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Genetics and health
Genetics and health
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Genetics and health

  2. 2. contents • Introduction • Genetic disorders • Disease burden • Human genomic project • Gene therapy • Preventive and social measures in genetics • Research in India • Future
  3. 3. Introduction Charles Darwin (1809 - 1882) 1859: Theory of natural selection- members of a population who are better adapted to the environment survive and pass on their traits. Gregor Mendel (1822 – 1884) 1866: Gregor Mendel published his work “Experiments in Plant Hybridization”, which set out the basic theory of genetics.
  4. 4. Introduction Friedrich Miescher (1844 – 1895) 1871: Isolated “nucleic acid” from pus cells. 1902: Archibald Garrod discovered that alkaptonuria has a genetic basis. Archibald Garrod
  5. 5. Introduction • 1953: James Watson and Francis Crick determine the structure of the DNA molecule. • 1966: Marshall Nirenberg solves Marshall Nirenberg Watson and Crick the genetic code, showing that 3 DNA bases code for one amino acid. • 1990: First gene therapy was performed, Ashanti DeSilva was treated for SCID by Dr. W.French Anderson. Dr. W.French Anderson Ashanti DeSilva and Ashanti DeSilva
  6. 6. Introduction • 1993: Dr. Kary Mullis discovers the PCR procedure • 1997: Dolly the sheep - the first adult animal clone. Dr. Kary Mullis • 2003: Sequence of the entire human genome is announced
  7. 7. Classification Classification of diseases based on their genetic basis as • Monogenic (Mendelian) disorders • Chromosomal aberrations • Polygenic disorders
  8. 8. Mendelian disorders 6 general patterns of inheritance are observed: • Autosomal recessive • Autosomal dominant • X-linked recessive • X-linked dominant • Co-dominant • Mitochondrial
  9. 9. Mendelian disorders Autosomal recessive • The disease appears in male and female children of unaffected parents. • e.g., Cystic Fibrosis, Phenylketonuria
  10. 10. Mendelian disorders Autosomal dominant • Affected males and females appear in each generation of the pedigree. • Affected mothers and fathers transmit the phenotype to both sons and daughters. • e.g., Neurofibromatosis, Adul t polycystic kidney disease
  11. 11. Mendelian disorders X-linked recessive • Many more males than females show the disorder. • All the daughters of an affected male are “carriers”. • None of the sons of an affected male show the disorder or are carriers. • e.g., Hemophilia A and B, Colour blindness
  12. 12. Mendelian disorders X-linked dominant • Affected males pass the disorder to all daughters but to none of their sons. • Affected heterozygous females married to unaffected males pass the condition to half their sons and daughters • e.g. Vitamin D resistant rickets, Familial hypophosphatemia
  13. 13. Mendelian disorders Co-dominant inheritance • Two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein • Both alleles influence the genetic trait or determine the characteristics of the genetic condition. • E.g. ABO locus
  14. 14. Mendelian disorders Mitochondrial inheritance • This type of inheritance applies to genes in mitochondrial DNA • Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. • E.g. Leber's hereditary optic neuropathy (LHON)
  15. 15. Chromosomal aberrations • Alternations in the number or structure of chromosomes • Autosomes or sex chromosomes • Numerical abnormalities – – Polyploidy (3n or 4n), – Trisomy (2n+1): Klienfelter’s syndrome – Monosomy (2n-1): Turner’s syndrome • Structural abnormalities - breakage followed by loss or rearrangement deletion, translocation. E.g. t(9;22) in CML
  16. 16. multifactorial inheritance (polygenic) • Influence of multiple genes and environmental factors • These include mainly the non-communicable diseases – Diabetes mellitus – Hypertension – Cardiovascular diseases – Cancers
  17. 17. Burden of genetic diseases • Each year more than 3 million children born with a serious genetic defect die; most of these deaths (90%) occur in developing countries. • In the western world, there is 1% chance of having an inherited disease at birth. • Approximately 5% of the world‟s population carries trait genes for haemoglobin disorders, mainly sickle-cell disease and thalassemia. • Over 300 000 babies with severe haemoglobin disorders are born each year.
  18. 18. Burden of genetic diseases • The estimated incidence of Down Syndrome is 1 in 1,000 live births worldwide. • Each year approximately 3,000 to 5,000 children are born with this chromosome disorder and it is believed there are about 250,000 families in the United States of America who are affected by Down Syndrome. • The incidence of Cystic Fibrosis varies across the globe. Although it is severely underdiagnosed in Asia, existing evidence indicates that the prevelance of CF is rare. In the United States of America the incidence of CF is reported to be 1 in every 3500 births.
  19. 19. Burden of genetic diseases in india DISORDER INCIDENCE BIRTHS/YEAR Congenital Malformations 1:50 678,000 Down syndrome 1:800 34,000 Metabolic disorders 1:1200 22,500 Β-thalassemia & sickle cell 1:1700 16,700 disease Congenital hypothyroidism 1:2500 10,900 Duchenne muscular 1:10000 2,700 dystrophy Spinal muscular atrophy 1:10000 2,700 Source: Center of Medical Genetics, New Delhi, 2011
  20. 20. High Prevalence in india is due to: • Consanguineous marriages • High birth rate • Poor governmental support facilities • Lack of expertise in genetic counseling • Lack of improved diagnostic facilities
  21. 21. Burden of ncd in india Diseases Prevalence (per Cases (in millions)/ Deaths (in thousand) year millions)/ year Diabetes mellitus 62.4 37.7 0.11 Ischemic heart 37 22.3 0.55 disease Stroke 1.54 1.64 0.63 Hypertension 159.4 94.8
  22. 22. Most diseases have a genetic component Heart disease Cystic PKU Schizophrenia Motor Cancer fibrosis vehicle Fragile X Multiple Alzheimers accident TB sclerosis Diabetes Obesity Duchenne Struck Asthma Autism muscular Rheumatoid by dystrophy arthritis Meningococcus lightning Totally Totally Genetic Environmental
  23. 23. Gene-Environment Interaction • Some vegetarians with 'acceptable' cholesterol levels suffer myocardial infarction in the 30's. • Other individuals seem to live forever despite personal stress, smoking, obesity and sedentary lifestyle.
  24. 24. Genetics v/s genomics • Genetics: – Conditions caused by an extra or missing chromosome or part of a chromosome, caused by a mutation in a single gene in chromosome or in a mitochondria. – Are important to the individuals and families who have them • Genomics: – refers to those conditions plus discoveries from the Human Genome Project (HGP) which show that most adult onset and chronic diseases can be partially caused or prevented by genetic factors. – Environmental factors also play a significant role Genomics 101: An Introduction
  25. 25. The Human Genome Project • 1990: Project initiated as joint effort of U.S. Department of Energy and the National Institutes of Health. • June 2000: Completion of a working draft of the entire human genome • February 2001: Analyses of the working draft are published • April 2003: Human Genomic Project sequencing is completed and Project is declared finished two years ahead of schedule
  26. 26. The Human Genome Project Results • The human genome contains 3 billion chemical nucleotide bases (A, C, T, and G). • The average gene consists of 3000 bases, but sizes vary greatly, with the largest known human gene being dystrophin at 2.4 million bases. • The total number of genes is estimated at around 30,000--much lower than previous estimates of 80,000 to 140,000. • Almost all (99.9%) nucleotide bases are exactly the same in all people. • The functions are unknown for over 50% of discovered genes. U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003
  27. 27. The Human Genome Project  Benefits of Genome Project • Improve diagnosis of disease • Detect genetic predispositions to disease: Screening advice, risk factor modification • Create drugs based on molecular information • Design “custom drugs” (pharmacogenomics) based on individual genetic profiles • Use gene therapy for treatment • Identify potential suspects whose DNA may match evidence left at crime scenes • Exonerate persons wrongly accused of crimes U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003
  28. 28. Pharmacogenomics  Pharmacogenomics – The development of drugs tailored to specific subpopulations based on genes – Pharmacogenomics has the potential to: • Decrease side effects of drugs • Increase drug effectiveness • Make drug development faster and less costly • use of medications otherwise rejected because of side effects • new medications for specific genotypic disease subtypes Genomics 101: An Introduction
  29. 29. Closing the Gap HuGENet Population Human Studies Genome US Genome Profile Epidemiology Public Health Studies Network Gene Population Closing the Gap Discovery Health EGAPP Practice Evaluation of Family history Genomic State Capacity Applications in Genomics Centers Practice & Prevention
  30. 30. Human Genome Epidemiology Network • HuGENet: A global collaboration of individuals and organizations committed to – the assessment of the impact of human genome variation on population health. – how genetic information can be used to improve health and prevent disease.
  31. 31. EGAPP Evaluation of CDC-funded initiative intended to Genomic establish and test a systematic, evidence- Applications in based process for evaluating genetic tests Practice and and other applications of genomic Prevention technology in transition from research to practice.
  32. 32. Approach to Genomics Translation: Application to Cancer Promising Evidence based Application Guideline/ (e.g. genetic test) Policy Cancer Discoveries Population Practice & (e.g. genetic risk factor) Sciences Control Programs Reducing the Burden of Cancer
  33. 33. gene therapy • Gene Therapy: Introduction of normal genes into cells that contain defective genes to reconstitute a missing protein product. • Gene therapy is used to correct a deficient phenotype so that sufficient amounts of a normal gene product are synthesized to improve a genetic disorder • Modification of cells by transferring desired gene sequences into the genome. • Delivery systems available: – In vivo: delivery of genes takes place in the body – Ex vivo: delivery takes place out of the body, and then cells are placed back into the body
  34. 34. gene therapy • In vivo techniques usually utilize viral vectors – Virus: carrier of desired gene, e.g. adenovirus, retroviruses, herpes simplex virus. – Virus is usually “crippled” to disable its ability to cause disease – Viral methods have proved to be the most efficient to date – Many viral vectors can stably integrate the desired gene into the target cell’s genome
  35. 35. gene therapy • Ex vivo manipulation techniques – Electroporation – Liposomes – Calcium phosphate – Gold bullets (fired within helium pressurized gun) – Retrotransposons (jumping gene) – Human artificial chromosomes
  36. 36. gene therapy Somatic Cell Nuclear Transfer (SCNT)
  37. 37. Successful Gene Therapy for Severe Combine Immunodeficiency • Infants with severe combined immunodeficiency are unable to mount an adaptive immune response, because they have a profound deficiency of lymphocytes due to a deficiency of adenosine deaminase. • In these patients, peripheral T cells were transduced with a vector bearing the gene for adenosine deaminase. • The experiment was extremely labor intensive, because mature peripheral-blood T cells were modified rather than stem cells, and the procedure therefore had to be repeated many times to achieve success.
  38. 38. Unsuccessful Gene therapy • Jesse Gelsinger, a gene therapy patient who lacked ornithine transcarbamylase activity, died in 1999 due to multi-organ failure following gene therapy. • One problem with gene therapy is that one does not have control over where the gene will be inserted into the genome. The location of a gene in the genome is of importance for the degree of expression of the gene and for the regulation of the gene (the so-called "position effect"), and thus the gene regulatory aspects are always uncertain after gene therapy
  39. 39. Problems with Gene Therapy • Short Lived – Hard to rapidly integrate therapeutic DNA into genome and rapidly dividing nature of cells prevent gene therapy from long time – Would have to have multiple rounds of therapy • Immune Response – new things introduced leads to immune response – increased response when a repeat offender enters • Viral Vectors – patient could have toxic, immune, inflammatory response – also may cause disease once inside • Multigene Disorders – Heart disease, high blood pressure, Alzheimer‟s, arthritis and diabetes are hard to treat because you need to introduce more than one gene • May induce a tumor if integrated in a tumor suppressor gene because insertional mutagenesis
  40. 40. Preventive and social measures in genetics 1. Health promotional measures – Eugenics: Positive and Negative Eugenics – Euthenics – Genetic counseling – Nutritional genomics 2. Specific protection 3. Early diagnosis and treatment 4. Rehabilitation
  41. 41. eugenics • In 1883 coins the word „Eugenics‟ from the Greek for good („eu‟) and born („genics‟). • Defined as “the science of improvement of the human race through better breeding.” Francis Galton (1822-1911)
  42. 42. eugenics • Negative eugenics • Positive eugenics
  43. 43. Negative eugenics • Negative eugenics: improving the quality of the human race by eliminating or excluding biologically inferior people from the population. • This goal required severe restrictions on reproductive rights, for those with "defects" had to be kept from reproducing, if necessary through the forceful sterilization. • Elderly and sick people killed under Hitler's policy of eugenics.
  44. 44. Positive eugenics • Positive eugenics: promotes marriage and breeding between people considered "desirable", and though a positive Eugenist may view certain persons as "undesirable", they will not initiate in such practices as non-voluntary sterilization, genocide, active euthanasia, or any other forms of violence. • In fact, as these eugenists say that, “the defective will always be with us, since people with hereditary defects come from the general population and not strictly, from other defectives there is no logical way to get rid of them. By promoting marriage and unions between Desirables, it may be possible to increase the national even universal average in the course of four or so generations”
  45. 45. Euthenics • Euthenics: a science concerned with improving the well-being of mankind through improvement of the environment. – Mere improvement of genotype is of no use unless the improved genotype is given access to a suitable environment, which will enable the gene to express themselves readily. – E.g. Children with mild mental retardation when placed in an encouraging environment showed improvement in their IQ.
  46. 46. Genetic Counseling • The genetic is done by a genetic counselor who is a health professional who is academically and clinically prepared to provide genetic services to individuals and families seeking information about the occurrence, of risk of occurrence, of a genetic condition or birth defect. • The counselor provides client-centered, supportive counseling regarding the issues, concerns, and experiences meaningful to the client‟s circumstances. American Board of Genetic Counseling
  47. 47. Genetic Counseling • The genetic counselor communicates – Genetic, – Medical and – Technical information in a comprehensive, understandable manner with knowledge of psychosocial and cultural background of each client and their family. American Board of Genetic Counseling
  48. 48. Prenatal Genetic Counseling • Preconception Counseling: if learned prior to conception that female and/or her partner are at high risk for having a child with a severe or fatal defect. • Options will be: – Pre-implantation diagnosis - when eggs that have been fertilized in vitro (in a laboratory, outside of the womb) are tested for defects at the 8-cell (blastocyst) stage, and only non-affected blastocysts are implanted in the uterus to establish a pregnancy – Using donor sperm or donor eggs – Adoption
  49. 49. Indications for Prenatal Diagnosis • Advanced maternal age • Family history of other • Previous child with a congenital structural chromosome abnormality abnormalities • Family history of a • Abnormalities identified in chromosome abnormality pregnancy • Family history of single • Other high risk factors gene disorder (consanguinity, poor • Family history of neural obstetric history, maternal tube defect (NTD) illnesses)
  50. 50. Prenatal screening for genetic disorders • Invasive testing: • Non-invasive testing: − Amniocentesis − Ultrasonography − Chorionic villus sampling − Maternal serum AFP (CVS) − Isolation of foetal cells from − Cordocentesis maternal circulation − Preimplatation genetic diagnosis − Fetoscopy
  51. 51. Prenatal screening techniques • Preimplantation Genetic Diagnosis (PGD) uses in vitro fertilisation (IVF) to create embryos. • Test one or two cells from each embryo for a specific genetic abnormality. • Identify unaffected embryos for transfer to the uterus. • Assists couples at risk of an inherited disorder to avoid the birth of an affected child.
  52. 52. Nutritional Genomics • The study of how different foods can interact with particular genes and alter the diseases process, as in type 2 diabetes, obesity, heart disease and some cancers.
  53. 53. Nutritional Genomics • Potential Benefits: – Increased focus on a healthy diet and lifestyle – Motivate positive behavior change – Improved health and quality of life – Focus on prevention – Decreased morbidity and premature mortality – Reduced health care costs – Identify subgroups who might be particularly responsive or resistant to environmental (dietary) intervention – Better understanding of the mechanisms involved in
  54. 54. Nutritional Genomics • Potential Harms: – Focus on specific nutrients/foods – Attention is drawn away from other modifiable risk factors – Decreased use of other services – False sense of security – Misleading claims – Increased costs associated with personalized diets and designer foods
  55. 55. Specific protection • Specific protection: – Protection of individuals and whole community against mutagens such as X-rays and other ionizing radiations – Patients undergoing X-ray examination should be protected against unnecessary exposure of gonads to radiations. – Prevention of Rh hemolytic disease of newborn by immunization with anti-D globulin
  56. 56. Early diagnosis and treatment • Post-implantation: Received a diagnosis of a severe or fatal defect after conception. • Options might include : - – Preparing family for the challenges they will face when they have a baby – Fetal surgery to repair the defect before birth (surgery can only be used to treat some defects, such as spina bifida or congenital diaphragmatic hernia. Most defects cannot be surgically repaired.) – Ending the pregnancy: For some families, knowing that they'll have an infant with a severe or fatal genetic condition seems too much to bear. – Referral to cardiologist to discuss heart surgery, and a neonatologist to discuss the care of a post-operative newborn.
  57. 57. screening for thalassemia and hemoglobinopathies • Carrier screening for thalassemia and hemoglobinopathies should be offered to a woman if she and/or her partner are having a positive family history. • Ideally, this screening should be done pre-conceptionally or as early as possible in the pregnancy. • Screening should consist of a complete blood count, as well as hemoglobin electrophoresis include quantitation of HbA2 and HbF. • If a woman‟s initial screening is abnormal (e.g., showing microcytosis or hypochromia with or without an elevated HbA2, or a variant Hb on electrophoresis or high performance liquid chromatography) then screening of the partner should be performed.
  58. 58. screening for thalassemia and hemoglobinopathies • If both partners are found to be carriers of thalassemia or an Hb variant, or of a combination of thalassemia and a hemoglobin variant, they should be referred for genetic counselling. Ideally, this should be prior to conception, or as early as possible in the pregnancy. • Prenatal diagnosis should be offered to the pregnant woman/couple at risk for having a fetus affected with a clinically significant thalassemia or hemoglobinopathy. • Prenatal diagnosis by DNA analysis can be performed using cells obtained by chorionic villus sampling or amniocentesis.
  59. 59. Average treatment cost • Blood transfusion therapy in a government setup - Rs 250-350 • Average annual expenditure - around Rs 5000/- • Bone marrow transplantation - Rs10 lakh
  60. 60. Rehabilitation • Rehabilitation: Early referral of children with genetic disorders which are known to cause physical or mental disability.
  61. 61. Disorder/Effect Test Target Population Intended Use Risk assessment; Diabetes, Type II TCF7L2 General population nutritional/lifestyle management Risk assessment; drug or Multigene Cardiovascular Disease General population nutritional/lifestyle panels management Management of individuals Individuals diagnosed with Hereditary Nonpolyposis Mismatch repair and prevention/early CRC and their family Colorectal Cancer (HNPCC) gene mutations detection for family members members Individuals with family Prevention and Thrombophilia F5, F2 history or clinical suspicion management of thrombophilia Gene expression Women diagnosed with Treatment and recurrence Breast Cancer profiles breast cancer risk Source: National office of Public Health Genomics, CDC
  62. 62. Research in india • National Centre of Applied Human Genetics: started in March 1980 at the Institute of Medical Sciences, Banaras Hindu University followed by establishing Human Genetics in a university setting at Jawaharlal Nehru University since March 1989. • April 2002: Human Genetics Laboratory of JNU was announced as National Centre of Applied Human Genetics.
  63. 63. Research in india • CURRENT RESEARCH ACTIVITY: 1. Genetic Susceptibility to Infectious Diseases: Leprosy, Liver Failure. 2. Genetic Susceptibility to Cancer : In-Vitro and In-Vivo models and Cancer Patient studies. 3. Molecular Characterization of Pyruvate kinase-M2 and its inhibitor in Bloom syndrome cells. 4. Structural and Functional Genomic studies and offering molecular diagnostic services for common and rare genetic diseases
  64. 64. Research in india • Research institutes in India: 1. NII (National Institute of Immunology) New Delhi. 2. NCCS (National Centre for Cell Science) Pune. 3. CDFD (Centre for DNA Fingerprinting and Diagnostics) Hyderabad. 4. NBRC (National Brain Research Centre) Manesar. 5. Institute for Bioresources and Sustainable Development, Imphal. 6. Institute of Life Sciences, Bhubaneshwar. 7. Bharat Immunologicals and Biologicals Corporation Limited, Bulandshehar. 8. Indian Vaccines Corporation Limited Gurgaon. • These institutions are equipped with world-class instrumentation and have been provided with highly competent human resources.
  65. 65. Research in haryana • Haryana: Department of Genetics and Department of Biotechnology, MDU, Rohtak • Current projects: 1. Evaluation of mental retardation cases in Haryana population by cytogenetic analysis. (ICMR) 2. Molecular cytogenetic characterization of X-linked mental retardation patients. • Other research topics : – Cytogenetic and pathological analysis of AML and its significance as prognostic indicators – Hematological and molecular genetic analysis of β- thalassemia patients in Haryana
  66. 66. Future "I am convinced that within five years every college-educated person in America is going to have a profile like this. You cannot afford not having this.“ Kari Stefansson, 2009 neurologist, President and co-founder of deCODE Genetics
  67. 67. Future “The Year of perfect vision 2020” JAMA March 20, 2008 "I predict that comprehensive, genomics- based health care will become the norm with individualized preventive medicine and early detection of illnesses” Elias Zerhouni NIH Director (2002-06) Predictive, Preventive and Personalized Medicine
  68. 68. references • National health profile 2010. Health Status Indicators Available from: http://cbhidghs.nic.in/writereaddata/mainlinkFile/File1012.pdf • Making Sense of Your Gene. American Board of Genetic Counseling http://www.abgc.net/docs/gcbrochure%20final.pdf • U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003. available from: http://www.ornl.gov/sci/techresources/Human_Genome/publicat/primer200 1/index.shtml • Genetic Counselling. Centre for Genetics Education. Available from: http://www.genetics.edu.au • Genetic Counseling In India. Available from: www.indiahospitaltour.com/ivf/genetic-counseling-india.html • Maharshi Dayanand University, Rohtak. Department of Genetics. Available from: www.mduonline.net • Genetic Disorders & Gene Therapy. Available from: http://genmed.yolasite.com/basics-of-gene-therapy.php
  69. 69. references • K. Park. Textbook of Preventive and Social Medicine. Genetics and health: 2011: 21:760-770 • Sunder Lal. Textbook of Community Medicine. Medical genetics 2011: 3: 366-375National Centre of Applied Human Genetics. Available from: www.ncahg.org/vision&mission.html • Human Genome Project Information. Available from: www.ornl.gov/sci/techresources/Human_Genome/project/about.shtml • Diseases and Gene Therapy - ADA-SCID. Available from: www.bgmoedlingkeim.ac.at/fachbereiche/biologie/gentherapie/pages/krank heiten/krankheiten_6.html • Verma IC. Exciting World of Genetics in India – From Clinical to Chromosomes, and Metabolic to Molecular. Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi. May 23, 2012 Available from: http://southeastgenetics.org/pdf/presentations/2012-06- 07_1100_2012-05-24_1030_Atlanta_Verma_May_FF_2012.pdf.pdf
  70. 70. references • Gregor Mendel. Available from: http://en.wikipedia.org/wiki/Gregor_Mendel • Archibald Garrod. Available from: http://en.wikipedia.org/wiki/Archibald_Garrod • Elias Zerhouni. Available from: http://en.wikipedia.org/wiki/Elias_Zerhouni • Friedrich Miescher. Available from: http://en.wikipedia.org/wiki/Friedrich_Miescher • Genetic Research in India. Available from: www.chillibreeze.com/articles_various/Genetic-Research.asp • The Basics of Gene Therapy. Available from: http://genmed.yolasite.com/basics-of-gene-therapy.php • Thalassemia Prevention: Screening and Prenatal Diagnostic Approaches. http://www.gfmer.ch/SRH-Course-2011/community-genetics/Thalassemia- Kleanthous-2011.html • S Mallik, C Chatterjee, Pankaj K Mandal, Jadab C Sardar, P Ghosh, N Manna. Expenditure to Treat Thalassaemia: An Experience at a Tertiary Care Hospital in India. Iranian J Publ Health 2010: 39(1); 2010:78-84

Hinweis der Redaktion

  • Add spoken commentsCDC-funded initiative intended to establish and test a systematic, evidence-based process for evaluating genetic tests and other applications of genomic technology in transition from research to practice.Non-regulatory – focused on knowledge synthesis