GWAS & CVD

Question 1

Haemostasis

Answer 1

Process to prevent and stop bleeding

1) Blood vessels constrict
2) Platelet plug
3) Activation of coagulation cascade
4) Formation of fibrin

Question 2

Platelet Function

Answer 2

Resting platelets change from disc shaped to an activated more spread out shape under injury

The shape change enables platelets to better interact and adhere to one another, forming a cohesive platelet plug

Question 3

Blood Coagulation

Answer 3

Blood coagulation is the sequential process by which the multiple coagulation factors of blood interact in the ‘coagulation cascade’, resulting in the formation of an insoluble fibrin clot.

Thrombin catalyses the conversion of fibrinogen to fibrin

Question 4

Human Genome and effects

Answer 4

• 3.2 bill base pairs and 20k genes
• 4-5 mill genetic variants in everyone
• Eye colour regulated by few genes and is entirely genetic with no environmental impact
• Heigh regulated by 1000s of genes and environement

Question 5

Complexity

Answer 5

Question 6

Genetic Disorders of Coagulation Cascade

Answer 6

• Haemophilia A, B + Thrombosis

Question 7

Haemophilia

Answer 7

Blood clotting disorder where essential clotting factors in coagulation pathway are deficient

• X linked recessive disorders, females are carriers but rarely affected
• Affects 1 in 500 / 1 in 1000 male births

Question 8

Haemophilia A

Answer 8

Male - inversions - lack of x chromosome pairing

Females - deletions - x chromosome promoting recombination

33% of missense mutations identified

Question 9

Haemophilia B

Answer 9

• Less prevalant than A
• 66% missense

Question 10

Factor V Leiden

Answer 10

• Promotes thrombosis (20-30%)

Question 11

Genetic Disorders of Platelet Function

Answer 11

• Bernard-Soulier Syndrome
• Glanzmann’s thombasthenia
• Grey platelet syndrome

Question 12

Bernard-Soulier Syndrome

Answer 12

• Mutations in the GPIb/V/IX complex lead to loss of receptor expression or function
• Leading to an inability of platelets to undergo initial tethering to vWf matrix
• Results in prolonged bleeding time, a low platelet count and large platelets
• Bleeding episodes that are severe usually require transfusion of blood and or platelets

males and females are affected with equal frequency

Question 13

Glanzmann’s Thrombasthenia

Answer 13

• Fibrinogen receptor, integrin alpha-IIb beta-3 defect
• Mutations lead to loss of receptor expression or function
• Inability of platelets to bind fibrinogen and generate stable platelet thrombus

Question 14

Grey-plate thombrosis

Answer 14

• Many introns of MBO2 transcribed into mRNA. loss of MBO2 production

Question 15

GWAS

Answer 15

• Annotated genome
• Technology - chip array or sequencing

Limitations: massive amount of data, cost