Genetics:  A piece of the puzzle<br />Michael J. Ombrello, M.D.<br />Senior Clinical Fellow, Inflammatory Disease Section<...
Genetics:  A piece of the puzzle<br />Michael J. Ombrello, M.D.<br />Senior Clinical Fellow, Inflammatory Disease Section<...
Himmelfarb J. et al. Kidney International (2002) 62: 1524–1538.<br />
What is Juvenile Idiopathic Arthritis?<br />	Juvenile arthritis<br />	Juvenile rheumatoid arthritis<br />	Juvenile chronic...
Classification Criteria of JIA<br />International League of Associations for Rheumatology (ILAR) Classification Criteria:<...
Review of genetics principles<br />What is DNA?<br />What is a chromosome?<br />What is a gene?<br />What is a protein?<br...
What is DNA?<br />Deoxyribonucleic Acid<br />
What is a chromosome?<br />Largest organizational unit of genetic material<br />One cell has 6 feet of DNA<br />Linear DNA...
What is a gene?<br />The organizational unit of DNA that produces one specific protein<br />Range of 300 to 4300 genes per...
DNA is the template for making proteins<br />Proteins are the things within cells that “do” things<br />	Changes in DNA co...
What can genetics research teach us?<br />We hope to identify:<br />Genetic variants that affect risk<br />Cellular pathwa...
Mendelian (Simple) Genetics<br />Simple Genetic Trait<br />GregorMendel first described in garden peas<br />A trait (pheno...
Mendelian (Simple) Genetics<br />Mendeliantraits in humans<br />Freckles <br />Dimples<br />Cleft chin<br />Kinky hair<br ...
Hemophilia
Duchenne Muscular Dystrophy
Huntington’s Disease</li></li></ul><li>Complex Genetics<br />Complex Genetic Trait<br />A trait (phenotype) caused by the ...
Complex Genetics<br />Complex genetic traits in humans<br />Eye color<br />Hair color<br />Blood type (ABO)<br />Tongue ro...
Types of Genetic Studies<br />Candidate gene studies<br />Investigator chooses gene<br />Variants/markers in the region ar...
Types of Genetic Studies<br />Genome-wide association studies<br />Performed using commercial arrays that type variants/ma...
Manolio T. N Engl J Med 2010; 363:166-176.<br />
Genetics of juvenile arthritis<br />
“Lumping” studies of Juvenile Arthritis<br />ARGUMENT AGAINST “LUMPING” STUDIES<br />The seven JIA subtypes are different ...
“Juvenile Idiopathic Arthritis”<br />Autoimmunity susceptibility genes<br />TNF-a:  Inflammatory cytokine with broad effec...
Systemic Arthritis<br /><ul><li>Systemic juvenile idiopathic arthritis (sJIA) is characterized by:
Arthritis
Fever
One or more of the following:
Rash
Generalized lymphadenopathy
Organomegaly
Serositis
Causes are poorly understood
Innate immune involvement
Unclear role of adaptive immunity
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Genetics: A Piece of the Puzzle

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Genetics: A Piece of the Puzzle

  1. 1. Genetics: A piece of the puzzle<br />Michael J. Ombrello, M.D.<br />Senior Clinical Fellow, Inflammatory Disease Section<br />National Human Genome Research Institute<br />National Institutes of Health<br />Michael.Ombrello@nih.gov<br />
  2. 2. Genetics: A piece of the puzzle<br />Michael J. Ombrello, M.D.<br />Senior Clinical Fellow, Inflammatory Disease Section<br />National Human Genome Research Institute<br />National Institutes of Health<br />Michael.Ombrello@nih.gov<br />
  3. 3. Himmelfarb J. et al. Kidney International (2002) 62: 1524–1538.<br />
  4. 4. What is Juvenile Idiopathic Arthritis?<br /> Juvenile arthritis<br /> Juvenile rheumatoid arthritis<br /> Juvenile chronic arthritis<br />Juvenile idiopathic arthritis:<br />Onset of symptoms prior to 16th birthday<br />Arthritis present > 6 weeks without other cause<br />{<br />Juvenile Idiopathic Arthritis<br />Petty R.E. et al. J Rheumatology (2004) 31:390-392.<br />
  5. 5. Classification Criteria of JIA<br />International League of Associations for Rheumatology (ILAR) Classification Criteria:<br />Systemic arthritis<br />Oligoarthritis<br />Rheumatoid factor positive polyarthritis<br />Rheumatoid factor negative polyarthritis<br />Psoriatic arthritis<br />Enthesitis related arthritis<br />Undifferentiated arthritis<br />Petty R.E. et al. J Rheumatology (2004) 31:390-392.<br />
  6. 6. Review of genetics principles<br />What is DNA?<br />What is a chromosome?<br />What is a gene?<br />What is a protein?<br />Why perform genetic research?<br />What is a simple genetic trait?<br />What is a complex genetic trait?<br />
  7. 7. What is DNA?<br />Deoxyribonucleic Acid<br />
  8. 8. What is a chromosome?<br />Largest organizational unit of genetic material<br />One cell has 6 feet of DNA<br />Linear DNA folds into chromosomes<br />Normal Human Female<br />Image courtesy of U.S. National Library of Medicine<br />
  9. 9. What is a gene?<br />The organizational unit of DNA that produces one specific protein<br />Range of 300 to 4300 genes per human chromosome<br />Humans have 20,000 – 25,000 genes<br />
  10. 10. DNA is the template for making proteins<br />Proteins are the things within cells that “do” things<br /> Changes in DNA code may change the structure and function of the protein it encodes<br />
  11. 11. What can genetics research teach us?<br />We hope to identify:<br />Genetic variants that affect risk<br />Cellular pathways<br />Identification of these things may:<br />Reveal a novel or unrecognized therapeutic target<br />Allow prediction of therapeutic response<br />Uncover a novel biomarker<br />Advance our understanding of disease process<br />
  12. 12. Mendelian (Simple) Genetics<br />Simple Genetic Trait<br />GregorMendel first described in garden peas<br />A trait (phenotype) caused by variation in a single gene<br />Dominant trait caused by 1 copy of genetic variant<br />Recessive trait caused by 2 copies of genetic variant<br />
  13. 13. Mendelian (Simple) Genetics<br />Mendeliantraits in humans<br />Freckles <br />Dimples<br />Cleft chin<br />Kinky hair<br />Nearsightedness<br />Astigmatism<br />Lip size<br />Eye size<br />Blood Rh factor <br /><ul><li>Earlobe type</li></ul>Mendeliandiseases in humans<br />Cystic fibrosis<br /><ul><li>Sickle cell anemia
  14. 14. Hemophilia
  15. 15. Duchenne Muscular Dystrophy
  16. 16. Huntington’s Disease</li></li></ul><li>Complex Genetics<br />Complex Genetic Trait<br />A trait (phenotype) caused by the interaction of one or more genetic variants with environmental factors<br />Multiple genes may participate in a trait<br />Common and rare genetic variants<br />They are not always intuitive<br />Not always related to one another<br />Environmental factors may be involved<br />Infectious agents (viruses, bacteria, fungi, etc.)<br />Exogenous substances (diet, chemicals, etc.)<br />Endogenous substances (degradative or waste products)<br />Chance is also involved<br />
  17. 17. Complex Genetics<br />Complex genetic traits in humans<br />Eye color<br />Hair color<br />Blood type (ABO)<br />Tongue rolling<br />Complex genetic diseases in humans<br />Cancer<br />Lung cancer<br />Autoimmune Diseases<br />Rheumatoid arthritis<br />Inflammatory bowel disease<br />Type 1 diabetes mellitus<br />Atherosclerosis<br />Parkinson’s disease<br />Autism<br />Juvenile Idiopathic Arthritis<br />
  18. 18. Types of Genetic Studies<br />Candidate gene studies<br />Investigator chooses gene<br />Variants/markers in the region are typed<br />Compare frequency of markers<br />Advantages of candidate gene studies<br />Low cost study design<br />Relatively easy to perform<br />Limitations of candidate gene studies<br />Selection bias for genes studied<br />Differences in ethnic composition of cases and control groups<br />Sampling bias unless many individuals studied<br />Results are inconsistently replicated<br />
  19. 19. Types of Genetic Studies<br />Genome-wide association studies<br />Performed using commercial arrays that type variants/markers across the entire genome (usually over 1 million markers)<br />Compare frequency of many more markers<br />Advantages of genome wide association studies<br />Genome wide data allows exclusion of ethnically dissimilar subjects<br />Unlimited ability to detect <br />Limitations of genome wide association studies<br />Require very large numbers of cases and controls<br />Relatively expensive to perform<br />Arrays only examine common variants<br />
  20. 20. Manolio T. N Engl J Med 2010; 363:166-176.<br />
  21. 21. Genetics of juvenile arthritis<br />
  22. 22. “Lumping” studies of Juvenile Arthritis<br />ARGUMENT AGAINST “LUMPING” STUDIES<br />The seven JIA subtypes are different diseases<br />We should not expect the same genetic causes<br />ARGUMENT FOR “LUMPING” STUDIES<br />JIA is rare, and lumping increases statistical power<br />Though different, all subtypes involve arthritis developing at a young age<br />All JIA subtypes appear to be complex diseases<br />Some genes are bound to overlap among types<br />
  23. 23. “Juvenile Idiopathic Arthritis”<br />Autoimmunity susceptibility genes<br />TNF-a: Inflammatory cytokine with broad effects<br />Numerous therapeutics are widely used in JIA<br />CTLA-4: Signaling molecule that protects “self” from T cells<br />Therapeutic in use as second line agent in JIA<br />PTPN22: Signaling molecule that affects adaptive immune system<br />Variants can influence autoimmunity<br />STAT4: Transcription factor for inflammatory genes<br />
  24. 24. Systemic Arthritis<br /><ul><li>Systemic juvenile idiopathic arthritis (sJIA) is characterized by:
  25. 25. Arthritis
  26. 26. Fever
  27. 27. One or more of the following:
  28. 28. Rash
  29. 29. Generalized lymphadenopathy
  30. 30. Organomegaly
  31. 31. Serositis
  32. 32. Causes are poorly understood
  33. 33. Innate immune involvement
  34. 34. Unclear role of adaptive immunity
  35. 35. Autoimmune vs. autoinflammatory</li></ul>Sir George Frederick Still<br />
  36. 36. Adaptive vs. Innate Immune Systems<br />Innate Immunity<br />Innate immune cells<br />Macrophage/monocyte<br />Neutrophil<br />Mast cell<br />Receptors (sensors)<br />Detect products of pathogens<br />Detect host danger signals<br />NOT variable<br />Inflammatory cytokines<br />Adaptive Immunity<br />Adaptive immune cells<br />B lymphocyte (antibodies)<br />T lymphocyte<br />Receptors (sensors)<br />Detect pieces of protein<br />VARIABLE (via recombination)<br />Inflammatory cytokines<br />
  37. 37. Genetic Studies of Systemic Arthritis<br />Receptor for inflammatory cytokines<br />Inflammatory cytokines<br />Receptors for inflammatory cytokines<br />Inflammatory cytokine<br />Anti-inflammatory cytokine<br />Inflammatory cytokine<br />Ion channel<br />Antigen recognition<br />
  38. 38. Genetic Studies of Systemic Arthritis<br />Major Histocompatibility Complex<br /><ul><li> Display peptides for T cells
  39. 39. Small, specific “binding cleft”
  40. 40. TCRs recognize antigen + MHC</li></li></ul><li>Systemic Arthritis<br />Translation of genetic findings to therapeutics?<br />Anti-interleukin 1 therapies<br />Anakinra<br />Canakinumab<br />Rilonacept<br />Anti-interleukin 6 therapy<br />Tocilizumab<br />
  41. 41. Genome Wide Association Study of Systemic Arthritis<br />
  42. 42. Oligoarthritis<br />Oligoarticular JIA is characterized by:<br />Arthritis present in 4 or less joints at presentation<br />Persistent oligoarthritis: Arthritis “persists” in 4 or less joints <br />Extended oligoarthritis: Arthritis “extends” to involve >4 joints<br />High rate of inflammatory eye disease (uveitis)<br />Very strong association with specific MHC types<br />Functional importance is not clear<br />
  43. 43. Polyarthritis (RF negative)<br />RF negative polyarticular JIA is characterized by: <br />Arthritis present in 5 or more joints at presentation<br />Typically more large joint involvement<br />Often asymmetrical involvement<br />Absent rheumatoid factor<br />Rate of eye disease comparable to oligoarthritis<br />
  44. 44. Polyarthritis (RF positive)<br />RF positive polyarticularJIA is characterized by:<br />Arthritis present in 5 or more joints at presentation<br />Typically involves large and small joints<br />Clinical course is comparable to rheumatoid arthritis<br />
  45. 45. Psoriatic Arthritis<br />Psoriatic JIA is characterized by:<br />Arthritis and psoriasis<br />Arthritis PLUS 2 of the following:<br />Dactylitis (sausage-like swelling of a digit)<br />Characteristic fingernail changes<br />Psoriasis in a first degree relative<br />Much genetic work in adult form of the disease<br />Interleukin 23 receptor plays a central role<br />Therapeutic against this already FDA approved for psoriasis<br />Still under consideration for psoriatic arthritis<br />
  46. 46. Enthesitis Related Arthritis<br />Enthesitis-related JIA (ERA) is characterized by:<br />Arthritis and enthesitis, OR<br />Arthritis OR enthesitis, AND 2 or more of the following<br />Sacro-iliac joint tenderness or inflammatory back pain<br />HLA-B*27 antigen positive<br />Arthritis in male over 6 years of age<br />Acute anterior uveitis<br />History of similar disease in first degree relative<br />HLA-B*27 is strongest association (MHC gene)<br />Other genes have been identified in adult form of disease <br />
  47. 47. Summary<br />State of the art genetic studies are coming to JIA<br />In the past  candidate gene studies<br />Today  genome wide association studies<br />Tomorrow  whole genome sequencing studies<br />The scale and scope of the studies are expanding<br />Larger numbers of patients being enrolled (collaboration)<br />Larger numbers of markers being checked (technology)<br />Separate investigations of different JIA subtypes<br />
  48. 48. Questions or Comments?<br />If you are interested in more information about our ongoing genome wide association study of systemic juvenile idiopathic arthritis, please ask me or send an email to:<br />Michael.Ombrello@mail.nih.gov<br />

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