5.3 - Complex Diseases and Pharmacogenetics

Question 1

What are Mendelian traits?

Answer 1

• controlled by a single gene
• inheritance follows Mendel’s principles
• phenotypes are easily identified in humans - e.g. earlobe attachment and ABO blood group

Question 2

What is a complex trait?

Answer 2

• controlled by multiple genes and the effect of the environment
• complex traits = quantitative traits e.g. height, weight, intelligence, blood pressure
• complex disease - cardiovascular disease
• Mendelian vs complex traits - separation artificial, complex traits are really a continuum Mendelian trait
• epigenetics - how environment and behaviour influence genetics

Question 3

Calculating heritability

Answer 3

How much of our phenotypic differences is due to genetic differences?
Causes of phenotypic differences:

1. genetic differences
2. shared environment
3. unique environment

• monozygotic twins share 100% DNA, dizygotic twins share 50% DNA

Question 4

How do we study heritability of Mendelian / monogenic diseases?

Answer 4

• they are rare so we cannot easily study them in a population
• best way to study them is through studying families by producing pedigrees
• e.g. haemophilia, sickle cell anaemia, cystic fibrosis, thalassaemia

Question 5

How do we study heritability of complex diseases?

Answer 5

• more common and controlled by many genes in population
• common human diseases cluster in families (genetic)
• collect samples of individuals with disease of interest and compare them to healthy individuals
• e.g. diabetes, cardiovascular disease, cancer, hypertension, asthma, mental health diseases, autoimmune diseases

Question 6

What are SNPs?

Answer 6

• single nucleotide polymorphisms - DNA sequence variations that occur when a single nucleotide is changed at a specific point in the genome that is present in a sufficiently large fraction of the population (1%)
• e.g. at a specific base position in human genome, the G nucleotide appears in most people but a minority have T instead = SNP at this position with two possible nucleotide variants (alleles)
• most common variation in human genome i.e. will account for the majority of polymorphism responsible for human disease
• change in a single nucleotide in genetic sequence
• can be in coding or non-coding region (can still have effect)

Question 7

How do we test for SNPs in a population?

Answer 7

• association studies - examine association between SNP and disease risk (if across entire genome, then known as genome-wide association studies GWAS)
• split sample with both healthy and diseased people into their genotype groups
• then do statistical analysis using p=0.05 to see if the number of diseases in one group is different from the other ones
• GWAS - over 10 million SNPs in genome recognised so far
• research shows 5% chance of false positive for each SNP, but for over 10mil SNPs the chance increases so we might find associations by chance - multiple testing effect
• multiple testing correction - corrects for this, new p value = 5 x 10^-8 = need much larger sample size

Question 8

Evaluation of genome-wide association studies

Answer 8

+ can identify SNP-variant associations e.g. loci for complex disease
+ identify at risk individuals
+ discovery of novel biological mechanisms
+ inform drug discovery or repurposing
+ identify ethnic differences
-doesn’t identify causal variants - further testing required
-can’t identify all heritability - ‘missing heritability’
-thresholds - won’t identify rare variants
-environmental influence - epigenetics

Question 9

Whole genome sequencing (WGS)

Answer 9

• entire genome scrutinised - every SNP can be identified
• clear identification of disease and disease risk
• roles of many genes undetermined e.g. benign or pathogenic

Question 10

What are pharmacogenomics?

Answer 10

• the study of variability in drug response due to genetic differences
• improve drug therapy and prescribing in the future
• principle same as complex diseases - provides more information on the role of specific proteins / genes
• if patients have different responses to a drug, it is likely due to genetics

Question 11

How can genes affect drug interactions within the body?

Answer 11

• absorption –> activation –> target –> effect –> inactivation –> excretion
• when a drug is given to a patient, it is absorbed by the body and travels to target organ
• genes can affect drug interactions by controlling things like receptors on surface of target cells –> obstruct interaction of drug with organ etc
• drug would then be metabolised and removed from the body via the kidneys, liver etc - here genes can increase/decrease drug metabolism, affecting interaction with the body
• increasing metabolism = drug has no effect as it is quickly removed from the body
• decreasing metabolism = can cause overdoses
• pharmacokinetics - what the body does to the drug

Question 12

Drug absorption

Answer 12

• majority of drugs given orally
• majority of drugs absorbed in small intestine
• use specific transporter proteins
• wide variety of transporters used - although transporters can increase absorption or enhance removal
• digoxin/fexafenodine - substrates for P-gp (transporter protein) - prevents drug entering blood, sends it back to small intestine
• P-gp SNP leads to two-fold decrease in duodenal P-gp levels

Question 13

Drug activation / inactivation (metabolism)

Answer 13

• drug metabolism - many SNPs identified in drug metabolising enzymes
• some drugs require ‘metabolism’ to become activated - these are prodrugs i.e. initial drug inactive, metabolised drug active

Question 14

What is personalised medicine?

Answer 14

• tailoring treatment to patients depending on specific characteristics of their disease
• e.g. several patients with lung tumours but they all have different characteristics so we can prescribe medicine based off those to maximise the effect and decrease adverse effects
• ideal drug scenario - drugs with increased efficacy and decreased adverse effects