Gene expression profiling of peripheral blood in patients with abdominal aortic aneurysm.

OBJECT Abdominal aortic aneurysm (AAA) pathogenesis remains poorly understood. This study investigated the gene expression profile of peripheral blood from patients with AAA using microarray technology. METHODS AND RESULTS We determined gene expression profiles in pooled RNA from 10 AAA patients and 10 matched controls with arrays representing 14,000 transcripts. Microarray data for selected genes were confirmed by real-time PCR in two different AAA (n=36) and control (n=36) populations and integrated with biochemical data. We identified 91 genes which were differentially expressed in AAA patients. Gene Ontology analysis indicated a significant alteration of oxygen transport (increased hemoglobin gene expression) and lipid metabolism [including monoglyceride lipase and low density lipoprotein receptor-related protein 5 (LRP5) gene]. LRP5 expression was associated inversely with serum lipoprotein(a) [Lp(a)] concentration. CONCLUSIONS Increased expression of hemoglobin chain genes as well as of genes involved in erythrocyte mechanical stability were observed in the AAA RNA pools. The association between low levels of LRP5 gene expression and increased levels of Lp(a) in AAA patients suggests a potential role of LRP5 in Lp(a) catabolism. Our data underline the power of microarrays in identifying further molecular perturbations associated with AAA.

[1]  M. Thompson.  Infrarenal abdominal aortic aneurysms , 2003, Current treatment options in cardiovascular medicine.

[2]  Masato Nose,et al.  Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  B. Goswami,et al.  Atherosclerosis Pathophysiology and the Role of Novel Risk Factors: A Clinicobiochemical Perspective , 2007, Angiology.

[4]  Jun Ma,et al.  The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool. , 2006, The Journal of laboratory and clinical medicine.

[5]  D. Ardigò,et al.  Application of leukocyte transcriptomes to assess systemic consequences of risk factors for cardiovascular disease , 2007, Clinical chemistry and laboratory medicine.

[6]  Emily Dimmer,et al.  The Gene Ontology Annotation (GOA) Database: sharing knowledge in Uniprot with Gene Ontology , 2004, Nucleic Acids Res..

[7]  Gerard Tromp,et al.  Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms , 2007, BMC Genomics.

[8]  T. Sundt,et al.  Altered patterns of gene expression distinguishing ascending aortic aneurysms from abdominal aortic aneurysms: complementary DNA expression profiling in the molecular characterization of aortic disease. , 2003, The Journal of thoracic and cardiovascular surgery.

[9]  B. Giusti,et al.  The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis. , 2005, Arthritis and rheumatism.

[10]  A. Gottsäter,et al.  Factors associated with development of large abdominal aortic aneurysm in middle-aged men. , 2005, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[11]  B. Giusti,et al.  High levels of homocysteine, lipoprotein (a) and plasminogen activator inhibitor-1 are present in patients with abdominal aortic aneurysm , 2005, Thrombosis and Haemostasis.

[12]  H. Armenian,et al.  Risk factors for abdominal aortic aneurysm: results of a case-control study. , 2000, American journal of epidemiology.

[13]  M. Bown,et al.  The genetic basis of abdominal aortic aneurysms: a review. , 2007, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[14]  M. Ono,et al.  Severe Hypercholesterolemia, Impaired Fat Tolerance, and Advanced Atherosclerosis in Mice Lacking Both Low Density Lipoprotein Receptor-related Protein 5 and Apolipoprotein E* , 2003, The Journal of Biological Chemistry.

[15]  H. Barnett,et al.  The inappropriate use of carotid endarterectomy , 2004, Canadian Medical Association Journal.

[16]  W. Van Hul,et al.  The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. , 2007, Endocrinology.

[17]  M. Egger,et al.  Risk factors for asymptomatic abdominal aortic aneurysm: systematic review and meta-analysis of population-based screening studies. , 2004, European journal of public health.

[18]  M. Gassmann,et al.  Hypoxic up-regulation of erythroid 5-aminolevulinate synthase. , 2003, Blood.

[19]  S. Dudoit,et al.  Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. , 2002, Nucleic acids research.

[20]  C. Liew,et al.  The peripheral-blood transcriptome: new insights into disease and risk assessment. , 2007, Trends in molecular medicine.

[21]  Emily Dimmer,et al.  The Gene Ontology Annotation (GOA) Database - An integrated resource of GO annotations to the UniProt Knowledgebase , 2003, Silico Biol..

[22]  David C. Han,et al.  Differential gene expression in human abdominal aorta: aneurysmal versus occlusive disease. , 2002, Journal of vascular surgery.

[23]  Gary R Johnson,et al.  Rupture rate of large abdominal aortic aneurysms in patients refusing or unfit for elective repair. , 2002, JAMA.

[24]  J. Cole,et al.  Plasma lipoprotein(a) indicates risk for 4 distinct forms of vascular disease. , 2007, Clinical chemistry.

[25]  B. Giusti,et al.  A model of anti-angiogenesis: differential transcriptosome profiling of microvascular endothelial cells from diffuse systemic sclerosis patients , 2006, Arthritis research & therapy.

[26]  H. Meldrum,et al.  Appropriate Use of Carotid Endarterectomy , 2000, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[27]  S. Kalantarian,et al.  Lipoprotein(a) and venous thromboembolism in adults: a meta-analysis. , 2008, The American journal of medicine.

[28]  M. Björck,et al.  Risk factors associated with abdominal aortic aneurysm: a population-based study with historical and current data. , 2005, Journal of vascular surgery.

[29]  Gene expression profiling of abdominal aortic aneurysms. , 2002, Journal of vascular surgery.

[30]  L. Hofbauer,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.

[31]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Richard P Lifton,et al.  High bone density due to a mutation in LDL-receptor-related protein 5. , 2002, The New England journal of medicine.