LT9 Pharmacogenetics of T2D

Question 1

What are the groups of genetic mutations?

Answer 1

Point mutation = SNP (single nucleotide polymorphism)

Frame-shift mutations = deletion/insertion (all amino acids change beyond that place)

Question 2

What are 3 point mutations?

Answer 2

Silent = no change in amino acid sequence

Mis-sense = Changes amino acid

Nonsense = results in premature stop codon

Question 3

What is the similarity between human DNA sequences?

Answer 3

We share 99% of DNA sequences

Question 4

How has genome sequencing changed?

Answer 4

Used to be too expensive to sequences a whole genome

Now can pay £20 for 1 million common variants

Question 5

What factors affect phenotypic variation?

Answer 5

Genetic variaiton
Environmental variation

Question 6

Do different alleles for genes produce different effects?

Question 7

How many loci are invovled for a trait?

Answer 7

Depends on the complexity of the trait

Question 8

How much of a genome predicts development of T2D?

Answer 8

The heritability of T2D (how much of the disease risk is due to genetics) is estimated to be 30–70%, depending on the population.

This means a substantial part is genetic, but lifestyle factors like diet, exercise, and body weight are also crucial.

Question 9

What are the steps in gene mapping?

Answer 9

Is there a genetic component?Twin/family studies

Genetic architecture = Monogenic/polygenic

Study design = linkage/association

Fine mapping analysis

Functional analysis

Question 10

What is the heritability?

Answer 10

The amount of phenotypic variation in a populaiton that is attributable to individual genetic differences

Question 11

What is the heritability scale?

Answer 11

0 to 1
H = 0 means that all variability observed in a trait in a given population is due to environemntal differences

H = 1 means that all differences are due to genetic differences among people

For most continuous traits, heritability is somewhere in between

Question 12

What is the difference between dizygotic and monozygotic twins?

Answer 12

DZ = two egg twins, same degree of genetic relatedness as normal siblings (50% genes in common)

MZ = one egg twins, genetically identical (100% genes in common)

Question 13

What was used to measure heritability and now what can be?

Answer 13

Twin studies used to be used

Now can use genome wide association studies (GWAS)

Question 14

What are the two study designs for gene mapping?

Answer 14

Linkage study = high magnitude of effect because runs in the family tree (lower freq in population)

Association studies = high frequency in the population but low magnitude of effect

Question 15

Why are linkage studies and associaiton studies used?

Answer 15

Because linkage studies are likely to exist between relatives

Associaiton studies are likely to be found in the population

Question 16

What are limitations of linkage analysis?

Answer 16

Family data required = problem for late onset disease

Inefficient

Expensive

Does not identify the caustive variant = instead identified a region and further work is reuired

Question 17

What is fine mapping analysis for?

Answer 17

To identify the causal genes

Question 18

What is the functional analysis for?

Answer 18

To understand how the causal gene affects the disease risk

Question 19

Which diabetes is more heritable?

Answer 19

T2D because there are more gene loci involved in its development

Whereas T1D is only affected by HLA genes

Question 20

Why is the HLA region of genome important in T1D?

Answer 20

Because it is an autoimmune disease

Question 21

What predispositions lead to T2D?

Answer 21

Reduced insulin secretion = due to beta-cell dysfunction and reduced mass

Insulin resistance = due to obesity and not due to obesity

Question 22

What important genes lead to insulin resistance?

Answer 22

FTO gene = obesity

IRS1 and PPAR-gamma = not due to obesity

Question 23

What occurs in isolated populations?

Answer 23

Founder effect = the loss of genetic variation that occurs when a new population is established by a small number of individuals from a larger population

Genetic drift = may cause gene variants to disappear completely and thereby reduce genetic variation in small populations

In summary, disease-causing variants are likely to be common in the small population but very rare in other populations

Because their effect gets amplified

Question 24

What is TBC1D4 gene function?

Answer 24

Increases GLUT4 translocation

Loss of TBC1D4 results in reduced insulin stimulated glucose uptake into MUSCLE

Question 25

Define pharmacogenetics vs pharmacogenomics

Answer 25

GENETICS = focuses on how variations in a single gene influence drug response GENOMICS = explores the broader impact of all genes (the entire genome) on drug responses and interactions

Question 26

What do candidate gene pharmacogenetic studies mainly focus on?

Answer 26

Genes encoding protien in the PK and PD of the drug Pharmacokinetics is the movement of drugs through the body, whereas pharmacodynamics is the body's biological response to drugs

Question 27

What does ADME determine?

Answer 27

Absorption, distribution, metabolism, excretion Dose of drug taken and concentration that actually reaches the target

Question 28

What side effects do patients suffer on metformin?

Answer 28

GI side effects Metformin activates an enzyme called AMP-activated protein kinase (AMPK). This enzyme plays a critical role in cellular energy regulation. When activated, AMPK decreases the production of glucose in the liver, which is usually driven by a hormone called glucagon. Metformin, especially in higher doses, can irritate the gastrointestinal tract. This is because it increases the release of certain molecules like glucagon-like peptide-1 (GLP-1), which can lead to delayed gastric emptying (meaning food stays in the stomach longer than normal). This can cause nausea, bloating, and diarrhea.

Question 29

Who were most likely to develop GI side effects to metformin? Which transporters were involved?

Answer 29

Women and older people were more likely to develop metformin intolerance An impair the absorption and clearance of metformin, leading to higher blood levels of the drug and increased risk of intolerance, especially in women and older people PMAT = plasma membrane monoamine transporter OCT 1 = organic cation tranpsorter 1

Question 30

What are OATP1B and CYP450 2C8?

Answer 30

TZDs are transported into the liver by OATP1B (encoded by SLCO1B1) TZD metabolized by CYP450 2C8 enzyme (encoded by CYP2C8)

Question 31

What is CYP2C8*3 and its consequences?

Answer 31

Gain of function mutation = associated with reduced glycaemic response to rosiglitazone CYP2C8*3 is a gain-of-function mutation that increases the activity of the CYP2C8 enzyme, leading to faster metabolism of TZDs

Question 32

What did SLCO1B1 521T>C variant cause?

Answer 32

Loss of function mutation of the TZD transporter Enhanced glycaemic response to rosiglitazone

Question 33

Define a TZD super responders genotype

Answer 33

Combined genotype at CYP2C8 and SLCO1B1 Had a greater HbA1c reduction than the poor responders Neither of the variants had a significant impact on pioglitazone response

Question 34

What is CYP2C9?

Answer 34

Gene coding for enzyme that metabolizes sulphonylureas DO NOT CONFUSE WITH CYP2C8 which is for metabolizing TZDs

Question 35

What is the role of beta-arrestin-1?

Answer 35

Mediates GLP-1 signalling to insulin secretion in cultured pancreatic beta-cells It is a scaffold protein

Question 36

What is the mechanism of action of beta-arrestin-1 in assocaition with GLP-1?***

Answer 36

Blocks further G-protein activations Helps receptors become internalized Triggers other pathways such as ERK and Akt 1. Support b-cell survivla 2. Decrease inflamamtion and apoptosis BIASED AGONISM Some GLP-1 agonists do NOT recriut b-arrestin1 so that GLP-1 signal is longer

Question 37

What is HNF1A?

Answer 37

A gene that encodes the protein hepatocyte nuclear factor 1 alpha (HNF-1α) A transcription factor crucial for pancreatic beta cell function and insulin production, and its mutations are a common cause of maturity-onset diabetes of the young (MODY)

Question 38

Why are sulphonylureas so effective in HNF1A mutation MODY?

Answer 38

HNF1A mutations impair the normal function of the transcription factor HNF1A, which regulates the expression of genes essential for insulin production and secretion. This mutation leads to defective insulin release in response to glucose. In HNF1A mutation MODY, the β-cell insulin secretion pathway is often dysfunctional due to the impaired transcription of insulin-related genes. However, sulfonylureas bypass this defect by directly stimulating insulin release through the K_ATP channel mechanism, which remains functional despite the genetic mutation.

Question 39

Summarize the type of person metformin is best for

Answer 39

Best in people with reduced GLUT2 transport ATM SIde effects in those w reduced OCT1/PMAT/SERT transport

Question 40

Summarize the type of person sulphonylureas are best for

Answer 40

BEST in thsoe with HNF1A/4A mutation Better in people with reduced SLCO1B1 transport Better in those who metabolize SU slowly (CYP2C9) Worse in those with TCF7L2 risk variants

Question 41

Summarize the type of person Rosiglitazone (TZD) is best for

Answer 41

Response and weight gain with altered CYP2C8 and SLCO1B1 activity

Question 42

Summarize the type of person GLP1RA are best for

Answer 42

Better in ARRB1 mutation WOrse with Gly168Ser of the GLP1R