Genetics of Osteoarthritis Flashcards
What is present in a joint?
Bones
Muscles
Synovial fluid
Fat
Cartilage
What is Osteoarthritis (OA) ?
The gradual loss of articular cartilage.
How thick is cartliage?
Only a few mm thick.
What is the function of cartilage?
Allows for friction free movement, and compression.
What is compression?
The pressure build up when you stand up.
What is cartilage made up of?
Chondrocytes
What is the role of chondrocytes?
The make and maintain cartilage.
How are chondrocytes arranged?
They sit in isolation then connect to each other through pericellular space.
What is the matrix in cartilage composed?
Collagen
Proteoglycan
Water
What is the role of collagen?
Structural rigidity
When the cartilage expands it holds it together.
What is the role of the proteoglycan?
Pulls water into the tissue.
How do proteoglycans and collagen work together?
Proteoglycans draw in water which expands the tissue making it spongey and collagen holds it all together.
What is the other major symptom of OA?
Low level inflammation due to loss of cartilage.
Why does low level inflammation occur due to OA?
Because cartilage is releasing molecules to the sigmoidal space which is triggering am immune response.
What are osteophytes?
Bone out growth in response to OA.
Why does the joint grow osteophytes?
In an attempt to stabilise itself and replace cartliage.
What structural change occurs during OA in an attempt of the joint stabilising itself?
Angulation in the bones above and bellow.
How many adults in the UK have OA?
5 million
What are the symptoms of OA?
Joint pain, stiffness and reduced function
Consequential loss of muscle mass
Increased morbidity and mortality
What are the current treatments for OA?
No licensed disease-modifying drugs
Pain relief moderately effective
Surgery
What are the OA risk factors?
Age
Obesity
Injury
Genetics
Why is obesity a factor for OA?
Biomechanical (pressure on bone) plus systemic effects (metabolism).
What is the concordance percentage in monozygotic twins for OA?
50%
What is the concordance percentage in dizygotic twins for OA?
20%
What does the concordance difference in monozygotic twins and dizygotic twins tell us about the genetic impact on the disease?
High possibility genetics plays a major role but as not 100% other factors clearly play a role.W
What kind of disorder id OA?
Polygenic and multifactorial
How to identify OA susceptibility alleles?
Case-control association analysis of DNA polymorphisms.
How many risk loci have been identified so far?
110
What percentage of OA heritability has been discovered so far?
25%
How many of the 110 discovered disease loci for OA are cartilage structural protein genes
6
What kind of structural protein gene are potential OA disease loci?
CHADL
Collagen 2, 11 (A1 and 2) and 27
FBN2
What is CHADL?
Chondroadherin-like protein
What is FBN2?
Fibrillin 2
What kinds of Dynamic disease pathways are present in OA (making cartilage)?
Transcriptional regulation
Proteoglycan synthesis
Chondrocyte development
Cell proliferation
What kinds of Dynamic disease pathways are present in OA (maintaining cartilage)?
Skeletal development and morphogenesis
Regulation of apoptosis
What is fine mapping?
Conditional analysis to determine statistically the
most significant SNP (CAUSAL)
What is the causal SNP doing?
Amino acid substitution - rare
Modifies a gene regulatory element - common
What happens once you have your causal SNP?
Find the likely effector gene.
Location, normal function an effect.
In OA where are most causal SNPs?
Predicted gene regulatory elements.
What additional step can occur between a genetic effect and a gene expression chnage?
Epigenetic change
What is the role of DNA methyl transferases?
Add methylation onto CPG sites.
What are TET?
Removes methylation at CPG sites
Why can SNP affect DNA methylation?
Removes the binding site for the TF which allows DNMT to bind which leads to methylation which reduces gene transcription therefore expression.
What is the function of Collagen galactosyltransferase
Glycosylation post-translational modifications of Collagen?
What is the importance of glycosylation within collagen?
Allows it to form correctly in telopeptide cleavage which crosslinks.
What is COLGALT2?
Collagen Beta(1-O)Galactosyltransferase 2
