Novel Pharmacogene Single Nucleotide Polymorphisms and Methods of Detecting Same

• US 20140038836A1
• Filed: 05/29/2013
• Published: 02/06/2014
• Est. Priority Date: 05/29/2012
• Status: Abandoned Application

• Current Assignee: Assurex Health, Inc. (Myriad Genetics, Inc.)
• Original Assignee: Assurex Health, Inc. (Myriad Genetics, Inc.)
• Inventors: Higgins, Gerald A., Altar, C. Anthony
• Application Number:
  US13/904,792
• Publication Number:
  US 20140038836A1
• Time in Patent Office: Days
• US Class Current: 506/9
• CPC Class Codes: C12Q 1/6827 for detection of mutation or polymorphism
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G16B 15/00 ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 30/00 ICT specially adapted for sequence analysis involving nucleotides or amino acids
• CPC Class Codes: G16B 30/10 Sequence alignment; Homology search

Abstract

The present invention provides pharmacogene polymorphisms and their use in predicting therapeutic effectiveness. The present invention also provides methods comprising targeted analysis of selected pharmacogenes in thousands of compiled whole human genome sequences for identifying polymorphic sequences associated with drug response are described. The methods also provide confirmation and validation of these pharmacogene polymorphisms, based on concordance between different sequencing technologies, and statistical error-checking. Imputation of the deleterious consequences of novel variants is predicted by bioinformatics analysis.

Claims

1. A method for interrogating thousands of aggregated whole human genome sequences, the method comprising (a) using a targeted analysis of one or more selected pharmacogenes and (b) determining polymorphic sequences that may associate with a drug response, wherein the method is executed on an inexpensive, energy-efficient, and heterogeneous graphics processing unit (GPU)-cluster based workstation.

2. The method of claim 1, comprising the steps of (a) aggregating and performing a concordance check on populations of completed whole genome DNA sequences;

(b) scanning assembled whole human genomes for target enrichment of one or more selected pharmacogenes, wherein said scanning is performed by using genome browser coordinates for the one or more selected pharmacogenes based on user input;

(c) applying a multi-genome variant analysis algorithm to identify gene variants in said one or more pharmacogenes;

(d) optionally, applying an algorithm to identify a potentially deleterious mutation that could impact a drug response; and

(e) detecting a single nucleotide polymorphism (SNP), a multi-nucleotide polymorphism (MNP) or both SNP and MNP, but not other structural variants, and applying a statistical error-checking method to validate the SNP, MNP, or both SNP and MNP having allele frequencies of 0.1% to 99%.

3. The method of claim 1, wherein the one or more selected pharmacogenes comprises one or more genes selected from the group consisting of the ABCB1 gene, the ADCYAP1R1 gene, the ADRA2A gene, the BDNF gene, the COMT gene, the CRHBP gene, the CRHR1 gene, the DBI gene, the DRD2 gene, the DRD4 gene, the FKBP5 gene, the GCR gene, the HTR2A gene, the HTR2C gene, the NPY gene, the NT3 gene, the NTRK2 gene, the OPRM1 gene, the SLC6A2 gene, the SLC6A3 gene, and the SLCA4 gene.

4. The method of claim 3, wherein the SNP, MNP, or both SNP and MNP is selected from one or more of the polymorphisms identified in SEQ ID NOs:

1-15 (gene;

ABCB1), 16 (ADCYAPIR1), 17-18 (ADRA2A), 19-20 (BDNF), 21-23 (COMT), 24 (CRHBP), 25-28 (CRHR1), 29-46 (DBI), 47-51 (DRD2), 52-54 (DRD4), 55-64 (FKBP5), 65-71 (GCR), 72-76 (HTR2A), 77 (HTR2C), 78-79 (NPY), 80-83 (NT3), 84-93 (NTRK2), 94-96 (OPRM1), 97-98 (SLC6A2), 99-110 (SLC6A3), and 111-118 (SLC6A4).

5. A method for determining likelihood of an adverse or modified response to an anti-depressant or psychiatric drug in a patient in need thereof, the method comprising obtaining a biological sample from said patient and assaying the biological sample for the presence at least one polymorphism in one or more pharmacogenes selected from those identified in SEQ ID NOs:

1-118, wherein the presence of at least one polymorphism indicates that an adverse or modified response to the anti-depressant or psychiatric drug is likely.

6. The method of claim 5, wherein the anti-depressant or psychiatric drug is selected from the group consisting of clozapine, fluvoxamine, escitalopram, paroxetine, amitriptyline, venlafaxine, citalopram, risperidone, nortriptyline, fluoxetine, olanzapine, tricyclic antidepressants, selective serotonin reuptake inhibitors, mitrtazapine, oxymetazoline, clonidine, epinephrine, norepinephrine, phenylephrine, dopamine, p-synephrine, p-tyramine, serotonin, p-octopamine, yohimbine, phentolamine, mianserine, chlorpromazine, spiperone, prazosin, propranolol, alprenolol, and pindolol.

7. An isolated nucleic acid consisting of any one of the sequences identified by SEQ ID NOs:

1-118.

8. The isolated nucleic acid of claim 7, wherein the nucleic acid is a cDNA.

9. A vector comprising the isolated nucleic acid of claim 7.

10. A cell comprising the isolated nucleic acid of claim 7.