Human intronic and polymorphic SR-BI nucleic acids and uses...

Details Human intronic and polymorphic SR-BI nucleic acids and uses... Human intronic and polymorphic SR-BI nucleic acids and uses...

1998-02-27

2001-05-08

Fredman, Jeffrey (Department: 1655)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C204S606000, C536S024300

Reexamination Certificate

active

06228581

ABSTRACT:

1. BACKGROUND OF THE INVENTION
Coronary heart disease is a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principle cause of death in the United States. Although historically much emphasis has been placed on total plasma cholesterol levels as a risk factor for coronary heart disease, it has been clearly established that low levels of high density lipoprotein cholesterol (HDL-C) is an independent risk factor for this disease. Family and twin studies have shown that there are genetic components that affect HDL levels. However, mutations in the main protein components of HDL (ApoAI and ApoAII) and in the enzymes that are known to be involved in HDL metabolism (e.g., CETP, HL, LPL and LCAT) do not explain all of the genetic factors affecting HDL levels in the general population (J. L. Breslow, in
The Metabolic and Molecular Bases of Inherited Disease
, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2031-2052; and S. M. Grundy, (1995)
J. Am. Med. Assoc
. 256: 2849). This finding in combination with the fact that the mechanisms of HDL metabolism are poorly understood, suggests that there are other as yet unknown factors that contribute to the genetic variability of HDL levels.
Another disorder that is often associated with high triglyceride and low high density lipoprotein (HDL) concentrations is obesity, which renders a subject susceptible to cardiovascular diseases, such as ischemia, restenosis, congestive heart failure, and atherosclerosis. Severely obese individuals (weighing 60% over a normal weight) have a high risk of developing cardiorespiratory problems. They are also at risk of developing chronic hypoventilation, which can lead to hypercapnia, pulmonary hypertension, and heart failure. Severe episodic hypoxia, which can cause arrhythmias and sudden death, is 10 times more common in the severely obese. Severely obese individuals are also at increased risk of suffering from obstructive sleep apnea, pickwickian syndrome (i.e., daytime hypoventilation, somnolence, polycythemia, cor pulmonale), and renal vein thrombosis. (“Cecil Essentials of Medicine”, Andreoli et al., Third Edition, 1993, W. B. Saunders Company).
Moderate obesity (corresponding to a weight between 20-60% above normal weight) poses increased risk of early mortality. Obese individuals suffer more frequently than non obese individuals from hypertension. Type II diabetes mellitus can also be aggravated by excess weight. Obesity can also increase the risk of a subject developing cholelithiasis and endometrial carcinoma.
One candidate factor that is likely to be involved both in obesity and cardiovascular disease is the SR-BI receptor, which has been shown to bind HDL and LDL cholesterol and mediate uptake into cells (Acton, S. et al., (1996) Science 271:518-520). SR-BI is likely to contribute to genetic lipoprotein variability, thereby playing a role in the development of lipid metabolism disorders and thus generally, cardiovascular diseases.
In addition, cholesterol gallstone formation could be caused by a defective SR-BI receptor, since the SR-BI receptor is likely to be involved in transferring HDL-cholesterol from extrahepatic tissues to the liver (reverse cholesterol transport) e.g. for incorporation into bile (J. L. Breslow, in
The Metabolic and Molecular Bases of Inherited Disease
, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2031-2052; S. M. Grundy, (1995)
J. Am. Med. Assoc.
256: 2849; G. Assman, A. von Eckardstein, H. B. Brewer Jr. in
The Metabolic and Molecular Bases of Inherited Disease
, C. R. Scriver, A. L. Beaudet, W. Sly, D. Valle, Eds. (McGraw-Hill, New York, 1995), pp 2053-2072; W. J. Johnson et al., (1991)
Biochem. Biophys. Acta
1085:273; M. N. Pieters et al., (1994)
Ibid
1225:125; and C. J. Fielding and P. E. Fielding, (1995)
J. Lipid Res
36:211).
Further, a defective SR-BI receptor or abnormal levels of SR-BI receptor could influence the fertility of a subject, since SR-BI appears to be involved in HDL-cholesteryl ester delivery to steroidogenic tissues (ovary, adrenal glands and testis) for hormone synthesis (Acton, S. et al., (1996)
Science
271:518-520; Landschulz, et al., (1996)
J. Clin. Invest.
98:984-95; J. M. Anderson and J. M. Dietschy (1981)
J. Biol. Chem.
256: 7362; M. S. Brown et al., (1979)
Recent Prog Horm. Res.
35:215; J. T. Gwynne and J. F. Strauss III, (1982)
Endocr. Rev.
3:299; B. D. Murphy et al., (1985)
Endocrinology
116: 1587).
The SR-BI receptor (Scavenger Receptor-BI) is a scavenger receptor that mediates endocytosis of unmodified and modified lipoproteins, e.g., LDL, acetylated LDL, oxidized LDL (Acton et al. (1994) J. Biol. Chem. 269:21003), HDL ((Acton, S. et al., (1996)
Science
271:518-520), anionic phospholipids (Rigotti et al. (1995) J. Biol. Chem. 270:16221), negatively charged liposomes and apoptotic cells (Fukasawa et al. (1996) Exp. Cell Res. 222:246). The human SR-BI receptor (also termed “CLA-1) exists in two differentially spliced forms (Calvo and Vega (1993) J. Biol. Chem. 268:18929). The predominant form of human SR-BI is a protein of 509 amino acids. The shorter form of the SR-BI receptor has 409 amino acids, and is lacking the 100 amino acids located 42 amino acids downstream of the initiation codon (Calvo and Vega, supra). The nucleotide sequence of a cDNA encoding human SR-BI is disclosed in Calvo and Vega, supra and the nucleotide sequence of a cDNA encoding hamster SR-BI is disclosed in Acton et al. (1994) J. Biol. Chem. 269:21003 and in PCT Application WO 96/00288.
2. SUMMARY OF THE INVENTION
The present invention is based at least in part on the discovery of the genomic structure of the human SR-BI gene and on the identification of polymorphic regions within the gene, which are associated with specific diseases or disorders, including abnormal body mass and abnormal lipoprotein levels, i.e., high HDL and low LDL levels. The human SR-BI gene contains 12 coding exons and one non coding exon (exon 13). The structure of the gene and the position of the introns relative to the nucleotide sequence of the exons are shown in
FIGS. 1
,
2
, and
3
.
Several polymorphic regions that are associated with specific diseases or disorders, have been found in the human SR-BI gene by analyzing the DNA of a specific population of individuals. One polymorphism found in the population is a change from a guanine to an adenine at position 146 in exon 1, which results in a change from a glycine to a serine at amino acid residue 2 of the encoded protein. A second polymorphism is a change from a guanine to an adenine at position 119 in exon 3, which results in a change from a valine to an isoleucine at amino acid residue 135 of the encoded protein. A third polymorphism is a change from a cytidine to a thymidine at position 41 of exon 8, which does not result in a difference in the amino acid sequence of the encoded protein. A fourth polymorphism is a change from a cytidine to a thymidine at position 56 of intron 5. A fifth polymorphism is a change from a cytidine to a guanine at position −41 of intron 10 (position −1 corresponds to the first nucleotide upstream of exon 11).
Specific allelic variants of these polymorphic regions are shown herein to be associated with specific disorders. In particular, the presence of a thymidine at position 41 in exon 8 was found to be associated with low plasma LDL levels in women. Furthermore, a thymidine at position 54 of intron 5 was found to be associated with a high BMI and high plasma LDL levels in women. In men, the presence of a thymidine at position 41 in exon 8, a thymidine at position 54 of intron 5 and/or an adenine at position 146 of exon 1 was found to be associated with a high plasma HDL level. Since abnormal lipid, lipoprotein levels, and BMI may be associated with obesity, cachexia, cardiovascular disease, gallstone formation and other diso

Affiliated with

Also associated with

Rating

Human intronic and polymorphic SR-BI nucleic acids and uses... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Human intronic and polymorphic SR-BI nucleic acids and uses..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Human intronic and polymorphic SR-BI nucleic acids and uses... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2444412