Disease susceptibility

Abstract

The invention provides a method of assessing the susceptibility of a subject to, or aiding the diagnosis of, an anxiety disorder or depression, the method comprising determining whether the subject has a haplotype comprising rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951 with respective alleles ‘+CT, ‘C’, ‘T’, ‘C’ and ‘C’. The invention provides a kit of parts or solid substrate for use in assessing the susceptibility of a subject to an anxiety disorder or depression, the kit comprising or the solid substrate having attached thereto one or more nucleic acid molecules that hybridise selectively to a genomic region encompassing any two or more SNPs selected from the group consisting of rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951, and/or that hybridise selectively to a genomic region encompassing two or more polymorphic sites in linkage disequilibrium with any one or more SNPs selected from the group consisting of rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951.

1 . A method of assessing the susceptibility of a subject to, or of aiding the diagnosis of, an anxiety disorder or depression, the method comprising determining whether the subject has a haplotype comprising rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951 with respective alleles ‘+CT’, ‘C’, ‘T’, ‘C’ and ‘C’. 
     
     
         2 . The method according to  claim 1 , wherein determining whether the subject has a haplotype comprising rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951 with respective alleles ‘+CT’, ‘C’, ‘T’, ‘C’ and ‘C’, comprises genotyping any one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951, and/or one or more polymorphic sites which are in linkage disequilibrium with any one or more SNPs selected from the group consisting of rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951, wherein reduced susceptibility is indicated when the allele of the one or more SNPs is respectively one or more of ‘+CT’, ‘C’, ‘T’, ‘C’ and ‘C’, and/or when the allele of the one or more polymorphic sites is one that is in linkage disequilibrium with the respective one or more ‘+CT’, ‘C’, ‘T’, ‘C’ and ‘C’ alleles of the one or more SNPs. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The method according to  claim 1 , wherein the one or more polymorphic sites which are in linkage disequilibrium with any one or more SNPs selected from the group consisting of rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951, are SNPs selected from the group consisting of rs5522, rs5525 and rs7671250, wherein reduced susceptibility is indicated when the allele of one or more of rs5522, rs5525 and rs7671250 is respectively ‘A’, ‘C’ and ‘T’. 
     
     
         6 . The method according to  claim 1 , wherein the one or more polymorphic sites are SNPs selected from the group consisting of rs7671250, rs5522, rs5525, rs4835519, rs2172002, rs11929719, rs11099695, rs11730626, rs2070949, rs2248038, rs9992256, rs5520, and SNP x at position 149585620 in the MR gene as numbered in  FIG. 4 . 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A method of combating an anxiety disorder or depression in a subject, the method comprising assessing the susceptibility of a subject to, or aiding the diagnosis of, an anxiety disorder or depression according to  claim 1 , and depending upon the outcome of the assessment treating the subject. 
     
     
         13 . The method according to  claim 12 , wherein treating the subject comprises administering any one or more of an anti-depressant, an anti-convulsant, a beta-blocker, Cortisol, a Cortisol agonist, a Cortisol antagonist, an MR agonist, an MR antagonist, or an agent that modulates MR-expression to the subject. 
     
     
         14 . The method according to  claim 1 , wherein the anxiety disorder is any of substance-induced anxiety disorder, generalised anxiety, panic disorder, acute stress disorder, post-traumatic stress disorder, adjustment disorder with anxious features, social phobia, obsessive-compulsive disorder or specific phobias. 
     
     
         15 . (canceled) 
     
     
         16 . A method of selecting an agent that modulates at least one activity of an MR in a MR gene haplotype-dependent manner, comprising:
 i) providing two or more MRs encodable by a respective two or more of a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘G’ and ‘A’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘C’ and ‘A’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘C’ and ‘G’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘G’ and ‘G’;   ii) providing a test agent; and   iii) assessing whether the test agent modulates at least one activity of each MR in a MR gene haplotype-dependent manner.   
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The method according to  claim 16 , wherein the test agent is a steroid or a selective serotonin uptake inhibitor, or a tricyclic antidepressant. 
     
     
         20 . (canceled) 
     
     
         21 . The method according to  claim 16 , wherein step (iii) comprises assessing if the test agent modulates expression of a reporter polynucleotide operably linked to an MR responsive promoter. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method according to  claim 21 , wherein expression of the reporter polynucleotide is determined by measuring the level of mRNA expressed from the reporter polynucleotide, measuring the concentration of a protein encoded by the reporter polynucleotide or measuring the activity or function of a protein encoded by the reporter polynucleotide. 
     
     
         26 . The method according to  claim 16 , wherein step (iii) comprises assessing if the test agent modulates binding of the MR to a MR binding partner, or wherein step (iii) comprises assessing if the test agent modulates the effect of MR on Cortisol or ACTH levels. 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . The method according to  claim 16 , wherein the method is performed in vivo or ex vivo. 
     
     
         31 . The method according to  claim 30 , wherein the two or more MRs in step (i) are provided in two or more respective subjects whose MR genotype is known or in two or more respective cells obtained from subjects whose MR genotype is known. 
     
     
         32 . (canceled) 
     
     
         33 . A method for classifying a subject according to the effectiveness of a treatment regime for an MR-related disorder, the method comprising determining whether a subject has a haplotype comprising rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951 with respective alleles ‘−CT, ‘C’, ‘G’ and ‘G’, or a haplotype comprising rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951 with respective alleles ‘+CT’, ‘C’, ‘T’, ‘C’ and ‘C’, or a haplotype comprising rs2070951 and rs5522 with respective alleles ‘G’ and ‘G’, or a haplotype comprising rs3216799, rs6814934, rs7658048, rs2070950 and rs2070951 with respective alleles ‘−CT’, ‘C’, ‘C’, ‘C’ and ‘C’, and either (i) administering a treatment regime, and assessing the effectiveness of the treatment regime, or (ii) administering an appropriate treatment regime for that haplotype, wherein the subject is one that has an MR-related disorder. 
     
     
         34 . The method according to  claim 33 , wherein the MR-related disorder is anxiety disorder or depression, or a disorder associated with an anxiety disorder or depression such as any of cardiovascular disease, metabolic disorder (e.g. metabolic syndrome), Fibromyalgia, insomnia, Alzheimers disease, somatic disorder, bipolar disorder, pain, osteoporosis and immune disorder. 
     
     
         35 . A kit of parts for use in selecting an agent that modulates at least one activity of an MR in a MR gene haplotype-dependent manner, comprising two or more MRs encoded by a respective two or more of a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘G’ and ‘A’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘C’ and ‘A’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘C’ and ‘G’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘G’ and ‘G’, or a respective two or more polynucleotides encoding said MRs. 
     
     
         36 . The kit of parts according to  claim 35 , comprising three or four MRs encoded by a respective three or four of a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘G’ and ‘A’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘C’ and ‘A’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘C’ and ‘G’, or a MR gene haplotype comprising rs2070951 and rs5522 with respective alleles ‘G’ and ‘G’, or a respective three or four polynucleotides encoding said MRs. 
     
     
         37 . The kit of parts according to  claim 35 , further comprising a reporter gene operably linked to an MR responsive promoter. 
     
     
         38 . The kit of parts according to  claim 37 , wherein the kit further comprises a substrate for detecting the reporter gene.