Cedars-sinai Medical Center

University of California

The UAB Research Foundation (The University of Alabama at Birmingham)

Kent D Taylor

Jerome I Rotter

Stephan R Targan

Huiying Yang

Marla C Dubinsky

Ling Mei

Willa A Hsueh

Leslie J Raffel

Dermot McGovern

Dermot P Mcgovern

Xiuqing Guo

Carol J Landers

Mark O Goodarzi

Phillip R Fleshner

Maren Theresa Scheuner

Charles O Elson

Yii-Der Ida Chen

Maria T Abreu

Huiyang Yang

Talin Haritunians

Maren Scheuner

Kazuhito Sugimura

This invention provides methods of diagnosis, predicting and diagnosing susceptibility to, predicting disease progression and treatment of inflammatory bowel disease (IBD), including Crohn's disease and/or subtypes of Crohn's disease (CD) and/or Ulcerative Colitis (UC). In one embodiment, a method of the invention is practiced by determining the presence or absence of the genetic variants NOD2, TLR8, TLR2, CARD8, CARD15 and/or JAK3 to diagnose, predict and diagnose susceptibility and predict disease progression in an individual. In another embodiment, a method of the invention is practiced by determining the presence or absence of anti-Cbir1, anti-OmpC, ASCA, anti-I2 and/or pANCA in an individual. In another embodiment, the invention further associates the presence or absence of the risk variants with the expression of anti-Cbir1, anti-OmpC, ASCA, anti-I2 and/or pANCA for the diagnosis, prediction of susceptibility, prediction of disease progression and/or treatment of IBD, including CD and/or UC.

Diagnosis and treatment of inflammatory bowel disease

The present invention relates to methods of prognosing responsiveness to anti-TNFα therapy by determining the presence or absence of risk factors in the individual. In one embodiment, the risk factors are genetic markers, serological markers and/or clinical phenotypes associated with non-responsiveness to treatment with anti-TNFα therapy in an individual diagnosed with IBD.

Methods of determining responsiveness to anti-TNFα therapy in inflammatory bowel disease

The present invention relates to methods of prognosing responsiveness to anti-TNF&#x3b1; therapy by determining the presence or absence of risk factors in the individual. In one embodiment, the risk factors are genetic markers, serological markers and/or clinical phenotypes associated with non-responsiveness to treatment with anti-TNF&#x3b1; therapy in an individual diagnosed with IBD.

Methods of determining responsiveness to anti-TNF&#x3b1; therapy in inflammatory bowel disease

Methods of using genetic variants for the diagnosis and treatment of inflammatory bowel disease

Disclosed are methods of predicting the development of medically refractory ulcerative colitis (MR-UC) in a patient In one embodiment, disclosed is a method of prognosing ulcerative colitis in an individual by determining the presence or absence of one or more risk variants, where the presence of one or more risk variants is indicative of a severe and/or aggressive form of ulcerative colitis. In another embodiment, the severe form of ulcerative colitis is indicative of MR-UC.

Methods of predicting medically refractive ulcerative colitis (MR-UC) requiring colectomy

In one embodiment, the invention provides methods of identifying genes and genetic variants that, either alone or in combination, are important to the pathogenesis of a disease. In another embodiment, the disease is stratified by use of an immune response to disease-associated antigens. In another embodiment, the invention provides methods of identifying pathways that, either alone or in combination, are important to the pathogenesis of a disease. In another embodiment, the invention provides a method of diagnosing or predicting susceptibility to a disease in an individual by determining the presence or absence of genes and genetic variants that, either alone or in combination, are important to the pathogenesis of the disease.

Methods of identifying the genetic basis of a disease by a combinatorial genomics approach, biological pathway approach, and sequential approach

Disclosed is a method for determining haplotypes useful for large-scale genetic analysis, within a genomic reference sequence of interest, for a human subpopulation. The method can applied to statistically evaluating the genotypes of subjects for any statistically significant association with a phenotype of interest, such as insulin resistance or coronary artery disease. Thus, also disclosed are a method of detecting a genetic predisposition in a human subject for certain biological conditions, which may be related to coronary artery disease.

Method of haplotype-based genetic analysis for determining risk for developing insulin resistance, coronary artery disease and other phenotypes

This invention provides methods of diagnosing or predicting susceptibility to Crohn's Disease by determining the presence or absence of genetic variants. In one embodiment, the present invention provides methods to diagnose and/or predict susceptibility to Crohn's Disease in an individual by determining the presence or absence of anti-Cbir1 reactivity and the presence or absence of TLR5 risk variants. In another embodiment, the present invention provides methods to diagnose Crohn's Disease by determining the presence or absence of NFKB1 haplotype H3 and/or ASCA expression. In another embodiment, the present invention provides methods of diagnosing Crohn's Disease by determining the presence or absence of Cbir1 specific peripheral blood T cell proliferation.

Characterization of the CBir1 antigenic response for diagnosis and treatment of Crohn's disease

The present invention provides a method of diagnosing or predicting susceptibility to a clinical subtype of Crohn's disease characterized by fibrostenosing disease by determining the presence or absence in an individual of a fibrostenosis-predisposing allele linked to a NOD2/CARD15 locus, where the presence of the fibrostenosis-predisposing allele is diagnostic of or predictive of susceptibility to the clinical subtype of Crohn's disease characterized by fibrostenosing disease. In a method of the invention, the clinical subtype of Crohn's disease can be, for example, characterized by fibrostenosing disease independent of small bowel involvement. The invention also provides a method of optimizing therapy in an individual by determining the presence or absence in the individual of a fibrostenosis-predisposing allele linked to a NOD2/CARD15 locus, diagnosing individuals in which the fibrostenosis-predisposing allele is present as having a fibrostenosing subtype of Crohn's disease, and treating the individual having a fibrostenosing subtype of Crohn's disease based on the diagnosis.

Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease

The present invention provides a method of diagnosing or predicting susceptibility to an autoimmune disease in an individual by determining the presence or absence in the individual of a 2-2-4 haplotype at the Notch4, HSP70-HOM and D6S273 loci, where the presence of the haplotype diagnoses or predicts susceptibility to the autoimmune disease. The methods of the invention can be particularly useful for diagnosing or predicting susceptibility to Crohn's disease, rheumatoid arthritis or type I diabetes mellitus. In a preferred embodiment, a method of the invention is used to diagnose or predict susceptibility to Crohn's disease in an individual of Ashkenazi Jewish ethnicity.

Methods of using a major histocompatibility complex class III haplotype to diagnose Crohn's disease

Disclosed is a method for determining haplotypes useful for large-scale genetic analysis, within a genomic reference sequence of interest, for a human subpopulation. The method can applied to statistically evaluating the genotypes of subjects for any statistically significant association with a phenotype of interest, such as insulin resistance or coronary artery disease. Thus, also disclosed are a method of detecting a genetic predisposition in a Mexican-American human subject for developing insulin resistance and methods of detecting a lower than normal risk in a Mexican-American human subject for developing insulin resistance or coronary artery disease.

Method of haplotype-based genetic analysis for determining risk for developing insulin resistance and coronary artery disease

The present invention provides a method of determining a risk of pouchitis development following a surgical procedure where an internal pouch is created in a patient with ulcerative colitis. The method is practiced by determining in the patient the presence or absence of a pouchitis-associated allele linked to an interferon &ggr; receptor locus, where the presence of the pouchitis-associated allele indicates an increased risk of pouchitis development. The interferon &ggr; receptor locus to which the pouchitis-associated allele is linked can be, for example, an interferon &ggr; receptor 1 gene. A pouchitis-associated allele useful in the invention can be, for example, an allele located within the sixth intron of the interferon &ggr; receptor 1 gene, such as a FA1 microsatellite 171 allele.

Genetic testing for determining the risk of pouchitis development

In a method for detecting a genetic predisposition in a human for non-responsiveness to statin drug treatment for coronary artery disease, nucleic acids comprising nucleotide sequences of the human lipoprotein lipase (LPL) gene are amplified and analyzed. Homozygosity for a variant allele in a non-coding or untranslated region of the 3&prime; end of LPL, for example, LPL HindIII 2/2 or (TTTA),4/4 genotypes, is linked to non-responsiveness to treatment with statin drugs, including lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, or cerivastatin. Oligonucleotide primer sequences, primer sets, and genetic testing kits allow the practitioner to practice the method and thus better individualize the treatment and improve the care of patients with coronary artery disease.

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Ventura, CA, United States of America

Kent D Taylor