# US 2016/0258015 A1 · Estrogen receptor alleles that are predictive of increased susceptibility to bone fracture

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- Number: US 2016/0258015 A1
- Document ID: US20160258015A1
- Status: Published application
- Kind: A1
- Application number: 14/883,705
- Filed: 2015-10-15
- Published: 2016-09-08
- Earliest claimed: 2003-04-30
- Assignees: Bodysync, Inc.
- Applicants: BodySync, Inc.
- Inventors: Andreas Gerardus Uitterlinden; Johannes Petrus Thomas Maria Van Leeuwen; Huibert Adriaan Pieter Pols
- Web page: https://patentgrep.com/patent/US20160258015A1

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- A61P 19/00: Drugs for skeletal disorders
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/172: Haplotypes
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

In one aspect, the present invention provides methods of determining susceptibility to bone fracture in a mammalian subject, wherein the methods comprise analyzing nucleic acid molecules obtained from the mammalian subject to determine which of the P, p X, and x alleles of the estrogen receptor α gene are present, wherein the presence of a haplotype comprising the p and x alleles is indicative of an increased susceptibility to bone fracture. The present invention also provides kits for determining susceptibility to bone fracture in a mammalian subject.

## Claims

### Claim at position 1

1-30. (canceled)

### Claim 31

A method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene in a mammalian subject comprising at least one estrogen receptor α gene comprising a PvuII site and a XbaI site, wherein the PvuII site can exist as a P or p allelic form, and the XbaI site can exist as an X or x allelic form, said method comprising analyzing nucleic acid molecules obtained from the mammalian subject to determine which of the P, p X, and x alleles of the estrogen receptor α gene are present.

### Claim 32 (depends on 31)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 31, said method comprising analyzing nucleic acid molecules of the mammalian subject to determine whether the px haplotype of the estrogen receptor α gene is present.

### Claim 33 (depends on 31)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 31, said method further comprising analyzing nucleic acid molecules of the mammalian subject to determine whether an allele of a vitamin D receptor gene is present.

### Claim 34 (depends on 33)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 33, wherein the vitamin D receptor gene comprises a BsmI site, an ApaI site and a TaqI site, wherein the BsmI site can exist as a B or b allelic form, the ApaI site can exist as an A or a allelic form, and the TaqI site can exist as a T or t allelic form, the method comprising analyzing nucleic acid molecules of the mammalian subject to determine which of the B, b, A, a, T, and t alleles of the BsmI, ApaI and TaqI sites of the vitamin D receptor gene are present.

### Claim 35 (depends on 34)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 34, said method comprising analyzing nucleic acid molecules of the mammalian subject to determine whether a baT haplotype of the vitamin D receptor gene is present.

### Claim 36 (depends on 34)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 34, said method further comprising determining the copy number of a member of the group consisting of the P, p, X and x alleles of the estrogen receptor α. gene and the B, b, A, a, T and t alleles of the vitamin D receptor gene.

### Claim 37 (depends on 31)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 31, wherein the subject is a human female.

### Claim 38 (depends on 31)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 31, wherein said method is performed in vitro.

### Claim 39 (depends on 38)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 38, wherein said method is performed on a blood or tissue sample of a subject.

### Claim 40 (depends on 31)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 31 wherein the mammalian subject is suffering from low bone mineral density.

### Claim 41 (depends on 31)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 31 wherein the mammalian subject has a normal level of bone mineral density.

### Claim 42 (depends on 31)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 31, wherein the presence of the haplotype is determined by amplification of a portion of the first intron of the estrogen receptor α gene to yield an amplified fragment, followed by restriction enzyme digestion of the amplified fragment.

### Claim 43 (depends on 42)

The method of detecting p and x alleles of a PvuII site and a XbaI site in an estrogen receptor α gene according to claim 42, further comprising determining the haplotype of a vitamin D receptor gene by amplification of a portion of the vitamin D receptor gene between exon 7 and the 3′ untranslated region to yield an amplified fragment, followed by restriction enzyme digestion of the amplified fragment.

### Claim 44

A method of determining the susceptibility of bone fracture and treating the same in a mammalian subject to prevent or reduce the risk of bone fracture, wherein the mammalian subject comprises at least one estrogen receptor α gene comprising a PvuII site and a XbaI site, wherein the PvuII site can exist as a P or pallelic form, and the XbaI site can exist as an X or x allelic form, the method comprising analyzing nucleic acid molecules obtained from the mammalian subject to determine which of the P, p, X and x alleles of the PvuII and XbaI sites of the estrogen receptor α gene are present, wherein the presence of a haplotype comprising the p and x alleles is indicative of an increased susceptibility to bone fracture, and treating the mammalian subject to reduce the risk of bone fracture if the subject has a haplotype comprising the p and x alleles.

### Claim 45 (depends on 44)

The method of claim 44 further comprising analyzing nucleic acid molecules of the mammalian subject to determine whether the px haplotype of the estrogen receptor α gene is present, wherein the presence of the px haplotype is indicative of an increased susceptibility to bone fracture.

### Claim 46 (depends on 44)

The method of claim 44 further comprising analyzing nucleic acid molecules of the mammalian subject to determine which of the B, b, A, a, T and t alleles of the BsmI, ApaI and TaqI sites of the vitamin D receptor gene are present, wherein the presence of a haplotype comprising at least one of the b, a, and T alleles is indicative of an increased susceptibility to bone fracture.

### Claim 47 (depends on 44)

The method of claim 44 further comprising analyzing nucleic acid molecules of the mammalian subject to determine whether the baT haplotype of the vitamin D receptor gene is present, wherein the presence of the baT haplotype is indicative of an increased susceptibility to bone fracture.

### Claim 48 (depends on 44)

The method of claim 44, said method further comprising determining the copy number of a member of the group consisting of the P, p, X and x alleles of the estrogen receptor α gene and the B, b, A, a, T and t alleles of the vitamin D receptor gene, before treating the subject to reduce the risk of bone fracture if the subject has a haplotype comprising the p and x alleles of the estrogen receptor α gene.

### Claim 49 (depends on 44)

The method of claim 44, wherein the treatment comprises at least one of modifications to lifestyle, regular exercise, changes in diet and administration of a pharmaceutical preparation effective to prevent or reduce the risk of bone fracture.

### Claim 50 (depends on 44)

The method of claim 44, wherein the subject is a human female.