Genetic polymorphisms associated with rheumatoid arthritis, methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with rheumatoid arthritis. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

Description

FIELD OF THE INVENTION[0001]The present invention is in the field of diagnosis and therapy of autoimmune diseases. In particular, the present invention relates to specific single nucleotide polymorphisms (SNPs) in the human genome, and their association with rheumatoid arthritis and related pathologies such as other autoimmune diseases. Based on differences in allele frequencies in the rheumatoid arthritis patient population relative to normal individuals, the naturally-occurring SNPs disclosed herein can be used as targets for the design of diagnostic reagents and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the SNPs of the present invention are useful for identifying an individual who is at an increased or decreased risk of developing rheumatoid arthritis and for early detection of the disease, for providing clinically important information for the prevention and / or treatment of rheumatoid arthritis, and for screeni...

AI Technical Summary

Benefits of technology

The present invention provides novel SNPs, unique combinations of these SNPs, and haplotypes associated with rheumatoid arthritis and related pathologies. These SNPs can be used as targets for the development of diagnostic reagents and therapeutic agents for the diagnosis and treatment of rheumatoid arthritis and related autoimmune diseases. The invention also provides methods for detecting these SNPs and identifying individuals with an increased or decreased risk of developing rheumatoid arthritis or responding to treatment. The invention also includes gene information, transcript sequences, encoded amino acid sequences, genomic sequences, and detection reagents for these SNPs.

Problems solved by technology

These cells produce cytokines and degradative enzymes, which mediate inflammation and destruction of the joint architecture, often leading to permanent disability.

Although the course of RA is highly variable, most patients with clinical, persistent RA eventually develop debilitating joint damage and deformation, resulting in progressive functional limitation.

Unfortunately, classifying an arthritic disorder such as RA is challenging because no etiological agent has been identified and no clinical or laboratory features uniquely define the disease (Sangha, 2000, Rheumatology 39 (suppl.

However, these criteria are largely ineffective for patients during early stages of the disease, such as during the first 12 weeks of disease (Green et al., 1999, Arthritis Rheum.

42: 2184-2188), during which time irreversible joint damage has already begun, and cannot predict which patients will develop severe erosive disease and therefore benefit from aggressive early disease modifying therapy.

Additionally, the effects of a variant form may be both beneficial and detrimental, depending on the circumstances.

For example, a heterozygous sickle cell mutation confers resistance to malaria, but a homozygous sickle cell mutation is usually lethal.

A nonsense mutation results in a type of non-synonymous codon change in which a stop codon is formed, thereby leading to premature termination of a polypeptide chain and a truncated protein.

Furthermore, in the case of nonsense mutations, a SNP may lead to premature termination of a polypeptide product.

Such variant products can result in a pathological condition, e.g., genetic disease.

Clinical trials have shown that patient response to treatment with pharmaceuticals is often heterogeneous.

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