Genetics of Osteoarthritis

Question 1

What is present in a joint?

Answer 1

Bones

Muscles

Synovial fluid

Fat

Cartilage

Question 2

What is Osteoarthritis (OA) ?

Answer 2

The gradual loss of articular cartilage.

Question 3

How thick is cartliage?

Answer 3

Only a few mm thick.

Question 4

What is the function of cartilage?

Answer 4

Allows for friction free movement, and compression.

Question 5

What is compression?

Answer 5

The pressure build up when you stand up.

Question 6

What is cartilage made up of?

Answer 6

Chondrocytes

Question 7

What is the role of chondrocytes?

Answer 7

The make and maintain cartilage.

Question 8

How are chondrocytes arranged?

Answer 8

They sit in isolation then connect to each other through pericellular space.

Question 9

What is the matrix in cartilage composed?

Answer 9

Collagen

Proteoglycan

Water

Question 10

What is the role of collagen?

Answer 10

Structural rigidity

When the cartilage expands it holds it together.

Question 11

What is the role of the proteoglycan?

Answer 11

Pulls water into the tissue.

Question 12

How do proteoglycans and collagen work together?

Answer 12

Proteoglycans draw in water which expands the tissue making it spongey and collagen holds it all together.

Question 13

What is the other major symptom of OA?

Answer 13

Low level inflammation due to loss of cartilage.

Question 14

Why does low level inflammation occur due to OA?

Answer 14

Because cartilage is releasing molecules to the sigmoidal space which is triggering am immune response.

Question 15

What are osteophytes?

Answer 15

Bone out growth in response to OA.

Question 16

Why does the joint grow osteophytes?

Answer 16

In an attempt to stabilise itself and replace cartliage.

Question 17

What structural change occurs during OA in an attempt of the joint stabilising itself?

Answer 17

Angulation in the bones above and bellow.

Question 18

How many adults in the UK have OA?

Answer 18

5 million

Question 19

What are the symptoms of OA?

Answer 19

Joint pain, stiffness and reduced function

Consequential loss of muscle mass

Increased morbidity and mortality

Question 20

What are the current treatments for OA?

Answer 20

No licensed disease-modifying drugs

Pain relief moderately effective

Surgery

Question 21

What are the OA risk factors?

Answer 21

Age

Obesity

Injury

Genetics

Question 22

Why is obesity a factor for OA?

Answer 22

Biomechanical (pressure on bone) plus systemic effects (metabolism).

Question 23

What is the concordance percentage in monozygotic twins for OA?

Answer 23

50%

Question 24

What is the concordance percentage in dizygotic twins for OA?

Answer 24

20%

Question 25

What does the concordance difference in monozygotic twins and dizygotic twins tell us about the genetic impact on the disease?

Answer 25

High possibility genetics plays a major role but as not 100% other factors clearly play a role.W

Question 26

What kind of disorder id OA?

Answer 26

Polygenic and multifactorial

Question 27

How to identify OA susceptibility alleles?

Answer 27

Case-control association analysis of DNA polymorphisms.

Question 28

How many risk loci have been identified so far?

Answer 28

110

Question 29

What percentage of OA heritability has been discovered so far?

Answer 29

25%

Question 30

How many of the 110 discovered disease loci for OA are cartilage structural protein genes

Answer 30

6

Question 31

What kind of structural protein gene are potential OA disease loci?

Answer 31

CHADL Collagen 2, 11 (A1 and 2) and 27 FBN2

Question 32

What is CHADL?

Answer 32

Chondroadherin-like protein

Question 33

What is FBN2?

Answer 33

Fibrillin 2

Question 34

What kinds of Dynamic disease pathways are present in OA (making cartilage)?

Answer 34

Transcriptional regulation Proteoglycan synthesis Chondrocyte development Cell proliferation

Question 35

What kinds of Dynamic disease pathways are present in OA (maintaining cartilage)?

Answer 35

Skeletal development and morphogenesis Regulation of apoptosis

Question 36

What is fine mapping?

Answer 36

Conditional analysis to determine statistically the most significant SNP (CAUSAL)

Question 37

What is the causal SNP doing?

Answer 37

Amino acid substitution - rare Modifies a gene regulatory element - common

Question 38

What happens once you have your causal SNP?

Answer 38

Find the likely effector gene. Location, normal function an effect.

Question 39

In OA where are most causal SNPs?

Answer 39

Predicted gene regulatory elements.

Question 40

What additional step can occur between a genetic effect and a gene expression chnage?

Answer 40

Epigenetic change

Question 41

What is the role of DNA methyl transferases?

Answer 41

Add methylation onto CPG sites.

Question 42

What are TET?

Answer 42

Removes methylation at CPG sites

Question 43

Why can SNP affect DNA methylation?

Answer 43

Removes the binding site for the TF which allows DNMT to bind which leads to methylation which reduces gene transcription therefore expression.

Question 44

What is the function of Collagen galactosyltransferase

Answer 44

Glycosylation post-translational modifications of Collagen?

Question 45

What is the importance of glycosylation within collagen?

Answer 45

Allows it to form correctly in telopeptide cleavage which crosslinks.

Question 46

What is COLGALT2?

Answer 46

Collagen Beta(1-O)Galactosyltransferase 2