The Human Variome

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The Human Variome

• Implications for musculoskeletal disease

Assoc Prof Ravi Savarirayan Head, RCH Clinical
Genetics Service
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Why is this important?

• Diseases of the MSK system 2nd most common reason
  for doctor visit in Australia
• Third leading cause of health care expenditure
  (3 billion/annum)
• Significant burden of disease in men and women
  now and over next 20 years in Australia and
  worldwide
• (Mathers et al., Australian Burden of Disease
  Study, 2000)

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Further understanding of susceptibility genes

• Common sequence variants (polymorphisms) and
  their relationship to disease
• Common disease genetics
• Personalized genomics
• Interpretation of data is key

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Osteoarthritis genes

• Polymorphism in small ECM molecule (asporin)
  predisposes Japanese populations to knee and hip
  osteoarthritis
• Implications for population genetic screening,
  therapeutic management and prevention targeting
  of high risk groups

Nat Genet 37, 2005 (Kizawa et al.)
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Other genes and OA

• CILP
• ACAN
• GDF5
• SLC26A2
• WISP3
• COL2A1
• COL9A3
• MAT3

Genetic Profile of OA
Kannu,.. and Savarirayan Arthritis Rheumatism
in the press 2008
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Height genes

• Many genes that cause short-statured conditions
  also influence height generally
• polymorphisms in these genes (FRGF3, COL11A1)
  predispose to final adult height in our
  populations

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Osteoporosis genes

• Sclerosteosis/Van Buchem disease gene (SOST)
• Different polymorphisms in this gene associated
  with increased and decreased BMD in elderly Dutch
  white men and women (n2000) at femoral neck and
  lumbar spine
• Public health implications
• Uitterlinden et al., Am J Hum Genet Dec 2004

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Genes for lumbar disc disease (LDD)

• LDD caused by degeneration of intervertebral
  discs
• Common cause back pain/sciatica/spinal surgery
• Functional SNP (1184T-C) in CILP associated with
  LDD susceptibility
• Effects mediated by inhibition of TGFB1 induction
  of cartilage matrix genes in discs

Seki et al., Nat Genet, June 2005
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Important data

• Prenatal growth data (ultrasounds)
• Birth parameters and longitudinal growth data
  (height/parental heights)
• Radiographic data (incl. MRI)
• Bone density
• Joint pain assessments (qualitative measures)
• Activities of daily life
• Gait analysis
• Incorporate into structured assessment tools

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Gene databases

• Diagnostic testing (for various genes) now
  offered at GHSV
• Opportunity to be linked in with HVP databases as
  well as phenotype databases
• Phenotype-Genotype correlations
• Example type II collagenopathies

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Type II collagenopathies

• Achondrogenesis II
• Torrance type PLSD
• Hypochondrogenesis
• SED congenita
• SEMD Strudwick
• Spondyloperipheral dysplasia
• Kniest
• Stickler syndrome
• SED with premature arthritis
• Intermediate (bridging) phenotypes

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Consequences of collagen mutations?

• Tissue specificity of expression of the mutant
  collagen
• Functional role of the affected collagen
• Type of mutation
• reduced amount - null mutation
• structural mutation - dominant negative effect

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Achondrogenesis

• Collagen II mutations
• Extracellular matrix scaffold absent
• Alterations to chondrocyte gene expression

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Personalised Genomics
Disease
Environment Epigenetic factors
Phenotype Threshold
Subclinical phenotype
Genetic profile/Variome
High risk group
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Challenges

• Developing world how will this be practically
  relevant for them?
• Journals standardized reporting of
  phenotypes/genotypes
• Funding implications especially clinical
  interface with patients/families
• Use/Misuse of partial information

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Who is it can tell me who I am?