Endophenotypes of TBI: Insights into Pathophysiology and Implications for Therapy <br />Ramon Diaz-Arrastia, MD, PhD<br />...
Neuroprotective Drugs in Animal Models<br />GluR antagonists<br />NMDA antagonists<br />MK-801<br />Ketamine<br />Dextrome...
Endophenotypes<br />Endophenotype 1<br />Endophenotype 2<br />Phenotype<br />Endophenotype 3<br />Endophenotype n<br />
Endophenotypes of Myocardial Infarction<br />Hypertension<br />Hyperlipidemia<br />Myocardial Infarction<br />Vascular inf...
Endophenotypes of TBI<br />Intracranial <br />hemorrhage<br />Inflammation<br />Phenotype<br />Diffuse Axonal Injury<br />...
Subtypes of TBI<br />DAI<br />EDH<br />Contusion/Hematoma<br />SDH<br />SAH/IVH<br />Diffuse Swelling<br />Courtesy of Ali...
Subtypes of TBI Identified by MRI<br />ADC<br />CT<br />DWI<br />FLAIR<br />
Outline of Presentation<br />Principles of Allelic Association<br />Existing Allelic Association Studies in TBI<br />Lesso...
Types of Genetic Association Studies<br />Linkage analysis<br />Extremely effective for single-gene diseases <br />Caused ...
Types of Genetic Association Studies<br />Allelic Association Studies<br />Based on polymorphic alleles traveling with dis...
Types of Genetic Association Studies<br />Allelic Association Studies<br />Candidate Gene Approach<br />Feasible for past ...
Types of Genetic Association Studies<br />Allelic Association Studies<br />Genome Wide Allelic Association (GWAS)<br />Fea...
Power Calculation—Required number of subjects<br />in each group to detect genotypic risk<br /><ul><li> = 0.00005</li></ul...
Power Calculation—Required number of subjects<br />in each group to detect genotypic risk<br /><ul><li> = 0.00005</li></ul...
Candidate Gene Studies in TBI<br />Apolipoprotein E<br />E4 allele associated with poor outcome in several studies<br />No...
Allelic Association of APOE4 in TBI<br />
Negative Allelic Association of APOE4 in TBI<br />
Weight of evidence supports an association between APOE4 and poor outcome after TBI.  <br />The association is modest and ...
Allelic Association of Candidate Genes in TBI<br />
Multiple genes associated with poor outcome after TBI<br />None of published studies reach genome-wide level of significan...
Lessons from AD Research<br />State of AD Genetics Research in 2007<br /> Over 300genes had been associated in candidate g...
Haplotype Map of the Human Genome<br />Goals:<br /><ul><li>Define patterns of genetic variation across human genome
Guide selection of SNPs efficiently to “tag” common variants
Public release of all data (assays, genotypes)</li></ul>Phase I:      1.3 M markers in 269 people<br />Phase II:  +2.8 M m...
GWAS in AD<br />A total of 13 GWAS studies published so far<br />At least 10 genes have been reproducibly associated with ...
BIN1
CLU
ABCA7
CR1
PICALM
CD33
MS4A4E
MS4A6E
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Diaz-Arrastia, Ramon

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  • AddedNNZ-2566 (IGF-1 N-terminus tripeptide; Neuren Pharmaceuticals; penetrating TBI WRAIR and others)TRH
  • Diaz-Arrastia, Ramon

    1. 1. Endophenotypes of TBI: Insights into Pathophysiology and Implications for Therapy <br />Ramon Diaz-Arrastia, MD, PhD<br />Director of Clinical Research<br />Center for Neuroscience and Regenerative Medicine<br />Professor of Neurology<br />Uniformed Services University for Health Sciences<br />
    2. 2. Neuroprotective Drugs in Animal Models<br />GluR antagonists<br />NMDA antagonists<br />MK-801<br />Ketamine<br />Dextromethorphan<br />CGS19755<br />CPP<br />Cerostat<br />Selfotel<br />CP 101-606<br />AMPA/KA antagonists<br />CNQX<br />KYNA<br />GYKI-52466<br />Antioxidants<br />Alpha tocopherol<br />Tirilizad<br />SOD1<br />Dexanabinol<br />Anti-inflammatory<br />IL1-RA<br />TNF binding protein<br />Soluble CR-1 receptor<br />Anti-MAC-1<br />Minocycline<br />Immunophilins (CsA, FK-506)<br />Solumedrol<br />Neurotrophins<br />NGF<br />bFGF<br />IGF-1<br />NNZ-2566<br />EPO<br />Miscellaneous<br />TRH-related peptides<br />Hypothermia<br />Mg2+<br />CDP-Choline<br />Glyburide<br />Progesterone<br />
    3. 3. Endophenotypes<br />Endophenotype 1<br />Endophenotype 2<br />Phenotype<br />Endophenotype 3<br />Endophenotype n<br />
    4. 4. Endophenotypes of Myocardial Infarction<br />Hypertension<br />Hyperlipidemia<br />Myocardial Infarction<br />Vascular inflammation<br />Endophenotype n<br />
    5. 5. Endophenotypes of TBI<br />Intracranial <br />hemorrhage<br />Inflammation<br />Phenotype<br />Diffuse Axonal Injury<br />Endophenotype n<br />
    6. 6. Subtypes of TBI<br />DAI<br />EDH<br />Contusion/Hematoma<br />SDH<br />SAH/IVH<br />Diffuse Swelling<br />Courtesy of Alisa Gean, UCSF<br />
    7. 7. Subtypes of TBI Identified by MRI<br />ADC<br />CT<br />DWI<br />FLAIR<br />
    8. 8. Outline of Presentation<br />Principles of Allelic Association<br />Existing Allelic Association Studies in TBI<br />Lessons from Alzheimer’s Disease field<br />Future Genetic Studies in TBI<br />Need for International TBI Genetics Consortium<br />
    9. 9. Types of Genetic Association Studies<br />Linkage analysis<br />Extremely effective for single-gene diseases <br />Caused by mutations (polymorphisms) that are very rare (< 0.01) but highly penetrant (high phenotypic risk ratio, > 10)<br />Technology available for > 15 years<br />Not well suited for complex diseases<br />Multiple genes interact to produce phenotype<br />Caused by polymorphisms that are common (> 0.1) but with a low phenotypic risk ratio (1.5 – 4)<br />Environmental factors play a strong role <br />Particularly when environmental factors are rare and stochastic<br />
    10. 10. Types of Genetic Association Studies<br />Allelic Association Studies<br />Based on polymorphic alleles traveling with disease across families<br />Can be done in family, case-control, or population-based samples<br />Well-suited for studies on complex human diseases<br />Environmental factors can be identified and controlled <br />
    11. 11. Types of Genetic Association Studies<br />Allelic Association Studies<br />Candidate Gene Approach<br />Feasible for past 10 years<br />Many potential confounders<br />Multiple hypothesis testing and publication bias<br />Population stratification<br />Phenotypic heterogeneity<br />Most published studies are underpowered<br />Replication has been poor<br />
    12. 12. Types of Genetic Association Studies<br />Allelic Association Studies<br />Genome Wide Allelic Association (GWAS)<br />Feasible over the past 4 years<br />Human Genome Project and HapMap Project <br />Requires far larger samples of cases and controls (n = 2,000 – 20,000)<br />Requires sophisticated understanding of phenotypic variability of disease expression<br />Endophenome/ The “Human Phenome” Project<br />
    13. 13. Power Calculation—Required number of subjects<br />in each group to detect genotypic risk<br /><ul><li> = 0.00005</li></ul>b = 0.8<br />
    14. 14. Power Calculation—Required number of subjects<br />in each group to detect genotypic risk<br /><ul><li> = 0.00005</li></ul>b = 0.8<br />
    15. 15. Candidate Gene Studies in TBI<br />Apolipoprotein E<br />E4 allele associated with poor outcome in several studies<br />Not uniformly reproducible<br />Other gene variants associated with features of outcome<br />DRD2, DAT, ACE, IL1RN, IL1A*2, ACE, COMT, p53, MAO-A, bcl-2, BDNF, Neprilysin, NGB1, 5HTT <br />Very few have been confirmed<br />None with genome-wide level of significance<br />
    16. 16. Allelic Association of APOE4 in TBI<br />
    17. 17. Negative Allelic Association of APOE4 in TBI<br />
    18. 18. Weight of evidence supports an association between APOE4 and poor outcome after TBI. <br />The association is modest and does not extend to all endophenotypes<br />Mechanism of association is not known <br />Allelic Association of APOE4 in TBI<br />
    19. 19. Allelic Association of Candidate Genes in TBI<br />
    20. 20. Multiple genes associated with poor outcome after TBI<br />None of published studies reach genome-wide level of significance<br />Besides APOE4, replication has been very sparse<br />Allelic Association in TBI<br />
    21. 21. Lessons from AD Research<br />State of AD Genetics Research in 2007<br /> Over 300genes had been associated in candidate gene studies with AD risk<br />Most studies small. None reached genome-wide level of significance<br />Only APOE was consistently replicated<br />Since 2008, multiple GWAS studies have found reproducible associations with 10 additional genes<br />
    22. 22. Haplotype Map of the Human Genome<br />Goals:<br /><ul><li>Define patterns of genetic variation across human genome
    23. 23. Guide selection of SNPs efficiently to “tag” common variants
    24. 24. Public release of all data (assays, genotypes)</li></ul>Phase I: 1.3 M markers in 269 people<br />Phase II: +2.8 M markers in 270 people<br />
    25. 25. GWAS in AD<br />A total of 13 GWAS studies published so far<br />At least 10 genes have been reproducibly associated with AD risk at genome-wide significance levels<br /><ul><li>APOE
    26. 26. BIN1
    27. 27. CLU
    28. 28. ABCA7
    29. 29. CR1
    30. 30. PICALM
    31. 31. CD33
    32. 32. MS4A4E
    33. 33. MS4A6E
    34. 34. CD2AP</li></li></ul><li>
    35. 35. Lessons from AD Genetics Research<br />Number of TBI patients studied must increase by 1 order of magnitude<br />2,000 – 20,000 is standard these days<br />Large international collaborative efforts are required<br />Careful attention must be paid to quantitative endophenotypes <br />
    36. 36. High Throughput Biomarker Assays<br />Luminex-based Multiplex Immunoassays<br />Rules Based Medicine, Inc.<br />Austin, Texas<br />O’Bryant et al, Arch Neurol 2010;67:1077-1081<br />
    37. 37. Human MAP v.1.6--Antigens<br />
    38. 38. Significant Analysis of Microarray (SAM)<br />O’Bryant et al, Arch Neurol 2010;67:1077-1081<br />
    39. 39. SAM <br />0<br />0<br />0<br />25<br />Wilcoxon test<br />1<br />Logistic regression<br />1<br />0<br />GRO alpha<br />VDBP<br />Venn Diagram of Analytical Methods<br />O’Bryant et al, Arch Neurol 2010;67:1077-1081<br />
    40. 40.
    41. 41. GWAS with Quantitative Endophenotypes<br />
    42. 42. Conclusions<br />Genetic factors play a role in response of neural tissue to traumatic insults<br />Good evidence for role of APOE<br />Likely other genes also involved<br />Current studies in TBI are underpowered by an order of magnitude<br />Collaborative effort will be needed<br />Attention to endophenotypes (imaging, biochemical, physiologic, psychometric) essential<br />Please Email: Ramon.Diaz-Arrastia@usuhs.mil<br />
    43. 43. Collaborators<br />UT Southwestern<br />Chris Madden<br />Anne Hudak <br />Mike Devous <br />Roderick McColl<br />Tony Whittemore<br />Baylor Institute for Rehabilitation<br />Stuart Yablon<br />Mary Carlile<br />Randi Dubiel<br />Cindy Dunklin<br />Libranda Callender<br />Eva Wooster<br />Tiffany Wren<br />NIH <br />R01 HD48179<br />U01 HD42652<br />R01 AG17861<br />US Dept. of Education<br />H133A070027<br />UT Southwestern<br />Caryn Harper<br />Carol Moore<br />Kan Ding<br />Matthew Warner<br />Catherine Oldenkamp<br />Teddy Youn<br />Lifang Peng<br />Nasreen Sayed<br />Christopher Paliotta<br />Yale Gong<br />UT Dallas<br />Carlos Marquez de la Plata<br />Jun-Yi Wang<br />Khamid Bakhadirov<br />Ana Arenivas<br />Carlee Culver <br />University of North Carolina<br />Kirk Wilhelmsen<br />Scott Chasse<br />

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