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Human FcgammaRIIB gene polymorphisms for assessing development of systemic lupus erythematosus and compositions for use thereof

a technology of fcgammariib and fcgammariib, which is applied in the field of genetic polymorphisms and polymorphism patterns useful, can solve the problems of difficult diagnosis of lupus, no single laboratory test that can definitively detect lupus, and serious and life-threatening problems

Inactive Publication Date: 2006-05-11
NEW YORK SOC FOR THE RUPTURED & CRIPPLED MAINTAINING THE HOSPITAL FOR SPECIAL SURGERY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides methods for assessing if an individual has a genetic predisposition to systemic lupus erytheimatosus (SLE) by comparing a test polymorphic pattern with a reference pattern in a gene encoding the FcγRIIB receptor. The test pattern matches the reference pattern, there is a statistically significant probability that the individual has or may develop SLE. The invention also provides isolated nucleic acid sequences, libraries, nucleic acid probes, peptides, and polymorphic-specific antibodies that can be used for the determination of polymorphic patterns in an individual's genes. Kits for detecting polymorphic sequences are also provided.

Problems solved by technology

SLE may be a mild disease, however, may also be serious and life-threatening.
However, there may be stages of the disease when few symptoms are evident, and patients with SLE may not necessarily exhibit identical symptoms.
Therefore, lupus is difficult to diagnose.
To date there is no single laboratory test that can definitively detect lupus.
The immunofluorescent antinuclear antibody (ANA) test is more specific for SLE, however, positive results are inconclusive because they may be indicative of other diseases.

Method used

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  • Human FcgammaRIIB gene polymorphisms for assessing development of systemic lupus erythematosus and compositions for use thereof

Examples

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example 1

Identification of Polymorphic positions in Human Genes Encoding FcγRIIB Associated with SLE

A. Identification of Polymorphic Positions

[0120] The following studies were performed to identify polymorphic residues within the genes encoding human FcγRIIB.

[0121] A 536 bp region of the 5′ untranslated region (5′ UTR) (SEQ ID NO: 1) of the human FcγRIIB gene in over 300 donors was sequenced.

[0122] Genotyping by polymerase chain reaction (PCR) followed by dye primer sequence analysis was performed. The FcγRIIB promoter was amplified using the following primers: forward primer 5′-ACATACCTCCTTGTCCTTGTT-3′ (SEQ ID NO: 2) and reverse primer 5′-CAGCCCAGTCACTCTCAGT-3′ (SEQ ID NO: 3) to produce amplicons of about 800 bp. The primers for forward dye primer sequencing had the M13 tag linked to the 5′ end of the forward primer 5′-TGT AAA ACG GCC AGT ACA TAC CTC CTT GTC CTT GTT 3′ (SEQ ID NO: 4); reverse primer 5′ GCA GTC AGC CCA GTC ACT CTC AGT (SEQ ID NO:5). Primers for reverse sequencing had M1...

example 2

Polymorphisms and Differential Promoter Activity of Human FcγRIIB

[0132] The biological activity of the FcγRIIB promoter allelic polymorphisms was studied in a reporter construct assay to determine whether the polymorphisms result in differential promoter activity.

[0133] Described regulatory elements of the FcγRIIB genes are located in the promoter region located upstream of the transcription initiation site. The regulation of gene transcription by gamma interferon (INF-g), a prototypic Th1 cytokine, is mediated by a promoter sequence 5′-TTCNNGGAA-3′ (SEQ ID NO: 8) with the potential to bind STAT1. Several STAT binding sites are present in the promoter of human FcγRIIB genes. A similar 9-bp consensus sequence 5′-TTCNNNGAA-3′ (SEQ ID NO:9) is a potential STAT 6 binding site, which is preferentially activated by IL-4, a TH2 cytokine. A glucocorticoid response element (GRE) required for binding of the glucocorticoid receptor DNA-binding domain is present in the promoter of FcγRIIB gen...

example 3

Polymorphisms in the Promoter of FcγRIIB and Relative Expression and Function of FcγRIIB in Primary Monocytes and B Cells

[0139] Studies were performed to determine whether there was a correlation between specific promoter alleles and levels of FcγRIIB expression in peripheral blood monocytes and B cells.

Real Time PCR

[0140] Total RNA was extracted from monocytes, purified by CD14 positive selection, using TRIzol reagent (Life Technologies) and reverse transcribed with the SuperScript Preamplification System (Life Technologies), all according to manufacturer instructions. For FcγRIIB transcript expression, real time RT-PCR assay was used. The SYBR Green PCR Core Reagents kit (PE Biosystems) was used with the iQ Multi-Color Real Time PCR Detection System (Bio-Rad) to amplify FcγRIIB1, and FcγRIIB2 in samples of cDNA derived from monocytes. The real time PCR reaction consisted of 45 cycles of 94° C. for 20min. and 53° C. for 20 min. Primers pairs were designed specifically for FcγRI...

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Abstract

The present invention provides methods for predicting the likelihood of development of systemic lupus erythematosus (SLE) in an individual, which comprise determining the sequence at one or more polymorphic positions within the human genes encoding FcγRIIB. The invention also provides isolated nucleic acids encoding FcγRIIB polymorphisms, nucleic acid probes that hybridize to polymorphic positions and kits for the prediction of SLE status.

Description

RELATED APPLICATIONS [0001] The present application is a divisional application of U.S. application Ser. No. 10 / 085,484, filed on Feb. 26, 2002, the content of which is expressly incorporated herein by reference. [0002] The research described herein was funded in part by the following grants: National Institute of Health, NIAMS, R03 AR47106-01.FIELD OF THE INVENTION [0003] The present invention relates to genetic polymorphisms and polymorphism patterns useful for assessing development of systemic lupus erythematosus in humans. More particularly, the invention relates to identifying and using polymorphism patterns comprising a polymorphism in the human FcγIIB receptor to predict a treatment outcome or likelihood of developing systemic lupus erythematosus, and to assist in diagnosis and in prescription of an effective therapeutic regimen. BACKGROUND OF THE INVENTION Systemic Lupus Erythematosus [0004] Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that can affec...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68C07H21/04C12P21/06C07K16/18C12N5/06C07K14/725C12N15/12
CPCC12Q1/6883C12Q2600/156
Inventor PRICOP, LUMINITA
Owner NEW YORK SOC FOR THE RUPTURED & CRIPPLED MAINTAINING THE HOSPITAL FOR SPECIAL SURGERY
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