Disease risk factors and methods of use

Abstract

Provided herein are genetic variants associated with development of a condition of interest (e.g., Alzheimer's disease). 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.

1 - 26 . (canceled) 
     
     
         27 . 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.   
     
     
         28 . The method of  claim 27 , wherein the variant is a poly-T DIP at rs10524523 in intron 6 of the TOMM40 gene. 
     
     
         29 . The method of  claim 28 , 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. 
     
     
         30 . The method of  claim 28 , wherein the poly-T DIP has a poly-T length of from about 19 to about 30. 
     
     
         31 . The method of  claim 27 , further comprising detecting whether said subject has an ApoE genotype of E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. 
     
     
         32 . The method of  claim 27 , further comprising detecting whether said subject has an ApoE genotype of E3/E3 or E3/E4. 
     
     
         33 . The method of  claim 27 , wherein the detecting comprises PCR amplification and/or DNA sequencing. 
     
     
         34 . The method of  claim 33 , 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. 
     
     
         35 . The method of  claim 33 , 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. 
     
     
         36 . 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). 
     
     
         37 . The method of  claim 36 , wherein the poly-T DIP is at rs10524523 in intron 6 of the TOMM40 gene. 
     
     
         38 . The method of  claim 37 , wherein the poly-T DIP has a poly-T length of from about 19 to about 30 T residues. 
     
     
         39 . The method of  claim 37 , wherein the poly-T length is from 19±1.58 to 30±1.58 T residues. 
     
     
         40 . The method of  claim 37 , wherein the poly-T length is from 19 to 29 T residues. 
     
     
         41 . The method of  claim 37 , wherein the subject has an ApoE genotype of E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. 
     
     
         42 . The method of  claim 37 , wherein the subject has an ApoE genotype of E3/E3 or E3/E4. 
     
     
         43 . The method of  claim 36 , wherein the treating comprises delaying the progression of Alzheimer's disease. 
     
     
         44 . The method of  claim 36 , 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. 
     
     
         45 . The method of  claim 36 , wherein the active agent is a peroxisome proliferator-activated receptor agonist or modulator. 
     
     
         46 . The method of  claim 36 , wherein the active agent is a thiazolidinedione. 
     
     
         47 . The method of  claim 36 , wherein the active agent is pioglitazone. 
     
     
         48 . The method of  claim 47 , wherein the pioglitazone is formulated in a pharmaceutical carrier. 
     
     
         49 . The method of  claim 43 , wherein the subject has mild cognitive impairment. 
     
     
         50 . The method of  claim 49 , wherein the mild cognitive impairment comprises amnesic mild cognitive impairment. 
     
     
         51 . 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). 
     
     
         52 . The method of  claim 51 , wherein the poly-T DIP is at rs10524523 in intron 6 of the TOMM40 gene. 
     
     
         53 . The method of  claim 52 , wherein the poly-T DIP has a poly-T length of from about 19 to about 30. 
     
     
         54 . The method of  claim 53 , wherein the poly-T length is from 19±1.58 to 30±1.58 T residues. 
     
     
         55 . The method of  claim 53 , wherein the poly-T length is from 19 to 29 T residues. 
     
     
         56 . The method of  claim 52 , wherein the subject has an ApoE genotype of E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. 
     
     
         57 . The method of  claim 52 , wherein the subject has an ApoE genotype of E3/E3 or E3/E4. 
     
     
         58 . The method of  claim 52 , 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. 
     
     
         59 . The method of  claim 52 , wherein the active agent is a peroxisome proliferator-activated receptor agonist or modulator. 
     
     
         60 . The method of  claim 52 , wherein the active agent is a thiazolidinedione. 
     
     
         61 . The method of  claim 52 , wherein the active agent s pioglitazone. 
     
     
         62 . The method of  claim 61 , wherein the pioglitazone is formulated in a pharmaceutical carrier. 
     
     
         63 . The method of  claim 52 , wherein the subject has mild cognitive impairment. 
     
     
         64 . The method of  claim 63 , wherein the mild cognitive impairment comprises amnesic mild cognitive impairment.