135, adjusted p = 0.020) but not dialysis-dependent kidney failure patients (n = 73) compared to healthy controls (n = 309). The allele C of intronic SNP rs4293393 (UMOD) is more frequent in healthy controls (adjusted p = 0.042) than in CKD patients. The Allele T of intronic SNP rs9895661 (BCAS3) is associated with decreased eGFRcys (adjusted p = 0.001) and eGFRcrea (adjusted p = 0.017). Our results provide further evidence of a genetic difference between dialysis-dialysis-independent CKD and dialysis-dependent kidney failure, and add the GATM gene locus to the list of loci associated only with dialysis-independent CKD. GATM risk allele carriers in the dialysis-independent group may have a genetic susceptibility to higher creatinine production rather than increased serum creatinine due to kidney malfunction, and therefore, do not progress to dialysis-dependent kidney failure. When using eGFRcrea for CKD diagnosis, physicians might benefit from information about creatinine-increasing loci.
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Project description:Background and purposeSignificant advancements in therapeutic approaches are imperative to address the prevalent impact of myocardial infarction (MI) on morbidity and mortality rates worldwide. This study explores the therapeutic potential of GATM/Gel hydrogel, focusing on its ability to enhance cardiac repair and functionality after MI through modulation of inflammatory and repair pathways.Experimental approachThe effects of GATM/Gel hydrogel on cardiac recovery were studied in a murine MI model. HA-CHO and gelatin solutions were mixed in situ using a dual syringe with a static mixing needle, and the resulting hydrogel was applied directly to the epicardium during MI modeling, followed by repositioning of the heart and closure of the thorax. Comprehensive in vivo assessments-including echocardiography, electrocardiography, and histopathological analysis-were combined with molecular techniques such as RT-qPCR, Western blotting, and immunofluorescence to elucidate the underlying mechanisms. Key cellular and molecular changes were tracked, focusing on macrophage polarization, angiogenesis, and modulation of the TNF/TNFR2 signaling pathway.Key resultsEmploying the GATM/Gel hydrogel led to a substantial improvement in heart function, shown through enhanced ejection fraction and fractional shortening, and reduced infarction size compared to control groups. Mechanistically, the hydrogel promoted the polarization of anti-inflammatory M2 macrophages and stimulated angiogenesis. Moreover, treatment with GATM/Gel hydrogel altered the TNF/TNFR2 pathway, pivotal in mediating inflammatory responses and facilitating myocardial repair. The discoveries highlight the possibility of GATM/Gel hydrogels as an innovative remedy for MI, providing a twofold role in regulating inflammation and fostering recovery.
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Project description:Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (?11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).
| S-EPMC3286794 | biostudies-literature
Project description:Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.
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Project description:To increase our understanding of imprinting and epigenetic gene regulation, we undertook a search for new imprinted genes. We identified Gatm, a gene that encodes l-arginine:glycine amidinotransferase, which catalyzes the rate-limiting step in the synthesis of creatine. In mouse, Gatm is expressed during development and is imprinted in the placenta and yolk sac, but not in embryonic tissues. The Gatm gene maps to mouse chromosome 2 in a region not previously shown to contain imprinted genes. To determine whether Gatm is located in a cluster of imprinted genes, we investigated the expression pattern of genes located near Gatm: Duox1-2, Slc28a2, Slc30a4 and a transcript corresponding to LOC214616. We found no evidence that any of these genes is imprinted in placenta. We show that a CpG island associated with Gatm is unmethylated, as is a large CpG island associated with a neighboring gene. This genomic screen for novel imprinted genes has elucidated a new connection between imprinting and creatine metabolism during embryonic development in mammals.
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Project description: Not available
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Project description:Rhabdomyolysis (RM) is a clinical emergency characterized by fulminant skeletal muscle damage and release of intracellular muscle components into the blood stream leading to myoglobinuria and, in severe cases, acute renal failure. Apart from trauma, a wide range of causes have been reported including drug abuse and infections. Underlying genetic disorders are also a cause of RM and can often pose a diagnostic challenge, considering their marked heterogeneity and comparative rarity.In this paper we review the range of rare genetic defects known to be associated with RM. Each gene has been reviewed for the following: clinical phenotype, typical triggers for RM and recommended diagnostic approach. The purpose of this review is to highlight the most important features associated with specific genetic defects in order to aid the diagnosis of patients presenting with hereditary causes of recurrent RM.
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