Pomb Complex Genetics

Complex Genetic Disorder Introduction

• Complex genetic disorder: disorders that arise from the complex interactions of both genetic and environment factors. E.g. diabetes, coronary artery disease, Alzheimer disease
- 90% of disease morbidity and mortality in developed countries
- study techniques: observations studies, epidemiology, twin and family studies, linkage analysis and advanced molecular techniques such as mutational identification
• Purpose of studying complex disorder:
- Identifying the disease genes that contribute to complex disease
- Advance current understanding of pathophysiological processes
- Reclassify disease based on genetic processes and environment factors and how these lead to their outcome, e.g. diabetes is reclassified to type I and type II from independent/dependent
- Provide a tool for risk prediction
- Opportunity to minimize or prevent disease by environmental chance, e.g. clean water, sanitations
- Identify assays that monitor disease progression at molecular level before physiological measurement.
- Identify new targets for treatment with tradition drugs or new molecular therapies
• Disease continuum: diseases placed on a continuum from purely genetic (Duchenne Muscular dystrophy, cystic fibrosis) to purely environmental (trauma, scurvy) with complex disease in the middle.
• Complex inheritance: trait or phenotype that results from an interaction of genotype with environmental factors
• Penetrance: the frequency with which a heritable trait is manifested by individuals carrying the principle gene, i.e. its degree of expression
• Candidate gene: a gene that encodes a protein that may have importance in the pathophysiological processes involved in the development of the disease.
• Familial aggregation: the tendency of affected individuals to have affected relatives
• Concordance: two related individuals in a family have the same disease
• Phenocopy: when identical traits is caused by different gene mutations
• Genocopy: when identical gene mutations results in different trait/phenocopy
• Relative risk ratio: comparing the frequency (probability) of a disease in the relatives of an affected proband to the disease frequency in the general population.
• Monozygotic: twins derived from the same zygote
• Dizygotic: twins derived from different zygote independently
• Ascertainment bias: bias that occurs because recruitment favours families with more than one member having the disease and this can overestimate familial aggregation.
• Heritability: the fraction of total phenotypic variance of a quantitative trait that is caused by gene expression.
• Linkage model: likelihood score that genetic marker co-segregates with the disease causing gene.
- strength: identify and localize diseases causing genes in large pedigrees where single gene effects dominates without knowing the mutations of the disease gene.
- weakness: does not take into account of gene penetrance, frequency and multi-gene effect.
• Twin studies: compares concordance in disease/phenotype between twin of same genotype but different environmental (monozygotic) and between twins of different genotype but same environment (dizygotic)
- Strength: allows assessment of strength of environmental/disease relationship and sibpair method of linkage.
- Weakness: differences exist in X-chromosome inactive for female twins and important environmental effect may occur
• Associate studies: identifies statistically significant associations between potential disease causing mutations and disease phenotypes.
- Strengths: makes no assumptions about the model of inheritance and allows for control of important environmental influences
- Weakness: falsely claimed association in under-powered studies and can’t distinguish between functional mutations and just linkage effects.
• Differences of Mendelian to complex inheritance
- Characteristics: Mendelian is rare with no environmental effect and young age of onset while Complex is common with normal distribution and modified by environmental effects. Also later onset of disease
- Genetics: Mendelian is single gene effect, recessive or dominant with full penetrance while Complex is multiple genes having familial tendency and mutations occurs in regulator sequences meaning incomplete penetrance
- Method of discovery: Mendelian was discovered through segregation analysis and classic linkage score while Complex studies involve twin studies, associations studies etc.
- Treatment options: Mendelian can usually be cure through gene therapy with minimal lifestyle effects while Complex are strongly affected by lifestyle and often require combination of treatments. Gene therapy can only delay onset or severity.
- Predictive: Mendelian is highly predictive but Complex is much as due to environmental contribution
• Breast cancer treatment:
- Early screening
- Chemoprevention
- Mastectomy and hysterectomy

Complex Genetic Disorder Examples

• Features of complex genetic disorder:
- Interaction of genes and environment
- Variable penetrance and late onset
- Extremely common and heterogenous clinical entities
- Major contribution by SNP
- Imbalance in regulation of bodily processes
- Involves multiple proteins
• Complex disease of emphysema:
- 90% of affected patients have a smoking history and late onset of disease.
- Interaction: environmental effect of smoking age, height, gender
- Variability: penetrance depends on smoking
- Complexity: multiple gene interaction
• Genetics of emphysema: comparing monozygotic twins with dizygotic twins corrected for environmental factors. Monozygotic twins have increase proportion of both individuals conceiving COPD while dizygotic twins is much less
• Effect of smoking: depending on the susceptibility of the individual to smoke and amount he/she smokes, the decline of FEV1 will be variable. In general, smokers have a greater and faster decline of FEV1 than non-smokers.
• Features of emphysema:
- Pathophysiology: inflammation of bronchioles from smoking induces cytokine activation and immune response. High oxidative species damage cells and white blood cells infiltrates. The release of degradation enzymes (proteases) by neutrophil and macrophages against pathogens also digests away the extracellular matrix. Protease inhibitor downregulates which worsen the situation.
- Clinical presentation: breathlessness and barrel chest
- Tests: poor lung functions, and black lung with chest x-ray and CT
- Treatment: improvement in breathlessness (ventilator) but no cure
• Susceptible and resistant smoker:
- Protective variant: protective polymorphism found in greater frequency of resistant smokers (smokers without COPD)
- Susceptibility variant: susceptible polymorphism found in greater frequency of COPD smokers
• Interventions for COPD and lung cancer:
- Smoking cessation: access risk factors such as age, lung function, smoking exposure etc and aim to modify lifestyle. Decline of FEV1 immediately slows with cessation (flattens off)
- Early screening: CT scan and lung function test for smokers over 45 years of age
- Drug therapy: anti-inflammatory drugs
• Strategies of smoking cessation:
- Individual based: advice from health professional; genetic testing; screening spirometry
- Population based: taxes on cigarettes; bans on advertising; health warning on products; bans on smoking in public places.
• Alzhemer disease: chronic progressive loss of memory, intellectual functions and social skills. This is due to neuronal death and deposition of extracellular amyloid plaques
- Genetics: one of the the apolipoprotein E (major constituent of the amyloid plaque) allele, E4 is associated with 2-3 times greater frequency in alzhemer disease. However evidence for this is weak as most of the E4 carrier does not develop alzehemers before they die, i.e. study groups size is too small.
• Type 1 diabetes: insulin deficiency secondary pancreatic beta cell depletion. Beta cells are destroyed as part of an autoimmune process triggered by environmental factors such as viral infection.
- Genetics: HLA DR3 and DR4 alleles regulated immune functions which may mediate the autoimmunity. Further more, 90% of type 1 diabetes patients do not have the protective allele of the HLA region
• Coronary artery disease: heart failure and infarction.
- Genetics: familial aggregation in young onset of CAD. Over 200 candidates are described for CAD including lipid metabolism, coagulants, matrix remodelling proteins. Extremely complicated

Personalized Medicine

• Personalized medicine: using individual genetic information and status to make treatment options to improve health, i.e. interventions are designed exclusive for an individual according to their profile and signature of disease.
- This represents a paradigm shift in clinical medicine where screening, diagnosis and treatment have been generalized across populations.
- Human Genome Project, bioinformatics and sequencing technology have made this possible
- Benefits: effective intervention and selection of drugs that maximise clinical benefits and reduce side effects
• Importance of genetics: completion of the Human Genome Project revealed the most common genetic variant is the single nucleotide polymorphism that occur every 500-1000 bases and account for the majority of variation between individuals. Highly sensitive technologies can identify these DNA sequences variation with functional effects and this can be used to develop DNA based testing,
• Role of personalized medicine:
- Prevention: DNA based test identify those at high risk from adverse lifestyle which can be changed to prevent disease.
- Screening: DNA based tests can be used to identify high risk population and prioritize screening (e.g. early ages and greater frequency) to improve outcomes by early intervention.
- Diagnosis: DNA based tests allow diagnosis to be made before symptoms develop
- Prognostication: identify patients whose disease process may be aggressive and require an alternative therapeutic intervention, e.g. surgery instead of chemo
- Efficacy: DNA based tests indentify which patients would get greatest therapeutic benefits from a particular drug and avoid “trial and error” waste
- Tolerance: DNA based tests identify which patients are likely to suffer side effects from a drug and would benefit from lower dose or alternative.
• Other benefits:
- Understanding of molecular basis of disease allows development of new drugs targeting that pathway
- Drugs will no minimal effect on unselected patient group can be reused on more specific subgroups for more efficacy
• Development of disease and interventions:
- Early pre-symptomatic: part of high risk population and need for identification to change lifestyle factors, e.g. Melaris test for risk of melanoma and sun avoidance and Emphagene/Nronchogene to assess risk of COPD and lung cancer of smokers
- Late pre-symptomatic: targeted for screening, e.g. Colaris in family history of colon cancer for colonoscopy and Ovacheck (correlogic systems)
- Early symptoms: diagnosis for very high risk population and implement preventive measures, e.g. mastectomy for BRACA 1+.
- Diagnosed: tailor treatment to maximise drug efficacy and minimize side-effects, e.g. HER-2 breast cancer chemotherapy
• Example of personalized medicine:
- HER-2 gene: identify using HER-2 DNA probe test, FISH signature, (PathVysion; Abott) and used to assess Herceptin and chemotherapy responsiveness.
- BRCA 1 and 2 gene: sequencing of BRCA 1 and 2 is offered by Myriad and women that carry these mutations can lower their risk of cancer by aggressive mammographic screening, and prophylactic mastectomy.
- Melanoma: identify high risk of familial melanoma using Melaris tests and positive patients can mitigate risk by regular skin checks, removal of suspicious mole and avoidance of sun.
- EGFR mutation: cancer due to mutation in EGFR can be treated with Iressa chemotherapy
• Colaris: direct genetic testing for germline mutations of MLH1, MSH2, MSH6 for HNPCC in conjunction with the Amsterdam criteria
• Colaris AP: direct genetic testing for germline mutation in APC or MYH genes and used to diagnose adenomatous polyposis syndromes. These are offered to patient suffering colorectal adenoma, and relatives with APC or MYH mutation.
• BRACA Analysis: genetic test for hereditary breast and ovarian cancer
- Preventive screening: clinical breasts exams and mammography from 25 to 35 for breast cancer. Annual transvaginal ultrasound for ovarian cancer
- Preventative drug therapy: tamoxifen is a selective estrogen receptor modulator that can cut the risk of breast cancer for BRCA mutation by half. Oral contraceptives on the other hand can reduce ovarian cancer in woman
- Prophylactic surgery: bilateral mastectomy shown to reduce breast cancer by 90% while bilateral oophorectomy reduce ovarian cancer by 96%
• Genetic profiling for drug responsiveness:
- TPMT: identify poor metabolisers of the drug mercaptopurine and azathioprine so can tailor a dose that minimize toxicity
- ViroSeq HIV1: identify drug resistant strains of HIV and tailor treatment according to the strain
- EGRF: identify which patient has the mutations for their lung cancer and can respond to anti-EGRF therapy

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