Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that vascular risk factors contribute to the pathology of Alzheimer's disease. Increased concentrations of circulating homocysteine are associated with vascular risk factors and Alzheimer's disease but the mechanisms involved are unclear. Homocysteine inhibits the hydrolysis of S-adenosylhomocysteine (SAH) which is a product inhibitor of S-adenosylmethionine (SAM) dependent methyltransferase reactions. It has been shown previously that SAH inhibits phosphatidylethanolamine N-methyltransferase (PEMT) in the liver. The activity of PEMT in the liver plays an important role in the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) and the delivery of essential polyunsaturated fatty acids (PUFAs) to peripheral tissues. In the present study, the plasma concentrations of SAH, SAM and homocysteine and the erythrocyte composition of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and their respective polyunsaturated fatty acid concentrations were determined in 26 patients with Alzheimer's disease and compared to those in 29 healthy control subjects. There was a significant increase in the plasma concentrations of SAH (p<0.001) and homocysteine (p<0.001) and a significant increase in the plasma concentrations of SAM (p<0.001) in the Alzheimer's patients. A significant positive correlation was found between the plasma concentrations of SAH and homocysteine (r=0.738, p<0.001). There was a negative correlation between the plasma concentrations of homocysteine and the ratio of SAM/SAH (r=-0.637, p<0.01). There was a significant decrease in the erythrocyte content of PC (p<0.001) and an increase in the erythrocyte content of PE (p<0.001) in the Alzheimer's patients. Plasma SAH concentrations were negatively related to erythrocyte PC concentrations (r=-0.286, p<0.01) and positively related to erythrocyte PE concentrations (r=0.429, p<0.001). The erythrocyte PC from Alzheimer's patients had a significant depletion of docosahexaenoic acid (DHA) (p<0.001) while there was no significant difference in the DHA content of erythrocyte PE. There was a significant negative correlation between plasma SAH and the DHA composition of erythrocyte PC (r=-0.271, p<0.001). This data may reflect the inhibition of hepatic PEMT activity by SAH in Alzheimer's disease. The decreased mobilization of DHA from the liver into plasma and peripheral tissues may increases the risk of atherosclerosis and stroke leading to chronic cerebral hypoperfusion. The evidence suggests that a metabolic link between the increased production of SAH and phospholipid metabolism may contribute to cerebrovascular and neurodegenerative changes in Alzheimer's disease.
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PMID:A metabolic link between S-adenosylhomocysteine and polyunsaturated fatty acid metabolism in Alzheimer's disease. 1699 49

Genome-wide association studies have identified putative ischemic stroke risk genes, yet, their expression after stroke is unexplored in spite of growing interest in elucidating their specific role and identifying candidate genes for stroke treatment. Thus, we took an exploratory approach to investigate sexual dimorphism, alternative splicing, and etiology in putative risk gene expression in blood following cardioembolic, atherosclerotic large vessel disease and small vessel disease/lacunar causes of ischemic stroke in each sex compared to controls. Whole transcriptome arrays assessed 71 putative stroke/vascular risk factor genes for blood RNA expression at gene-, exon-, and alternative splicing-levels. Male (n = 122) and female (n = 123) stroke and control volunteers from three university medical centers were matched for race, age, vascular risk factors, and blood draw time since stroke onset. Exclusion criteria included: previous stroke, drug abuse, subarachnoid or intracerebral hemorrhage, hemorrhagic transformation, infection, dialysis, cancer, hematological abnormalities, thrombolytics, anticoagulants or immunosuppressants. Significant differential gene expression (fold change > |1.2|, p < 0.05, partial correlation > |0.4|) and alternative splicing (false discovery rate p < 0.3) were assessed. At gene level, few were differentially expressed: ALDH2, ALOX5AP, F13A1, and IMPA2 (males, all stroke); ITGB3 (females, cardioembolic); ADD1 (males, atherosclerotic); F13A1, IMPA2 (males, lacunar); and WNK1 (females, lacunar). GP1BA and ITGA2B were alternatively spliced in both sexes (all patients vs. controls). Six genes in males, five in females, were alternatively spliced in all stroke compared to controls. Alternative splicing and exon-level analyses associated many genes with specific etiology in either sex. Of 71 genes, 70 had differential exon-level expression in stroke patients compared to control subjects. Among stroke patients, 24 genes represented by differentially expressed exons were male-specific, six were common between sexes, and two were female-specific. In lacunar stroke, expression of 19 differentially expressed exons representing six genes (ADD1, NINJ2, PCSK9, PEMT, SMARCA4, WNK1) decreased in males and increased in females. Results demonstrate alternative splicing and sexually dimorphic expression of most putative risk genes in stroke patients' blood. Since expression was also often cause-specific, sex, and etiology are factors to consider in stroke treatment trials and genetic association studies as society trends toward more personalized medicine.
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PMID:Alternative Splicing of Putative Stroke/Vascular Risk Factor Genes Expressed in Blood Following Ischemic Stroke Is Sexually Dimorphic and Cause-Specific. 3319 47