Identification of molecular biomarkers for multiple sclerosis.

Multiple sclerosis is a demyelinating disease of the central nervous system with a presumed autoimmune etiology. Previous microarray analyses identified conserved gene expression signatures in peripheral blood mononuclear cells of patients with autoimmune diseases. We used quantitative real-time polymerase chain reaction analysis to identify a minimum number of genes of which transcript levels discriminated multiple sclerosis patients from patients with other chronic diseases and from controls. We used a computer program to search quantitative transcript levels to identify optimum ratios that distinguished among the different categories. A combination of a 4-ratio equation using expression levels of five genes segregated the multiple sclerosis cohort (n=55) from the control cohort (n=49) with a sensitivity of 91% and specificity of 98%. When autoimmune and other chronic disease groups were included (n=78), this discriminator still performed with a sensitivity of 79% and a specificity of 87%. This approach may have diagnostic utility not only for multiple sclerosis but also for other clinically complex autoimmune diseases.

[1]  Javed Khan,et al.  Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. , 2003, Human molecular genetics.

[2]  K. Maas,et al.  Defective ATM‐p53–mediated apoptotic pathway in multiple sclerosis , 2005, Annals of neurology.

[3]  M. Crow,et al.  Microarray Analysis of Interferon-regulated Genes in SLE , 2003, Autoimmunity.

[4]  J. Todd,et al.  A Protective Role of the Environment in the Development of Type 1 Diabetes? , 1991, Diabetic medicine : a journal of the British Diabetic Association.

[5]  N. Olsen,et al.  Reduced p53 in peripheral blood mononuclear cells from patients with rheumatoid arthritis is associated with loss of radiation-induced apoptosis. , 2005, Arthritis and rheumatism.

[6]  T. Aune,et al.  Identification of gene expression signatures in autoimmune disease without the influence of familial resemblance. , 2006, Human molecular genetics.

[7]  John A Todd,et al.  Genetic Analysis of Autoimmune Disease , 1996, Cell.

[8]  T. Beaty,et al.  Evidence that autoimmunity in man is a Mendelian dominant trait. , 1986, American journal of human genetics.

[9]  M. Alarcón‐Riquelme,et al.  The genetic basis of systemic lupus erythematosus--knowledge of today and thoughts for tomorrow. , 2004, Human molecular genetics.

[10]  Jorge R. Oksenberg,et al.  Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis , 2002, Nature Medicine.

[11]  Ec Beachler.  Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus , 2003 .

[12]  J. Saver,et al.  A Quantitative Study , 2005 .

[13]  A S Rigby,et al.  Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. , 2000, Arthritis and rheumatism.

[14]  J. Trent,et al.  Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  C I Amos,et al.  A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. , 2001, American journal of human genetics.

[16]  T. Mack,et al.  A revised estimate of twin concordance in systemic lupus erythematosus. , 1992, Arthritis and rheumatism.

[17]  E. Wakeland,et al.  The genetics of complex autoimmune diseases: non-MHC susceptibility genes , 2001, Nature Immunology.

[18]  F. Barkhof,et al.  The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis , 1999, Neurology.

[19]  C. Bao,et al.  Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray , 2003, Genes and Immunity.

[20]  A. Compston,et al.  Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis , 2001, Annals of neurology.

[21]  P M Matthews,et al.  Role of magnetic resonance imaging within diagnostic criteria for multiple sclerosis , 2004, Annals of neurology.

[22]  A. Theofilopoulos.  The basis of autoimmunity: Part II. Genetic predisposition. , 1995, Immunology today.

[23]  L. A. Stargell,et al.  Mapping and Functional Characterization of the TAF11 Interaction with TFIIA , 2005, Molecular and Cellular Biology.

[24]  I. Simon,et al.  Systematic analysis of essential yeast TAFs in genome‐wide transcription and preinitiation complex assembly , 2003, The EMBO journal.

[25]  N. Olsen,et al.  A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mononuclear cells , 2004, Annals of the rheumatic diseases.

[26]  Thomas M. Aune,et al.  Cutting Edge: Molecular Portrait of Human Autoimmune Disease1 , 2002, The Journal of Immunology.

[27]  Xin Lu,et al.  Live or let die: the cell's response to p53 , 2002, Nature Reviews Cancer.

[28]  Lawrence Js,et al.  A family survey of lupus erythematosus. 1. Heritability. , 1987 .

[29]  Virginia Pascual,et al.  Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus Blood , 2003, The Journal of experimental medicine.

[30]  C. Martins,et al.  A family survey of lupus erythematosus. 1. Heritability. , 1987, The Journal of rheumatology.

[31]  Yu Shyr,et al.  Shared gene expression profiles in individuals with autoimmune disease and unaffected first-degree relatives of individuals with autoimmune disease. , 2005, Human molecular genetics.

[32]  Philippa Marrack,et al.  Autoimmune disease: why and where it occurs , 2001, Nature Medicine.

[33]  Kaiyu Jiang,et al.  Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis , 2003, Arthritis research & therapy.

[34]  B E Kendall,et al.  The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions. A quantitative study. , 1987, Brain : a journal of neurology.

[35]  M. Crow,et al.  Microarray analysis of gene expression in lupus , 2003, Arthritis research & therapy.

[36]  P. Gregersen,et al.  Peripheral blood gene expression profiling in rheumatoid arthritis , 2005, Genes and Immunity.

[37]  G. Karypis,et al.  Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus , 2003, Proceedings of the National Academy of Sciences of the United States of America.