Method of 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.

That which is claimed is: 
     
         1 . A method of determining increased risk for development of Alzheimer's disease in a subject, comprising:
 (a) detecting from a biological sample containing DNA taken from said subject the presence or absence of a genetic variant of the TOMM40 gene associated with increased or decreased risk of Alzheimer's disease, wherein said variant is a deletion/insertion polymorphism (DIP) in intron 6 or intron 9 of the TOMM40 gene; and   (b) determining said subject is at increased or decreased risk of Alzheimer's disease when said genetic variant is present or absent.   
     
     
         2 . The method of  claim 1 , wherein said detecting comprises PCR amplification and/or DNA sequencing. 
     
     
         3 . The method of  claim 1 , further comprising detecting an Apo E genotype of the subject, and wherein said determining said subject is at increased or decreased risk of Alzheimer's disease is further based upon the Apo E genotype. 
     
     
         4 . The method of  claim 1 , further comprising the step of:
 (c) administering an anti-Alzheimer's disease active agent to said subject in a treatment effective amount when said subject is determined to be at increased risk of Alzheimer's disease.   
     
     
         5 . The method of  claim 4 , wherein said administering step is carried out in said subject at an earlier age when said subject is determined to be at increased risk by the presence or absence of said genetic variant as compared to a subject in which said genetic variant is not present or absent. 
     
     
         6 . The method of  claim 4 , wherein said active agent is selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, peroxisome proliferator-activated receptor agonists or modulators, antibodies, fusion proteins, therapeutic RNA molecules, and combinations thereof. 
     
     
         7 . The method of  claim 4 , wherein said active agent is a peroxisome proliferator-activated receptor agonist or modulator. 
     
     
         8 . The method of  claim 4 , wherein said active agent is a thiazolidinedione. 
     
     
         9 . The method of  claim 1 , wherein said genetic variant of the TOMM40 is a poly-T DIP length at rs10524523. 
     
     
         10 . A method of treating a subject for Alzheimer's disease comprising:
 administering an anti-Alzheimer's disease active agent to said subject in a treatment-effective amount, said administering carried out at an earlier age when said subject carries a genetic variant of the TOMM40 gene associated with increased risk of Alzheimer's disease as compared to a corresponding subject who does not carry said genetic variant,   wherein said genetic variant of the TOMM40 is a deletion/insertion polymorphism (DIP) in intron 6 or intron 9 of the TOMM40 gene.   
     
     
         11 . The method of  claim 10 , wherein said active agent is selected from the group consisting of acetylcholinesterase inhibitors, NMDA receptor antagonists, peroxisome proliferator-activated receptor agonists or modulators, antibodies, fusion proteins, therapeutic RNA molecules, and combinations thereof. 
     
     
         12 . The method of  claim 10 , wherein said active agent is a peroxisome proliferator-activated receptor agonist or modulator. 
     
     
         13 . The method of  claim 10 , wherein said active agent is a thiazolidinedione. 
     
     
         14 . The method of  claim 10 , wherein said genetic variant of the TOMM40 gene is a poly-T DIP length at rs10524523. 
     
     
         15 . A kit comprising:
 (A) at least one reagent to specifically detect a poly-T length at rs10524523 of the TOMM40 gene from a biological sample containing DNA from a human subject;   (B) buffers, enzymes and reagents for amplifying the DNA via primer-directed amplification; and   (C) optionally, instructions for use in amplifying a region of the TOMM40 gene comprising the poly-T at rs10524523.   
     
     
         16 . The kit of  claim 15 , wherein the at least one reagent comprises a nucleic acid for the primer-directed amplification. 
     
     
         17 . The kit of  claim 15 , wherein said kit further comprises: (D) at least one reagent to specifically detect an ApoE 3, ApoE 4, or ApoE 2 allele from the biological sample. 
     
     
         18 . The kit of  claim 17 , wherein the at least one reagent to specifically detect an ApoE 3, ApoE 4, or ApoE 2 allele comprises a nucleic acid for a primer-directed amplification of a region of the ApoE isoform. 
     
     
         19 . The kit of  claim 17 , wherein the at least one reagent to specifically detect an ApoE 3, ApoE 4, or ApoE 2 allele comprises an antibody that selectively binds an ApoE isoform, or an oligonucleotide probe that selectively binds to DNA encoding an ApoE isoform. 
     
     
         20 . The kit of  claim 19 , wherein the antibody or oligonucleotide probe is labeled with a detectable group.