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Genetics and Human Disease > Genetics of Osteoarthritis > Flashcards

Genetics of Osteoarthritis Flashcards

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Biology 101 flashcards
1
Q

What is present in a joint?

A

Bones

Muscles

Synovial fluid

Fat

Cartilage

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2
Q

What is Osteoarthritis (OA) ?

A

The gradual loss of articular cartilage.

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3
Q

How thick is cartliage?

A

Only a few mm thick.

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4
Q

What is the function of cartilage?

A

Allows for friction free movement, and compression.

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5
Q

What is compression?

A

The pressure build up when you stand up.

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6
Q

What is cartilage made up of?

A

Chondrocytes

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7
Q

What is the role of chondrocytes?

A

The make and maintain cartilage.

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8
Q

How are chondrocytes arranged?

A

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

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9
Q

What is the matrix in cartilage composed?

A

Collagen

Proteoglycan

Water

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10
Q

What is the role of collagen?

A

Structural rigidity

When the cartilage expands it holds it together.

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11
Q

What is the role of the proteoglycan?

A

Pulls water into the tissue.

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12
Q

How do proteoglycans and collagen work together?

A

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

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13
Q

What is the other major symptom of OA?

A

Low level inflammation due to loss of cartilage.

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14
Q

Why does low level inflammation occur due to OA?

A

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

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15
Q

What are osteophytes?

A

Bone out growth in response to OA.

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16
Q

Why does the joint grow osteophytes?

A

In an attempt to stabilise itself and replace cartliage.

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17
Q

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

A

Angulation in the bones above and bellow.

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18
Q

How many adults in the UK have OA?

A

5 million

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19
Q

What are the symptoms of OA?

A

Joint pain, stiffness and reduced function

Consequential loss of muscle mass

Increased morbidity and mortality

20
Q

What are the current treatments for OA?

A

No licensed disease-modifying drugs

Pain relief moderately effective

Surgery

21
Q

What are the OA risk factors?

A

Age

Obesity

Injury

Genetics

22
Q

Why is obesity a factor for OA?

A

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

23
Q

What is the concordance percentage in monozygotic twins for OA?

A

50%

24
Q

What is the concordance percentage in dizygotic twins for OA?

A

20%

25
Q

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

A

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

26
Q

What kind of disorder id OA?

A

Polygenic and multifactorial

27
Q

How to identify OA susceptibility alleles?

A

Case-control association analysis of DNA polymorphisms.

28
Q

How many risk loci have been identified so far?

A

110

29
Q

What percentage of OA heritability has been discovered so far?

A

25%

30
Q

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

A

6

31
Q

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

A

CHADL

Collagen 2, 11 (A1 and 2) and 27

FBN2

32
Q

What is CHADL?

A

Chondroadherin-like protein

33
Q

What is FBN2?

A

Fibrillin 2

34
Q

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

A

Transcriptional regulation

Proteoglycan synthesis

Chondrocyte development

Cell proliferation

35
Q

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

A

Skeletal development and morphogenesis

Regulation of apoptosis

36
Q

What is fine mapping?

A

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

37
Q

What is the causal SNP doing?

A

Amino acid substitution - rare

Modifies a gene regulatory element - common

38
Q

What happens once you have your causal SNP?

A

Find the likely effector gene.

Location, normal function an effect.

39
Q

In OA where are most causal SNPs?

A

Predicted gene regulatory elements.

40
Q

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

A

Epigenetic change

41
Q

What is the role of DNA methyl transferases?

A

Add methylation onto CPG sites.

42
Q

What are TET?

A

Removes methylation at CPG sites

43
Q

Why can SNP affect DNA methylation?

A

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

44
Q

What is the function of Collagen galactosyltransferase

A

Glycosylation post-translational modifications of Collagen?

45
Q

What is the importance of glycosylation within collagen?

A

Allows it to form correctly in telopeptide cleavage which crosslinks.

46
Q

What is COLGALT2?

A

Collagen Beta(1-O)Galactosyltransferase 2

47
Q
A

Genetics and Human Disease (16 decks)

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