Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-11-24
2001-06-19
Arthur, Lisa B. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S023100
Reexamination Certificate
active
06248533
ABSTRACT:
TECHNICAL FIELD
The present invention relates t o genetic diagnosis, and in particular, to genetic diagnosis of diseases wherein tumor necrosis factor-&agr; (hereinafter referred to as TNF-&agr;) participates.
BACKGROUND ART
TNF-&agr; is a protein which is produced from certain cells, including, for example, T cells, macrophages, and natural killer cells, by induction with prophlogistic agents such as bacteria, viruses, various mitogens or the like, and has the biological activities as described below:
1) a factor inducing hemorrhagic necrosis in tumors (in vivo),
2) induction of apoptosis in cancer cells (in vitro),
3) production of prostaglandins and collagenase,
4) expression of adhesion molecules (ICAM-1, ELAM-1),
5) expression of HLA class II,
6) production of inflammatory cytokines (IL-1, IL-6),
7) production of chemokines (IL-8, RANTES), and
8) enhancement of absorption of bone and cartilage.
TNF-&agr; is believed to be an important agent that is located at most upstream in pathogenetic cytokine cascades of various inflammatory diseases.
Individual differences in amount of production of TNF-&agr; have been previously pointed out. In addition, TNF-&agr; is an important cytokine that is involved in vascular disorders. In the acute phase of Kawasaki disease, TNF-&agr; exhibits an abnormally high level in serum, and it is said that the amount of production of TNF-&agr; is enhanced in peripheral blood monocytes in this phase. These facts suggest that TNF-&agr; plays an important role in onset of Kawasaki diseases of which major lesion is systemic vascular disorders (M. Sakaguchi, H. Kato, A. Nishiyori, K. Sagawa and K. Itho,
Production of tumor necrosis factor
-
alpha by V&bgr;
2−
or V&bgr;
8
−
CD
4
+
T cells in Kawasaki disease
in “Kawasaki disease” (H. Kato, Ed.), pp. 206-213, Elsevier, Amsterdam (1995)). It is thus expected that increased amount of TNF-&agr; production based on genetic factors may be involved in onset and severity of Kawasaki disease.
Similarly, production of TNF-&agr; is also enhanced in rheumatism (M. Sebbag, S. L. Parry, F. M. Brennan and M. Feldmann, “Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: possible relevance to pathophysiology of rheumatoid arthritis”,
Eur. J. Immunol.
27:624-632 (1997)).
On the contrary, the capacity to produce TNF is said to be low in SLE nephropathy (C. 0. Jacob, Z. Fronek, G. D. Lewis, M. Koo, J. A. Hansen and H. 0. McDevitt, “Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor c: Relevance to genetic predisposition to systemic lupus erythematosusf
Proc. Natl. Acad. Si. USA,
87:1233-1237 (1990)).
DISCLOSURE OF THE INVENTION
It is thus expected that onset and severity of certain diseases may be related to the capacity of the individual to produce TNF-&agr;.
Therefore, if one can objectively measure the capacity of a given individual to produce TNF-&agr; based on genetic factors, prior diagnosis (liability to a disease, severity upon onset of the disease, reactivity to treatments) or de termination of prognosis of diseases wherein TNF-&agr; participates can be conducted.
To attain such an object, the present inventors extensively studied. In result, the present inventors have found that there exists genetic polymorphisms of nucleotide changes in the 5′-flanking (promoter) region of TNF-&agr; gene, and that said nucleotide changes result in remarkable change in the capacity to produce TNF-&agr;. The present invention has been completed on the basis of these findings.
Accordingly, the gist of the present invention is a method for screening genetic polymorphisms for determination of diseases wherein TNF-&agr; participates, said method comprising detecting the presence or absence of one or more changes selected from the following nucleotide changes within the 5′-flanking region of TNF-&agr; gene:
1) a change from cytosine (C) to thymine (T) at position −857 (position 373 in SEQ ID NO: 9),
2) a change from cytosine (C) to adenine (A) at position −863 (position 367 in SEQ ID NO: 9),
3) a change from thymine (T) to cytosine (C) at position −1031 (position 199 in SEQ ID NO: 9), and
4) respective changes corresponding thereto in the complementary strand.
In this specification, “diseases wherein TNF-A participates” means diseases wherein onset or severity of the diseases and their reactivities to treatments are affected by the amount of production of TNF-&agr;. Included in such diseases are, for example, juvenile rheumatoid arthritis, rheumatoid arthritis, SLE naphropathy and Kawasaki disease, as well as insulin-dependent and noninsulin-dependent diabetes mellitus, and leptin-related diseases such as obesity (DIABETES, vol. 46, pp. 1468-1472 (1997)). Diseases wherein TNF-(participates also include those diseases that are related to HLA 4 or 9, for example, rheumatoid arthritis, pemphigus vulgaris, diabetes mellitus, Harada's disease, Crohn's disease, and the like.
REFERENCES:
Kamizono et al “Susceptible locus for obese type II diabetes mellitus in the 5′ flanking region of the tumor necrosis factor-alpha-gene” Tissue Antigens, vol. 55, p. 449-452, May 2000.*
Seki et al “Polymorphisms in the 5′-flanking region of tumor necrosis factor-alpha-gene in patients with rheumatoid arthritis” Tissue Antigens, vol. 54, p. 194-197, Aug. 1999.*
Higuchi et al “Polymorhpism of the 5′ flanking region of the human tumor necrosis factor (TNF)-alpha-gene in Japanese” Tissue Antigens, vol. 51, pp. 605-612, Jun. 1998.*
Deng et al “No primary association between the 308 polymorphism in the tumor necrosis factor alpha promoter region and IDDM” Human Immunology, vol. 45, p. 137-142, Feb. 1996.*
Huizinga et al “Disease susceptibility related to the -238 TNF alpha G to A promoter polymorphism” European Cytokine Network, vol. 7, No. 2, pp. 259, 1996.*
Shogo Takashiba et al., “Cloning and characterization of human TNF&agr; promoter region.”, Gene, vol. 131, pp. 307-308, 1993.
J. Vinasco et al., “Polymorphism at the TNF loci in rheumatoid arthritis.”, Tissue Antigens, vol. 49, pp. 74-78, 1997.
C.P. Day et al., “Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance.”, Diabetologia, vol. 41, pp. 430-434, 1998.
H. Rothe et al., “Abnormal TNF production in prediabetic BB rats is linked to defective CD45R exxpression.”, Immunology, vol. 77, pp. 1-6, 1992.
Takafumi Higuti et al., “Relationship between polymorphism of TNF-alpha gene promoter region and ability to produce TNF-alpha .”, Presentation, Japan Immunology Society, Pacifico Yokohama Meeting Center, Nov. 27, 1996, 19 pages, Certification, 2 pages.
Higuchi Takafumi
Itoh Kyogo
Kamizono Shintaro
Kato Hirohisa
Seki Naoko
Arthur Lisa B.
Foley & Lardner
Goldberg Jeanine
Shionogi & Co. Ltd.
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