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3s1: Evolution of health and disease > Week 9 > Flashcards

Week 9 Flashcards

1
Q

What is personalised medicine?

A

Personalised medicine is an emerging practice of medicine that uses an individual’s genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease

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2
Q

What is an overview of personalised medicine vs precision medicine?

A

Personalised medicine - focus on genomic data
Precision medicine - analysis of multiple data streams including genomics, electronic medical record data and medical imaging data

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3
Q

What are physiological factors for personalised medicine?

A

Disease status
Physiological status
Microbiota
Clinical/biochemical measures
Epigenetics, metabolomics, proteomics, transcriptomics
Age
Sex

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4
Q

What boosted the understanding of knowledge for personalised medicine?

A

Knowledge of a patient’s genetic profile can help doctors select the proper medication or therapy and administer it using the proper dose or regimen.
Personalised medicine is being advanced through data from the Human Genome Project

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5
Q

What contributes to diseases?

A

Genetics and its contribution to health status and its response to behavioural change (pharmacogenetics, nutrigenetics) along with physiological processes

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6
Q

Why is personalised medicine important?

A

90% of drugs only work in 30-50% of the population and 6.5% of hospital admissions are due to adverse drug reactions

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7
Q

What is the overview of the effects of personalised medicine?

A

Use genetics to identify and target those most likely to benefit for specific interventions
As recommeded intake may have negative effect, no response or beneficial response

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8
Q

What is an overview of personalised medicine in action?

A

Disease risk quantification prior to any pathology, clinical Signs of disease
Regular monitoring of at-risk individuals
Bespoke interventions (behavioural, pharmacological, psychological, surgical etc)
Cost saving (prevention, focus on effective strategies)
Improved understanding of health and disease (through identification of novel pathways and mechanisms)

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9
Q

What is the impact of dementia in the UK?

A

944,000 cases UK
16.5% of mortality women
8.7% of mortality men
1/14 over 65y
1/6 over 80y

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10
Q

What is a major gene associated with Alzheimers?

A

APOE4 gene

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11
Q

What is an overview of Alzheimer’s diseases deterministic genes?

A

Approximately 1%of Alzheimer’s cases are caused by deterministic genes
Early-onset Alzheimer’s disease (EOAD) is rare, ~ 10% of AD, where AD manifest <65y
Some cases are caused by an inherited change in one of three genes
- Amyloid precursor protein (APP) on chromosome 21
- Presenilin 1 (PSEN1) on chromosome 14
- Presenilin 2 (PSEN2) on chromosome 1

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12
Q

What is the overview of the Apolipoprotein E?

A

Produced Liver (80-90%), brain and macrophages
Amino acid different at 112 and 158 causing either Cys and Arg amino acid

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13
Q

What are the different varients of Apolipoprotein E?

A

Gene 112 AA 158 AA
APOE2 Cys Cys
APOE3 Cys Arg
APOE4 Arg Arg

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14
Q

What are the allele frequency of the different gene mutations for Apolipoprotein E?

A

E2/E2, 1%
E2/E3, 12%
E2/E4, 2%
E3/E3, 63%
E3/E4, 20%
E4/E4, 3%

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15
Q

What is an overview of APOE4 carrier?

A

50% of APOE4/E4 never develop dementia
Neither necessary nor sufficient
20-25% general population APOE4 carriers,
50-75% AD
66% AD are females
Therefore APOE4 females: ~ 12% general population, but 33-50% of AD
High risk, early onset group

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16
Q

What underpins the APOE4?

A

Neurotransmission/synaptic function
β- amyloid processing
Tau phosphorylation
(Neuro)inflammation
Glucose utilisation,
Oxidative stress
Cholesterol metabolism
Vascular health

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17
Q

What interventions are there for reducing alzheimers APOE4?

A

Targeting of AD specific medications
Statins
NSAID
HRT
Lifestyle behaviours, nutrition and Physical Activity

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18
Q

What is the impact of HRT on APOE?

A

HRT improves RBANS delayed memory index APOE4 only
HRT is seen with 6-10% medial temporal lobe in APOE4
HRT intervention associated with larger hippocampal volume APOE4 only

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19
Q

What is an overview of cancer inheritence on treatment?

A

5% of cancer are inherited
Somatic versus germline variant
Importance of genotyping the tumour to define prognosis and a treatment plan

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20
Q

What is BRCA?

A

Breast cancer susceptibility proteins (BCRAs) are human tumour suppressor genes responsible for repairing DNA

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21
Q

What is the impact of BRCA mutations?

A

Mutation in the BRCA1 or BRCA2 gene can lead to abnormal cells growth
~ 1 in every 400 people have a faulty BRCA1 or BRCA2 gene
Autosomal dominant
Increased risk of developing breast cancer, ovarian cancer, prostate cancer and pancreatic cancer

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22
Q

What is an overview of BRCA and breast cancer?

A

~ 70% with a BRCA1/BRCA2 mutation will develop breast cancer by the age of 80
3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.
Up to 10 in every 100 men (up to 10%) with a faulty BRCA2 will develop breast cancer

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23
Q

What is an overview of BRCA and ovarian cancer?

A

~45% with a faulty BRCA1 gene will develop ovarian cancer by the age of 80.
~20%) with a faulty BRCA2 gene

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24
Q

What is an overview of BRCA and prostate and pancreatic cancer?

A

Faulty BRCA1 and BRCA2 genes can also increase your risk of prostate and pancreatic cancer, but risk is lower

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25
Q

What is an overview of Lynch Syndrome?

A

Also called hereditary non polyposis colon cancer (HNPCC)
Caused by mutations in the following genes: MLH1, MSH2, MSH6, PMS2
175,000 cases UK

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26
Q

What is the impact of lynch syndrome?

A

Increased risk of developing bowel cancer.
Up to 70% with Lynch syndrome will develop bowel cancer, and most before the age of 50y
Lynch syndrome causes around 3% of bowel cancer cases

27
Q

What other cancers have an increased risj with lynch syndrome?

A

Also increases risk of stomach cancer, ovarian cancer, pancreatic cancer, kidney cancer, bladder cancer, ureteral cancer, brain cancer, small intestine cancer, gallbladder cancer, bile duct cancer and skin cancer

28
Q

How does genetics help with lynch syndrome treatment?

A

Diagnosed with Lynch syndrome should have a colonoscopy every one two years, from ~age 25-35y

29
Q

What is pharmacogenetics?

A

Study of genetic factors determining variability in response to drugs in terms of both efficacy and toxicity

30
Q

What is pharmacogenomics?

A

Aimed at identifying robust genetic predictors of drug repsonse to identify patients at risk of developing adverse drug reactions, who may not benefit and needs alternative treatments

31
Q

What is pharmacokinetics?

A

Receptors, ion channels, enzymes and immune system response to medicine

32
Q

What is pharmacodynamics?

A

Absorbtion, distrubution, metabolism and excretion in response to medicine

33
Q

What is the genetic polymorphism for CYP?

A

CYP2D645 - no enzyme = no reaction
CYP2D61 - normal enzyme = normal metabolism
CYP2D62N - higher enzyme levels = Increased metabolism

34
Q

What does metabolising function determine?

A

Ultrarapid metaboliser - responds to increased dosage
Extensive metaboliser - reponds to normal dosage
Poor metaboliser - responds to reduced dosage
Ultrarapid or Poor metaboliser - use of alternate medicine
Balance efficacy and toxicity

35
Q

How does ethnicity impact gene frequency?

A

European - CYP2C1917 = 22.4% genomes
East Asian - CYP2C1917 = 1.5% genomes
Native American CYP2C19*17 = 12% genomes

36
Q

What is an overview of statins and genetics for muscle problems in medicine?

A

Statins are transported into the liver by a protein made by the SLCO1B1 gene. A specific gene mutation reduces simvastatin uptake into the liver.
Simvastatin can build up in the blood, muscle weakness and pain.

37
Q

What is an overview of amitriptyline and genetics for depression in medicine?

A

Antidepressant drug amitriptyline is influenced by two genes called CYP2D6 and CYP2C19.
Doctor might suggest genetic testing for the CYP2D6 and CYP2C19 genes to help decide what dose of the drug you need.
If you breakdown amitriptyline too fast, you will need a higher dose and vice versa

38
Q

What is pharmacogenetic information for drug labelling?

A

Drug labels for genetic testing is required or recommended
Labels contains information about efficacy, dosage and toxicity with variations for genetics
Informative indicative there maybe links to a gene, protein but not enough evidence yet to predict responses

39
Q

How does diet impact health?

A

Genetics impact food intake and preferences which impacts dietaty profiles
Dietary profile through absorbtion and metabolism impacts nutrition status
Nutrition status impacts physiological process there can impact health

40
Q

Outside of Alzheimers what are the downsides of APOE4?

A

Modest impact on cardiovascular disease risk
↑ plasma lipids (triglycerides, total- and LDL-cholesterol)
↑Inflammatory response
↑ Oxidative stress
Large impact on risk of dementia (Alzheimer’s Disease)
- increased prevalence
- reduced age of onset

41
Q

How common is APOE4 across different populations?

A

Caucasian - ~12%
Japanese - ~30%
Higher in regions of higher latitudes and at equator

42
Q

What is the evolution of APOE?

A

Non-human primates are APOE4
APOE4 is the ancestral allele
E3 and E2 began to emerge 200,000 and ~40,000 years ago
E3 and E4 –vely correlated, i.e. E3 replaced E4.. thrifty genotype

43
Q

What are the advantages of APOE4?

A

Increase in immune response, inflammation/innate immunity and therefore
Increase in cognition in middle age
Increase in Vitamin D absorption and status
Increase in responsiveness to dietary fat (saturated fat, omega-3 fatty acids)
Decrease in Spontaneous abortions, still-births

44
Q

What is the relationship between APOE4 and fats?

A

APOE4 more responsive to omega-3 fatty acids
APOE4 more responsive to total fat and saturated fat

45
Q

What is the overview of haem?

A

Haem, contains iron. It is the iron atom that binds oxygen as the blood travels between the lungs and the tissues.
4 polypeptide chains
2α globins (chromosome 16)
2β globins (chromosome 11)
4 haem groups

46
Q

What are an overview of haemoglobinopathies?

A

Globin chain production e.g. thalassaemia. Thalassaemia disturbance of usual balance of 1:1 α and β chains
Structure of the globin chain e.g. sickle cell diseases
Combined defects in globin chain production and structure e.g. sickle cell β-thalassaemia

47
Q

What is the physiology of sickle cell disease?

A

SNP in β-globin gene (chromosome 11)
Glu → Val, amino acid 6
Low O2 tension, Hb polymerises (aggregates) → erythrocyte ‘sickling
Homozygosity resulting in HbS- HbSS, sickle cell disease (SCD)

48
Q

What are the clinical features of sickle cell disease?

A

Erythrocytes- abnormal, rigid, sickle shape, loss of flexibility
Life expectancy 40-50y
Sickle
Occlusion of small blood vessels, organ ischaemia and damage (spleen frequently affected), pain, tiredness

49
Q

How common is sickle cell?

A

In the UK, about 12,500 people have SCD most common in individuals of African, Afro-Caribbean and Asian Origin (~ 1 in 300)

50
Q

What is the treatment for sickle cell disease?

A

Treatments may include medications to reduce pain and prevent complications, blood transfusions and supplemental oxygen, as well as bone marrow transplant

51
Q

Why is sickle cell disease common?

A

~ 80% of sickle-cell disease cases are believed to occur in sub-Saharan Africa.
Evolutionary advantage: Protective against malaria (438,000 deaths 2015

52
Q

Why did bitter taste evolve?

A

To avoid toxic or potentially harmful foods?
often taste bitter
Our sensory systems are designed to help us detect and avoid these outcomes, through vision (seeing contaminants in our food), touch, smell and taste

53
Q

How does bitter taste work?

A

Bitter taste is mediated by bitter taste receptor G-coupled proteins, encoded by members of the TAS2R gene family
The human genome contains 25 apparently functional TAS2R genes
TAS2R38 bitter receptor is responsive to phenylthiocarbamide (PTC) or propylthiouracil (PROP) or other analogues in food, e.g. flavonoids (polyphenols)

54
Q

What are the genotypes of TASR38?

A

TAS2R38 taste receptor gene
In humans, there are three SNPs that may render its proteins unresponsive
Non-taster, medium taster or super-taster: ~20%, 50%, 30%

55
Q

What is an overview of bitter genes impacting taste preference?

A

The hTAS2R38 genotype affected the liking of polyphenol-rich extracts, which were significantly bitter and astringent. PAV homozygotes gave lower ratings to the attributes than AVI homozygotes.
In contrast, PAV homozygotes were predicted to dislike the extracts notably more than AVI homozygotes.

56
Q

Are peoples bitter taste impacted by genes?

A

YES: some evidence, but not fully conclusive eg fruits, dark chocolate and coffee

57
Q

Can tasting bitter impact immune system?

A

TAS2R38 links to immune system shown by the COVID pandemic

58
Q

What is an overview of lactose?

A

Lactose is the main carbohydrate in all mammals’ milk
Lactose is the most important energy source during the first year of human life, providing almost half of the total energy required by infants
Lactose digestion capacity declines after weaning
Some people retain ability to digest lactose (milk sugar) into adulthood, termed lactase persistence

59
Q

What are examples of the distrubution of lactose intolerance?

A

Dutch - 1%
Europeans in australia - 4%
Australian aborigines - 85%
Native americans - 100%

60
Q

What is the genetic basis of lactase persistance?

A

A single allele, T-13910 variant, 14kb upstream of lactase (LCT) is main causative mutation
Persistence alleles bind transcription factors (Oct-1) more strongly
Regulatory changes

61
Q

What is an overview of T-13910?

A

The T−13910 variant correlates perfectly with lactase persistence (LP) in Eurasian populations whereas the variant is almost non-existent among Sub-Saharan African populations, showing high prevalence of LP

62
Q

What are the origins of lactase persistance?

A

European H98 and African H100 alleles have same non lactase persistence ancestor H84
H99 has different background haplotype H107
Differing history of adaptation to milking culture

63
Q
A

3s1: Evolution of health and disease (10 decks)

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