Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-09-10
2004-11-30
Benzion, Gary (Department: 1634)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023740, C536S024330, C536S023100
Reexamination Certificate
active
06825336
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of osteoporosis diagnosis and therapy. The present invention specifically provides previously unknown single nucleotide polymorphisms (SNPs) in genes that have been identified as being involved in pathologies associated with osteoporosis. Since these genes are known to be associated with osteoporosis, the presently disclosed naturally occurring polymorphisms (variants) are valuable for association and linkage analysis. Specifically, the identified SNPs are useful for such applications as screening for osteoporosis susceptibility, prevention of osteoporosis, development of diagnostics and therapies for osteoporosis, development of drugs for osteoporosis, and development of individualized drug treatments based on an individual's SNP profile. The SNPs provided by the present invention are also useful for human identification. Methods and reagents for detecting the presence of these polymorphisms are provided.
BACKGROUND OF THE INVENTION
Osteoporosis
The human bones are generally subdivided into cortical bone and cancellous bone. The cortical bone is dense osseous tissue and is represented by the diaphysis of appendicular skeleton in the form of pipes. On the other hand, cancellous bone consists mainly of trabeculae. Such cancellous bone is present, for example, in the epiphysial portions of long shaft bones, vertebrae, carpal bones, calcanei, tali, and tarsal bones. However, since cancellous bone has a larger surface in contact with soft tissue containing vasculatures, cancellous bone shows higher metabolic turn over and is predisposed to rapid changes under bone diseases or treatments.
Metabolic bone diseases include those conditions producing diffusely decreased bone density (osteopenia) and diminished bone strength. It is categorized by histologic appearance: osteoporosis which is common and defined by decreased mineral and bone matrix, and osteomalacia which is unusual and defined by decreased mineral but intact bone matrix.
Osteoporosis is the most common metabolic bone disease and the cause of hundreds of thousands of fractures every year. The morbidity and indirect mortality rates are very high. Since the usual form of the disease is clinically evident in middle life and beyond and since women are more frequently affected than men, it may be referred to as “postmenopausal” osteoporosis. It is characterized by a decrease in the amount of bone present to a level below which it is capable of maintaining the structural integrity of the skeleton. The rate of bone formation is often normal, whereas the rate of bone resorption is increased. There is a greater loss of trabecular bone than compact bone, accounting for the primary features of disease, i.e., crush fractures of vertebrae, fractures of the neck of the femur, and fractures of distal end of the radius. Whatever bone is present is normally mineralized.
The cause of osteoporosisare among, but not limited to the hormone deficiency (estrogen or androgen), hormone excess (cushing's syndrome or glucocorticoid administration, thyrotoxicosis, hyperparathyroidism, excessive vitamin D administration), immobilization, tabacco, malignancy, idiopathic or geriatric, and genetic disorders (Type I collagen mutations, Ehlers-danlos syndrome, Marfan's syndrome, Homocystinuria).
Among the genetic disorders, osteogenesis imperfecta is caused by a major mutation in the gene encoding for type I collagen, the major collagen constituent of bone. This causes severe osteoporosis. Marfan's syndrome is caused by mutations in fibrillin gene on chromosome 15. Homocytinuria is caused by cystathionine beta-synthase deficiency and exhibits an autosomal recessive pattern of inheritance.
Researchers believe that genetic factors play a dominant role in the etiology of this disease among the ethnic or gender difference. Several genes have been shown to be associated with low bone density and research has focused on identifying those genes that may act as markers of disease. Common allelic variations of the vitamin D receptor gene have been found to be associated with decreased bone density in certain populations, including premenopausal women and young girls (Wood, R. J. and Fleet, J. C. Ann. Rev. Nutrit. 1998 18:233-258). Bone mineral density has also been associated with genetic variation in the estrogen receptor gene, both by itself and in conjunction with variations in the vitamin D receptor gene (Willing et al. J. Bone Min. Res. 1998 13:695-705). In Japanese women, the HLA-A*24-B*07-DRB*01 halotype has been linked to low peak bone mass (Tsuji et al. Hum. Immunol.1998 59:243-249). A variant of the gene encoding transforming growth factor-beta 1 has also been associated with low bone mass in osteoporotic women and with low bone mass and increased bone turnover in normal women (Langdahl et al. Bone 1997 20:289-294). A polymorphism of the COLIAI gene has been identified as a potential marker for low bone mass and vertebral fracture in women (Grant et al. Nat. Genet. 1996 14:203-205). Devoto et al. (Eur. J. Hum. Genet. 1998 6:151-157) determined that there was a gene or genes on chromosome 1 of humans that was linked to low bone density. Polymorphisms linked to osteoporosis have been described in the TGF-91 gene, whose protein product is abundant in bone and an important regulator of bone resorption and formation (Langdahl et al., 1997; Yamada et al., 1998; W097/28280). A polymorphism in the gene on chromosome 1 for tumor necrosis factor alpha receptor 2 has now been shown to be associated with low bone density. (Spotila et al. WO 0032826).
Genes associated with osteoporosis include, but not limit to: alcitonin receptor, collagen subunit (alpha-1 (X)) 3, Kuestner,et al Mol. Pharmacol. 46 (2), 246-255 (1994); insulin-like growth factor binding protein 1, Brewer et al., Biochem. Biophys. Res. Commun. 152 (3), 1289-1297 (1988), Brinkman et al., EMBO J. 7 (8), 2417-2423 (1988), Cubbage et al., Mol. Endocrinol. 3 (5), 846-851 (1989), Alitalo et al., Hum. Genet. 83 (4), 335-338 (1989), Ekstand et al.,Genomics 6 (3), 413-418 (1990), Suwanichkul et al., J. Biol. Chem. 265 (34), 21185-21193 (1990), Ehrenborg et al., Genomics 12 (3), 497-502 (1992); insulin-like growth factor 1 receptor beta chain, Francke et al., Cold Spring Harb. Symp. Quant. Biol. 51, 855-866 (1986), Ullrich et al., EMBO J. 5 (10), 2503-2512 (1986), Flier et al., Proc. Natl. Acad. Sci. U.S.A. 83 (3), 664-668 (1986), Abbott et al., J. Biol. Chem. 267 (15), 10759-10763 (1992), Werner et al., Proc. Natl. Acad. Sci. U.S.A. 93 (16), 8318-8323 (1996), Grant et al., J. Clin. Endocrinol. Metab. 83 (9), 3252-3257 (1998); interleukin 4 receptor, Idzerda et al., J. Exp. Med. 171 (3), 861-873 (1990), Pritchard et al., Genomics 10 (3), 801-806 (1991); Werner syndrome, Goto et al., Nature 355 (6362), 735-738 (1992).
Diagnosis of osteoporosis is most often done in conjunction with a study of bone density by radiography. Although clinical laboratory tests such as levels of calcium and phosphorus in blood can be examined, these measures are usually normal in osteoporotic patients. Only about 20% of postmenopausal women with osteoporosis exhibit hypercalciuria, or increased excretion of calcium in urine.
Therefore, such laboratory findings are not indicative of the presence of disease, and clearly would not be indicative of risk of developing disease. To date, the prediction of risk of developing disease relies on family history of the disease. However, no genetic test is currently available to screen individuals.
SNPs
The genomes of all organisms undergo spontaneous mutation in the course of their continuing evolution, generating variant forms of progenitor sequences (Gusella, Ann. Rev. Biochem. 55, 831-854 (1986)). The variant form may confer an evolutionary advantage or disadvantage relative to a progenitor form or may be neutral. In some instances, a variant form confers a lethal disadvantage and is not transmitted to subsequent generations of the organism. In other instances, a variant form confers an evolutionary advantage to th
Cravchik Anibal
Kalush Francis
Liu Xiangjun
Naik Ashwinikumar
Rowe William
Benzion Gary
Celera Genomics
Karjala Justin D.
Switzer Juliet C.
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