WO2004065630A1 - Detection of predisposition to osteoporosis - Google Patents
Detection of predisposition to osteoporosis Download PDFInfo
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- WO2004065630A1 WO2004065630A1 PCT/GB2004/000249 GB2004000249W WO2004065630A1 WO 2004065630 A1 WO2004065630 A1 WO 2004065630A1 GB 2004000249 W GB2004000249 W GB 2004000249W WO 2004065630 A1 WO2004065630 A1 WO 2004065630A1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Definitions
- This invention relates to the detection of predisposition to osteoporosis in women and particularly in post-menopausal women.
- Osteoporosis is a condition of skeletal fragility characterised by low bone mineral density (BMD) and disruption of bone micro-architecture resulting in increased susceptibility to fractures.
- BMD bone mineral density
- Low BMD values are strongly related to the risk of osteoporotic fracture. Osteoporosis-related fractures are an important cause of morbidity and mortality in the elderly and a major burden on health service resources, estimated at £900 million in the U.K.
- the technique widely used for the diagnosis of osteoporosis and the assessment of fracture risk is the measurement of BMD by dual energy X-ray absorptiometry (DEXA).
- DEXA dual energy X-ray absorptiometry
- Other methods used include quantitative computed tomography, quantitative ultrasound and single energy X-ray absorptiometry.
- Quantitative computed tomography is costly and the radiation dose required may prohibit its routine use.
- the use of quantitative ultrasound and single energy X-ray absorptiometry in clinical practice requires further validation. A better way of identifying those at greatest risk of osteoporosis, thus enabling targeting of preventative therapy before fractures have occurred, is much needed.
- the 17 ⁇ hydroxylase/17, 20-lyase (CYP 17) gene located on chromosome 10 in humans, encodes a protein which has both 17 ⁇ hydroxylase and 17, 20 lyase activity.
- the predominance of 17 hydroxylase activity converts progesterone to 17-hydroxyprogesterone, a precursor of cortisone.
- 17, 20 lyase activity results in the synthesis of androgens.
- the present invention relates to a common polymorphism found in the promoter region of CYP 17 and is thus unrelated to the mutation in the coding region of the CYP 17 gene and its mechanism of action described by Yanase et al. (1988).
- the polymorphism that we have studied has previously been identified as being associated with polycystic ovaries and premature male pattern baldness, which are accompanied by elevated levels of serum androgens (Carey et al. (1994) Hum. Mol. Genet. 3, 1873- 1876). Carey et al. (1994) have described a method of testing for this polymorphism, which they used in their study of its link with polycystic ovaries and premature male pattern baldness.
- Subjects with the 'CC genotype had significantly lower BMD than those with the 'TT' or 'TC genotypes ( Figure 1).
- Subjects with the 'CC genotype also had an increased prevalence of fractures (Figure 2) and osteoporosis (Figure 3).
- Figure 2 Subjects with the 'CC genotype is associated with increased femoral size).
- the association with osteoporosis is independent of levels of sex hormones in women, in contrast to the results for men (Zmuda et al. (2001) J. Bone Miner. Res. 16, 911-917).
- This polymorphism may have a gender specific effect on bone mineral density. We have thus found a novel use for this polymorphism in the prediction of osteoporosis in women.
- a method of detecting a predisposition to osteoporosis in women comprises testing for a polymorphism in the human 17-hydroxylase/17, 20-lyase gene (CYP 17).
- any method may be used in which an oligonucleotide probe is hybridised to a nucleic acid sample taken from the patient and the result is analysed to determine which nucleotide is present at the locus of the particular polymorphism being tested for.
- the significant polymorphism is a single base polymorphism.
- these may comprise providing a polynucleotide capable of hybridising to a segment of a patient's nucleic acid having a polymorphism in the human CYP 17 gene; hybridising said polynucleotide to a segment of the patient's nucleic acid; and determining which polymorphic form is present in said segment by analysing said hybridisation.
- the polynucleotide may conveniently be immobilised on a support.
- the polynucleotide is provided in an ordered array wherein the ordered array is addressable. This method allows for high-throughput testing for this polymorphism.
- the nucleic acid sample may be obtained from the patient using any suitable method. It may be obtained, for example, from a patient's blood, or from a cheek swab.
- the polymorphism maybe such that depending on the polymorphic form present the resulting amplicon contains or does not contain a restriction site and the presence or absence of said restriction site enables determination of which polymorphic form is present.
- the test for the polymorphism comprises digesting the amplicon and noting the number of or the size of the fragments formed in the digest. Such a method is simpler and more straightforward than current methods, and can be applied to large sample numbers.
- the technique uses the polymerase chain reaction (PCR) followed by restriction enzyme digestion which allows the detection of the three different genotypes.
- PCR polymerase chain reaction
- sequence of the 5' region of the CYP 17 gene showing the polymorphism at 34 bp upstream of the ATG start site is as follows (SEQ ID NO. 1):
- Reverse primer 5' AGGCTCTTGGGGTACTTG 3' (SEQ ID NO. 3)
- a PCR fragment of 419 bp containing the polymorphic site was amplified.
- the sequence of the amplicon was as follows (SEQ ID NO. 4):
- TCACTCCCAC CGCCTCTCTC CCTTCTGGAT ATGAGGAGCT CAGGCCTGGC TGGGCTCCAG
- Digestion of the PCR product with Msp Al results in a single 419 bp product for the 'TT' genotype, two products, one of 124 bp and one of 295 bp, for the 'CC genotype and three products, one of 124 bp, one of 295 bp and one of 419 bp for heterozygotes ('TC').
- Figure 4 shows an agarose gel through which the digestion products have been separated.
- Genomic DNA was isolated from peripheral leukocytes.
- the PCR conditions were as follows:
- thermocycler Applied Biosystems
- Bovine serum albumin (BSA) (100 ⁇ g/ml) 0.2 ⁇ l
- the PCR product and enzyme mixture was incubated overnight at 37 ° C.
- the digested products were then separated through a 1.5% agarose gel and visualised under UV illumination after ethidium bromide staining.
- An inventive realisation of the present applicant is that there is an association between a polymorphism at a position 34 bp upstream of the ATG start site of CYP 17, and a predisposition to osteoporosis. It will be apparent to those skilled in the art that there will be methods of testing for this polymorphism other than those described above. Since osteoporosis is a multi- factorial disease with a potentially large number of gene mutations combining to give an overall predisposition to the disease it is likely that the polymorphism described herein would not be used in isolation to assess an individual's predisposition to osteoporosis but in combination with a number of other polymorphisms. Any suitable method falls within the scope of the present invention.
- a segment of the gene containing the polymorphism can be immobilised on a solid support, which may comprise the wells of a microtitre plate, beads or membranes (e.g. nitrocellulose).
- a solid support which may comprise the wells of a microtitre plate, beads or membranes (e.g. nitrocellulose).
- DNA microarray technology may be used.
- Ordered addressable nucleic acid arrays give researchers the ability to analyse thousands of individual DNA bases at once. Additionally, such arrays make it possible to conduct elaborate diagnostic testing in non-specialist settings like a family doctor's office, using hand-held devices to meet mobile needs such as point-of-care settings or even in home testing kits.
- a square of fluid-covered, transparent film with up to 100,000 ohgonucleotides bound to its surface is bathed in a solution of DNA that has been prepared from a patient's blood and labelled with a fluorescent dye.
- Other methods of labelling include radioactive labelling, or the use of biotin.
- the patient's DNA will hybridise to the synthetic oligonucleotide.
- a laser activates the dye and a scanner can then record the intensity of the light signal at each of the addressable locations on the array.
- Figure 1 BMD values expressed as 'Z' score between the CYP 17 genotypes in the whole study population * P ⁇ 0.05 "TT' v/s ⁇ CC
- Figure 2 Fracture prevalence in subjects with the different CYP 17 genotypes
- Figure 3 Over-representation of the 'CC genotype in women with osteoporosis as compared to controls
- Figure 4 CYP 17 genotypes following Msp Al digestion showing the three fragment sizes 419, 295 and 124 bp.
- Lane 1 molecular weight marker.
- Lanes 8, 15 Homozygote 'CC
Abstract
An association has been made between polymorphisms in the human (17-) hydroxylase/17, 20-lyase gene (CYP 17) and osteoporosis. A test is described for detecting the presence of these polymorphisms in a human subject and thereby predicting likelihood of development of osteoporosis in women.
Description
DETECTION OF PREDISPOSITION TO OSTEOPOROSIS
This invention relates to the detection of predisposition to osteoporosis in women and particularly in post-menopausal women.
Osteoporosis is a condition of skeletal fragility characterised by low bone mineral density (BMD) and disruption of bone micro-architecture resulting in increased susceptibility to fractures. Low BMD values are strongly related to the risk of osteoporotic fracture. Osteoporosis-related fractures are an important cause of morbidity and mortality in the elderly and a major burden on health service resources, estimated at £900 million in the U.K.
At present, the technique widely used for the diagnosis of osteoporosis and the assessment of fracture risk is the measurement of BMD by dual energy X-ray absorptiometry (DEXA). However this method is time consuming, costly and may not be widely available for mass screening. Other methods used include quantitative computed tomography, quantitative ultrasound and single energy X-ray absorptiometry. Quantitative computed tomography is costly and the radiation dose required may prohibit its routine use. The use of quantitative ultrasound and single energy X-ray absorptiometry in clinical practice requires further validation. A better way of identifying those at greatest risk of osteoporosis, thus enabling targeting of preventative therapy before fractures have occurred, is much needed.
The 17~hydroxylase/17, 20-lyase (CYP 17) gene, located on chromosome 10 in humans, encodes a protein which has both 17 α hydroxylase and 17, 20 lyase activity. In the adrenal zona fasciculata, the predominance of 17 hydroxylase activity converts progesterone to 17-hydroxyprogesterone, a precursor of cortisone. In the adrenal zona reticularis and gonads, 17, 20 lyase activity results in the synthesis of androgens.
In a previous study (Yanase et al. (1988) Mol. Cell. Endocrinol. 59, 249-253), a rare loss of function mutation in exon 1 of CYP 17 was shown to cause osteoporosis in a
single Japanese patient. This 17 alpha-hydroxylase deficiency is a rare disease caused by a point mutation that results in formation ofa stop codon.
The pathogenesis of osteoporosis is multifactorial and genetic factors play an important role. In a study of 252 post-menopausal women, we have found that a common polymorphism located 34 bases upstream of the ATG start site in CYP 17 is associated with BMD at the femoral neck/hip. (This polymorphism is found at position 1929 of the GenBank database entry for this gene; accession number M63871). We have tested for this polymorphism in biological samples taken from patients and shown a significant association of this polymorphism with low bone mineral density and susceptibility to fractures.
The present invention relates to a common polymorphism found in the promoter region of CYP 17 and is thus unrelated to the mutation in the coding region of the CYP 17 gene and its mechanism of action described by Yanase et al. (1988). The polymorphism that we have studied has previously been identified as being associated with polycystic ovaries and premature male pattern baldness, which are accompanied by elevated levels of serum androgens (Carey et al. (1994) Hum. Mol. Genet. 3, 1873- 1876). Carey et al. (1994) have described a method of testing for this polymorphism, which they used in their study of its link with polycystic ovaries and premature male pattern baldness.
To date there have been no studies on testing for this polymorphism in order to detect a predisposition to osteoporosis in women. We have exploited the method of Carey et al. (1994) in order to recognise the association of this polymorphism with a risk of osteoporosis in women.
We investigated the association of the polymorphism 34 bp upstream of the ATG start site of CYP 17 with bone mineral density and fracture incidence in 252 post- menopausal women. We found a significant association between BMD values at the femoral neck with the CYP 17 polymorphism in the whole study population as shown
in the following Table (Multiple Linear Regression analysis of femoral neck BMD (Dependent variable: BMD femoral neck)):
Final adjusted R = 0.5
Subjects with the 'CC genotype had significantly lower BMD than those with the 'TT' or 'TC genotypes (Figure 1). Subjects with the 'CC genotype also had an increased prevalence of fractures (Figure 2) and osteoporosis (Figure 3). Surprisingly, our results are the opposite to what has been shown in men (where the CC genotype is associated with increased femoral size). Moreover, the association with osteoporosis is independent of levels of sex hormones in women, in contrast to the results for men (Zmuda et al. (2001) J. Bone Miner. Res. 16, 911-917). This polymorphism may have a gender specific effect on bone mineral density. We have thus found a novel use for this polymorphism in the prediction of osteoporosis in women.
In accordance with the present invention, a method of detecting a predisposition to osteoporosis in women is provided, which comprises testing for a polymorphism in the human 17-hydroxylase/17, 20-lyase gene (CYP 17).
One method we have used for the purposes of the present invention, described in detail hereinafter, is based on amplifying a segment of the CYP 17 gene and making use of a restriction site in the amplified product whereby restriction enzyme digestion of the product will result in one or more fragments indicative of which polymorphic
form is present. However, it will be readily understood that the use of the present invention for prognosis of these diseases is not limited to this particular method, since suitable alternative methods are available as will be readily appreciated by those skilled in the art. Thus, for example, any method may be used in which an oligonucleotide probe is hybridised to a nucleic acid sample taken from the patient and the result is analysed to determine which nucleotide is present at the locus of the particular polymorphism being tested for. In results obtained so far, the significant polymorphism is a single base polymorphism.
When other methods are used, these may comprise providing a polynucleotide capable of hybridising to a segment of a patient's nucleic acid having a polymorphism in the human CYP 17 gene; hybridising said polynucleotide to a segment of the patient's nucleic acid; and determining which polymorphic form is present in said segment by analysing said hybridisation. In this embodiment, the polynucleotide may conveniently be immobilised on a support. For example, the polynucleotide is provided in an ordered array wherein the ordered array is addressable. This method allows for high-throughput testing for this polymorphism.
The nucleic acid sample may be obtained from the patient using any suitable method. It may be obtained, for example, from a patient's blood, or from a cheek swab.
As indicated above, the polymorphism maybe such that depending on the polymorphic form present the resulting amplicon contains or does not contain a restriction site and the presence or absence of said restriction site enables determination of which polymorphic form is present. In this embodiment, the test for the polymorphism comprises digesting the amplicon and noting the number of or the size of the fragments formed in the digest. Such a method is simpler and more straightforward than current methods, and can be applied to large sample numbers.
METHODS
We have used a simple technique for the genotyping of large numbers of individuals. The technique uses the polymerase chain reaction (PCR) followed by restriction enzyme digestion which allows the detection of the three different genotypes.
The sequence of the 5' region of the CYP 17 gene showing the polymorphism at 34 bp upstream of the ATG start site is as follows (SEQ ID NO. 1):
-60bp -3 bp -1
GAGTTGCCACAGCTCTTCTACTCCACYGCTGTCTATCTTGCCTGCCGGCACCCAGCCACCATG where Y = thymine or cytosine. The thymine to cytosine substitution creates an additional Sρ-1 type (CCACC) promoter site (see underlining).
A PCR method using the primers shown below was optimised to detect this polymorphism.
Primer sequences :
Forward primer: 5' CATTCGCACTCTGGAGTC 3' (SEQ ID NO. 2)
Reverse primer: 5' AGGCTCTTGGGGTACTTG 3' (SEQ ID NO. 3)
A PCR fragment of 419 bp containing the polymorphic site was amplified. The sequence of the amplicon was as follows (SEQ ID NO. 4):
CATTCGCACT CTGGAGTCAT TCAAGCATGG GCTTCCAGAG GGTTTGATCA ACTGACCTCC
CTTACCTAGG TCCTCCTCCG GAGGTTTGCC CTGGAGTTGA GCCAGCCCTT GAGGAGGCCT
TCACTCCCAC CGCCTCTCTC CCTTCTGGAT ATGAGGAGCT CAGGCCTGGC TGGGCTCCAG
GAGAATCTTT CTTCCACAAG GCAAGAGATA ACACAAAAGT CAAGGTGAAG ATCAGGGTAG
CCCTTTAAAA GGCCTCCTTG TGCCCTAGAG TTGCCACAGC TCTTCTACTC CACYGCTGTC
TATCTTGCCT GCCGGCACCC AGCCACCATG TGGGAGCTCG TGGCTCTCTT GCTGCTTACC
CTAGCTTATT TGTTTTGGCC CAAGAGAAGG TGGCCTGGTG CCAAGTACCC CAAGAGCCT
The presence of a cytosine at the polymorphic site forms the sequence CCGCTG, which is a recognition site for the restriction enzyme Msp Al (CMG/CKG, where M = A or C and K = G or T). Digestion of the PCR product with Msp Al results in a single 419 bp product for the 'TT' genotype, two products, one of 124 bp and one of 295 bp, for the 'CC genotype and three products, one of 124 bp, one of 295 bp and one of
419 bp for heterozygotes ('TC'). Figure 4 shows an agarose gel through which the digestion products have been separated.
Genomic DNA was isolated from peripheral leukocytes. The PCR conditions were as follows:
25 μl amplification mixture containing:
100-200 ng genomic DNA
50 pmol of each primer
1.5 mM Mg Cl2
40 μmol dNTP
1.0 unit of Taq polymerase
PCR amplification was carried out using the 5700 thermocycler (Applied Biosystems) and included the following steps :
Initial denaturation at 94° C for 1 minute, followed by denaturation at 94 ° C for 1 minute, annealing at 60 ° C for 1 minute, extension at 72 °
C for 1 minute (forty cycles), followed by
Final extension at 72 ° C for 10 minutes
Following PCR, the product was digested with Msp Al as follows :
10 μl of the PCR product is then added to 10 μl of enzyme mix which consists of
Msp Al 5 Units
Buffer (1 OX NE buffer) 2 μl
Bovine serum albumin (BSA) (100 μg/ml) 0.2 μl
H2 O 7.3 μl
Total 10.0 μl
The PCR product and enzyme mixture was incubated overnight at 37 ° C. The digested products were then separated through a 1.5% agarose gel and visualised under UV illumination after ethidium bromide staining.
An inventive realisation of the present applicant is that there is an association between a polymorphism at a position 34 bp upstream of the ATG start site of CYP 17, and a predisposition to osteoporosis.
It will be apparent to those skilled in the art that there will be methods of testing for this polymorphism other than those described above. Since osteoporosis is a multi- factorial disease with a potentially large number of gene mutations combining to give an overall predisposition to the disease it is likely that the polymorphism described herein would not be used in isolation to assess an individual's predisposition to osteoporosis but in combination with a number of other polymorphisms. Any suitable method falls within the scope of the present invention. For example, a segment of the gene containing the polymorphism can be immobilised on a solid support, which may comprise the wells of a microtitre plate, beads or membranes (e.g. nitrocellulose). In particular, DNA microarray technology may be used.
Ordered addressable nucleic acid arrays give researchers the ability to analyse thousands of individual DNA bases at once. Additionally, such arrays make it possible to conduct elaborate diagnostic testing in non-specialist settings like a family doctor's office, using hand-held devices to meet mobile needs such as point-of-care settings or even in home testing kits.
In one example of the practical application of ordered addressable array technology, a square of fluid-covered, transparent film with up to 100,000 ohgonucleotides bound to its surface is bathed in a solution of DNA that has been prepared from a patient's blood and labelled with a fluorescent dye. Other methods of labelling include radioactive labelling, or the use of biotin. Depending on the stringency of hybridisation, where the patient's DNA corresponds exactly to the synthetic oligonucleotide, the patient's DNA will hybridise to the synthetic oligonucleotide. A laser activates the dye and a scanner can then record the intensity of the light signal at each of the addressable locations on the array. Analysis then yields information on which synthetic sequence bound to the patient's DNA, allowing identification of which polymorphic variants the patient's DNA contains.
Thus, the polymorphism described above can be analysed in a subject's DNA quickly and easily along with many other candidate polymorphisms in order to assess the overall predisposition to osteoporosis.
Figure Legends:
Figure 1 : BMD values expressed as 'Z' score between the CYP 17 genotypes in the whole study population * P < 0.05 "TT' v/s ζCC
Figure 2: Fracture prevalence in subjects with the different CYP 17 genotypes
Figure 3: Over-representation of the 'CC genotype in women with osteoporosis as compared to controls
Figure 4: CYP 17 genotypes following Msp Al digestion showing the three fragment sizes 419, 295 and 124 bp.
Lane 1 : molecular weight marker.
Lanes 2, 4, 6, 7, 10, 13 : Heterozygote 'TC
Lanes 3, 5, 9, 11, 12, 14 : Homozygote 'TT'
Lanes 8, 15 : Homozygote 'CC
Claims
1. A method of detecting a predisposition to osteoporosis in women comprising testing for a polymorphic variant in the human 17- hydroxylase/17, 20-lyase gene (CYP 17).
2. A method as claimed in claim 1, wherein a patient's sample of nucleic acid is tested for a polymorphic variant (T or C) at a position 34 bp upstream of the ATG start site of CYP 17.
3. A method as claimed in claim 2, in which a segment of the CYP 17 gene containing the polymorphic site 34 bp upstream of the ATG start site of CYP 17 is amplified and tested.
4. A method as claimed in claim 3, wherein the polymorphism is such that the resulting amplicon may or may not have a restriction site and whereby the presence or absence of said restriction site enables determination of which polymorphic form is present.
5. A method as claimed in claim 4, wherein the test comprises digesting the amplicon and noting the number of or the size of the fragments formed in the digest.
6. A method according to claim 5, in which the test is carried out by amplification of a segment of CYP 17 using the primers:
Forward primer: 5' CATTCGCACTCTGGAGTC 3' (SEQ ID NO. 2) Reverse primer: 5' AGGCTCTTGGGGTACTTG 3' (SEQ ID NO. 3)
7. A method as claimed in any of claims 4 to 6, which comprises digesting the resulting amplicon with the enzyme Msp Al
8. A method as claimed in claim 2 which comprises: providing a polynucleotide capable of hybridising to a segment of a patient's nucleic acid having a polymorphism in the human 17- hydroxylase/17, 20-lyase gene (CYP 17); hybridising said polynucleotide to a segment of the patient's nucleic acid; and determining which polymorphic form is present in said segment by analysing said hybridisation.
9. A method as claimed in claim 8, wherein the polynucleotide is immobilised on a support.
10. A method as claimed in any of claims 8 to 9, wherein the polynucleotide is provided in an ordered array and wherein the ordered array is addressable.
11. Use of a test for a polymorphic variant in the human 17-hydroxylase/l 7, 20-lyase gene (CYP 17) for detecting a predisposition to osteoporosis in women.
12. Use as claimed in claim 11, wherein a patient's sample of nucleic acid is tested for a polymorphic variant (T or C) at a position 34 bp upstream of the ATG start site of CYP 17.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0301715.9A GB0301715D0 (en) | 2003-01-24 | 2003-01-24 | Detection of predisposition to osteoporosis |
| GB0301715.9 | 2003-01-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004065630A1 true WO2004065630A1 (en) | 2004-08-05 |
Family
ID=9951782
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2004/000249 WO2004065630A1 (en) | 2003-01-24 | 2004-01-22 | Detection of predisposition to osteoporosis |
Country Status (2)
| Country | Link |
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| GB (1) | GB0301715D0 (en) |
| WO (1) | WO2004065630A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5698399A (en) * | 1996-04-05 | 1997-12-16 | Duff; Gordon W. | Detecting genetic predisposition for osteoporosis |
| WO2003054218A2 (en) * | 2001-12-20 | 2003-07-03 | Incyte Genomics, Inc. | Nucleotide polymorphisms associated with osteoporosis |
-
2003
- 2003-01-24 GB GBGB0301715.9A patent/GB0301715D0/en not_active Ceased
-
2004
- 2004-01-22 WO PCT/GB2004/000249 patent/WO2004065630A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5698399A (en) * | 1996-04-05 | 1997-12-16 | Duff; Gordon W. | Detecting genetic predisposition for osteoporosis |
| WO2003054218A2 (en) * | 2001-12-20 | 2003-07-03 | Incyte Genomics, Inc. | Nucleotide polymorphisms associated with osteoporosis |
Non-Patent Citations (10)
| Title |
|---|
| CAREY ADAM H ET AL: "Polycystic ovaries and premature male pattern baldness are associated with one allele of the steroid metabolism gene CYP17", HUMAN MOLECULAR GENETICS, vol. 3, no. 10, 1994, pages 1873 - 1876, XP002280402, ISSN: 0964-6906 * |
| CHENG Z-N ET AL: "CONTRIBUTION OF GENETIC VARIATIONS IN ESTRADIOL BIOSYNTHESIS AND METABOLISM ENZYMES TO OSTEOPOROSIS", ACTA PHARMACOLOGICA SINICA, XX, CN, vol. 21, no. 7, 4 July 2001 (2001-07-04), pages 587 - 590, XP008020829, ISSN: 1671-4083 * |
| HAIMAN CHRISTOPHER A ET AL: "The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer", CANCER RESEARCH, vol. 59, no. 5, 1 March 1999 (1999-03-01), pages 1015 - 1020, XP002280403, ISSN: 0008-5472 * |
| SOMNER J ET AL: "Polymorphisms in the P450 C17 (17-hydroxylase/17,20-lyase) and P450 C19 (aromatase) genes: Association with serum sex steroids concentrations and bone mineral density in post-menopausal women", CALCIFIED TISSUE INTERNATIONAL, NEW YORK, NY, US, vol. 72, no. 3, 20 March 2003 (2003-03-20), pages 267, XP002255836, ISSN: 0171-967X * |
| SOMNER JOHN ET AL: "Polymorphisms in the P450 c17 (17-hydroxylase/17,20-lyase) and P450 c19 (aromatase) genes: Association with serum sex steroid concentrations and bone mineral density in postmenopausal women.", JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 89, no. 1, January 2004 (2004-01-01), pages 344 - 351, XP008030539, ISSN: 0021-972X * |
| WILSON S G ET AL: "HuSNP genechips for linkage mapping in sib pairs concordant for low bone mineral density", CALCIFIED TISSUE INTERNATIONAL, NEW YORK, NY, US, vol. 67, no. 6, December 2000 (2000-12-01), pages 484, XP002253332, ISSN: 0171-967X * |
| YANASE T ET AL: "17ALPHA-HYDROXYLASE/17,20-LYASE DEFICIENCY: FROM CLINICAL INVESTIGATION TO MOLECULAR DEFINITION", ENDOCRINE REVIEWS, BALTIMORE, MD, US, vol. 12, no. 1, 1991, pages 91 - 108, XP002916115 * |
| YANASE T ET AL: "COMBINED 17-ALPHA HYDROXYLASE-17 20-LYASE DEFICIENCY DUE TO A STOP CODON IN THE AMINO-TERMINAL REGION OF 17-ALPHA HYDROXYLASE CYTOCHROME P-450", MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 59, no. 3, 1988, pages 249 - 254, XP002280401, ISSN: 0303-7207 * |
| ZMUDA J M ET AL: "A common promotor variant in the cytochrome P450c17alpha (CYP17) gene is associated with bioavailability testosterone levels and bone size in men.", JOURNAL OF BONE AND MINERAL RESEARCH : THE OFFICIAL JOURNAL OF THE AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH. MAY 2001, vol. 16, no. 5, May 2001 (2001-05-01), pages 911 - 917, XP008030585, ISSN: 0884-0431 * |
| ZMUDA JOSEPH M ET AL: "Recent progress in understanding the genetic susceptibility to osteoporosis", GENETIC EPIDEMIOLOGY, vol. 16, no. 4, 1999, pages 356 - 367, XP002280404, ISSN: 0741-0395 * |
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| GB0301715D0 (en) | 2003-02-26 |
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