Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-09-15
2001-04-17
Zitomer, Stephanie W. (Department: 1655)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S024300, C536S024310, C435S006120, C435S320100
Reexamination Certificate
active
06218524
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to allelic polymorphisms in the gene encoding microsomal triglyceride transfer protein (MTP). The invention further relates to the determination of MTP allelic patterns in an individual (i) to evaluate the individual's predisposition to cardiovascular disease; and (ii) in individuals in need of treatment, to determine the most appropriate therapeutic regimen that will result in a positive treatment outcome.
BACKGROUND OF THE INVENTION
Elevated serum cholesterol, particularly in the form of low density lipoprotein (LDL)-cholesterol, is a principal risk factor for cardiovascular disease. The protein component of LDL, apolipoprotein B (ApoB), is secreted from the liver, and the relative efficiency of apoB secretion is an important determinant of the plasma level of LDL. Microsomal triglyceride transfer protein (MTP) plays an important role in apoB secretion. Accordingly, any phenomenon that alters MTP expression or activity may influence apoB secretion and thereby affect serum LDL-cholesterol levels.
MTP is a heterodimer comprising two subunits: (i) an MTP-specific 97 kDa polypeptide and (ii) the multifunctional 55 kDa protein disulfide isomerase (PDI) (Gordon et al.,
Trends Cell Biol.,
5:317-321, 1995). MTP function is absolutely required for assembly and secretion of apoB-containing lipoproteins. Non-apoB-secreting cells can only be converted to apoB secretors if the MTP gene is provided together with the apoB gene (Gordon et al.,
Proc. Natl. Acad. Sci.
(
USA
), 9 1:7628-7632, 1994; Leiper et al.,
J. Biol. Chem.,
269:21951-21954, 1994). Conversely, inhibition of MTP activity in cells that normally secrete apoB results in a drastic reduction in apoB secretion (Jamil et al.,
Proc. Natl. Acad. Sci.
(
USA
), 9 3:11991-11995, 1996; Haghpassand et al.,
J. Lipid. Res.,
3 7:1468-1480, 1996). A complete lack of MTP activity, such as, e.g., in cells containing mutations in the MTP coding region, leads to abetalipoproteinemia (Sharp et al.,
Nature,
365:65-69, 1993; Shoulders et al.,
Hum. Mol. Gen.,
2:2109-2116, 1993; Narcisi et al.,
Am. J. Hum. Gen.,
5 7:1298-13, 1995.
The promoter region of the MTP gene is highly conserved across mammalian species and contains potential control sequences for regulating MTP expression in different cell types and in response to metabolic regulators. Transcriptional activation of the human MTP promoter is suppressed by insulin and enhanced by cholesterol (Haoan et al.,
J. Biol. Chem.,
269:28737-28744, 1994). The insulin response has also been demonstrated in HepG2 human liver carcinoma cells (Lin et al.,
J. Lipid Res.,
3 6:1073-1081, 1995). It has also been shown that liver cells in hamsters fed either a high-fat or a cholesterol-enriched diet contain higher concentrations of MTP mRNA.
The high morbidity and mortality associated with cardiovascular disease means that there is a need for methods and compositions that allow the identification of individuals who are at higher or lower risk for developing cardiovascular disease. There is also a need for methods and compositions that allow the identification of treatment regimens that result in the most positive therapeutic outcome.
REFERENCES:
patent: 5595872 (1997-01-01), Wetterau et al.
Sharpe et al. Human Microsomal Triglyceride Transfer Protein Large Subunit Gene Structure. Biochemistry, vol. 33, pp. 9057-9061, Aug. 1994.*
Sharp et al., Biochemistry, 33:9057-9061, 1994.
Narcisi et al., Am. J. Hum. Gen., 57:1298-1310, 1995.
Sharp et al., Nature, 365:65-69, 1993.
Hagan et al., J. Biol. Chem., 269:28737-28744, 1994.
Karpe, et al., Arterioscler Thromb Vasc Biol. 1998; 18:756-761.
Haghpassand et al., J. Lipid. Res., 37:1468-1480, 1996.
Maxam-Gilbert, Proc. Natl. Acad. Sci. USA, 74:560, 1977.
Sanger et al., Proc. Natl. Acad. Sci. USA, 74:5463, 1977.
Sudhof et al., Cell, 48:1061-1069,1987.
Cotton, et al., Proc. Natl. Acad. Sci., USA, 85:4397, 1988.
Law et al., Br. Med. J., 308:367-373, 1988.
Miller et al., Nucl. Acids Res., 16:1215, 1988.
Saiki et al., Science, 239:487, 1988.
Anderson et al., Circulation, 83:356-362, 1991.
Atzel et al., Biochemistry, 32:10444-10450, 1993.
Tornvall et al., Circulation, 88:2180-2189, 1993.
Gordon et al., Proc. Natl. Acad. Sci. (USA), 91:7628-7632, 1994.
Guldberg et al., Nuc. Acids Res., 22:880, 1994.
Ravnik-Glavac et al., Hum. Mol. Genet., 3:801, 1994.
Leiper et al. J. Biol. Chem., 269:21951-21954, 1994.
Lin et al., J. Lipid Res., 36:1073-1081, 1995.
Gordon et al., Trends Cell Biol., 5:317-321. 1995.
Narcisi et al., Am. J. Hum. Gen., 57:1298-13, 1995.
Jamil et al., Proc. Natl. Acad. Sci. (USA), 93:11991-11995, 1996.
Darby & Darby
Eurona Medical AB
Wilder Cynthia
Zitomer Stephanie W.
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