Method for identifying disease risk factors

Abstract

Provided herein is a method for identifying a genetic variant that is associated with development of a condition of interest (e.g., Alzheimer's disease), and genetic variants so identified. Methods of treatment with an active agent (e.g., with a particular active agent and/or at an earlier age) is also provided, upon detecting a genetic variant described herein. In some embodiments, the genetic variant is a deletion/insertion polymorphism (DIP) of the TOMM40 gene. Kits for determining if a subject is at increased risk of developing late onset Alzheimer's disease is also provided. Kits for determining if a subject is responsive to treatment for a condition of interest with an active agent are further provided.

1 - 86 . (canceled) 
     
     
         87 . A method of determining increased risk for developing Alzheimer's disease in a human subject, comprising:
 (a) detecting from a biological sample obtained from the subject the presence or absence of a genetic variant of the TOMM40 gene associated with increased or decreased risk of developing Alzheimer's disease, wherein the variant is a deletion/insertion polymorphism (DIP) in intron 6 or intron 9 of the TOMM40 gene; and   (b) determining the subject is at increased risk of developing of Alzheimer's disease if the genetic variant is detected.   
     
     
         88 . The method of  claim 87 , wherein the variant is a poly-T DIP at rs10524523 in intron 6 of the TOMM40 gene. 
     
     
         89 . The method of  claim 88 , comprising determining the subject is at increased risk of developing of Alzheimer's disease when the poly-T DIP at rs10524523 in intron 6 of the TOMM40 gene is present. 
     
     
         90 . The method of  claim 88 , wherein the poly-T DIP has a poly-T length of from about 21 to about 30. 
     
     
         91 . The method of  claim 87 , further comprising detecting whether said subject has an ApoE genotype of E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. 
     
     
         92 . The method of  claim 87 , further comprising detecting whether said subject has an ApoE genotype of E3/E3 or E3/E4. 
     
     
         93 . The method of  claim 87 , wherein the detecting comprises PCR amplification and/or DNA sequencing. 
     
     
         94 . The method of  claim 93 , wherein the PCR amplification comprises amplifying a DNA sequence with a primer selected from the group consisting of SEQ ID. NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, and 49. 
     
     
         95 . The method of  claim 93 , wherein the PCR amplification comprises amplifying a DNA sequence with a primer selected from the group consisting of SEQ ID. NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 32, 44, 46, 48, 50, 51, and 52. 
     
     
         96 . A method of treating Alzheimer's disease comprising administering an anti-Alzheimer's disease active agent to a subject when a genetic variant in intron 6 or intron 9 of the TOMM40 gene is present in the subject, wherein the genetic variant is a poly-T deletion/insertion polymorphism (DIP). 
     
     
         97 . The method of  claim 96 , wherein the poly-T DIP is at rs10524523 in intron 6 of the TOMM40 gene. 
     
     
         98 . The method of  claim 97 , wherein the poly-T DIP has a poly-T length of from about 21 to about 30 T residues. 
     
     
         99 . The method of  claim 98 , wherein the poly-T length is from 21 to 30±1.58 T residues. 
     
     
         100 . The method of  claim 99 , wherein the poly-T length is from 21 to 29 T residues. 
     
     
         101 . The method of  claim 97 , wherein the subject has an ApoE genotype of E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. 
     
     
         102 . The method of  claim 97 , wherein the subject has an ApoE genotype of E3/E3 or E3/E4. 
     
     
         103 . The method of  claim 96 , wherein the treating comprises delaying the progression of Alzheimer's disease. 
     
     
         104 . The method of  claim 96 , wherein the active agent is selected from the group consisting of an acetylcholinesterase inhibitor, a NMDA receptor antagonist, a peroxisome proliferator-activated receptor agonist or modulator, an antibody, a fusion proteins, a therapeutic RNA molecule, and combinations thereof. 
     
     
         105 . The method of  claim 96 , wherein the active agent is a peroxisome proliferator-activated receptor agonist or modulator. 
     
     
         106 . The method of  claim 96 , wherein the active agent is a thiazolidinedione. 
     
     
         107 . A method of delaying the onset of Alzheimer's disease comprising administering an anti-Alzheimer's disease active agent to a subject when a genetic variant in intron 6 or intron 9 of the TOMM40 gene is present in the subject, wherein the genetic variant is a poly-T deletion/insertion polymorphism (DIP). 
     
     
         108 . The method of  claim 107 , wherein the poly-T DIP is at rs10524523 in intron 6 of the TOMM40 gene. 
     
     
         109 . The method of  claim 108 , wherein the poly-T DIP has a poly-T length of from about 21 to about 30 T residues. 
     
     
         110 . The method of  claim 109 , wherein the poly-T length is from 21 to 30±1.58 T residues. 
     
     
         111 . The method of  claim 110 , wherein the poly-T length is from 21 to 29 T residues. 
     
     
         112 . The method of  claim 108 , wherein the subject has an ApoE genotype of E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. 
     
     
         113 . The method of  claim 108 , wherein the subject has an ApoE genotype of E3/E3 or E3/E4. 
     
     
         114 . The method of  claim 108 , wherein the active agent is selected from the group consisting of an acetylcholinesterase inhibitor, a NMDA receptor antagonist, a peroxisome proliferator-activated receptor agonist or modulator, an antibody, a fusion proteins, a therapeutic RNA molecule, and combinations thereof. 
     
     
         115 . The method of  claim 108 , wherein the active agent is a peroxisome proliferator-activated receptor agonist or modulator. 
     
     
         116 . The method of  claim 108 , wherein the active agent is a thiazolidinedione. 
     
     
         117 . The method of  claim 116 , wherein the thiazolidinedione is formulated in a pharmaceutical carrier.