1. The potential of genetics
to enable personalization of healthcare
Professor Ian N M Day
MRC Centre (CAiTE) and
Bristol Genetic Epidemiology Laboratory
Department of Social Medicine
Oakfield House, Oakfield Grove
University of Bristol
Bristol Enterprise Network event „The Personalised Healthcare Revolution‟
8th October 2009
Bristol Zoo
2. What is in your genome?
• 3000 million A,C,G,T bases strung together into 23 long
molecules (chromosomes)
• The base sequence is your blueprint
• There are about 20,000 ‘genes’
• Each gene encodes a protein, e.g.haemoglobin
• 99% does NOT encode proteins. ?junk
• About 1% of bases are ‘polymorphic’
• You may have about 1m more ‘private’ variations
• Mutation of one base may cause a major disease
• You are 96% the same as chimp, 99.5% in protein coding
3. Where is your genome?
• There is a copy in every cell of your body
• Different genes are active in different cells
• However, you only copy half your genome
into a sperm or an egg
5. Melt-MADGE
Loading the gel
Pouring one gel Pouring 16 gels
Melt-MADGE system
Melt-MADGE tank
Glass-gel-glass sandwich
6. “ScanLab”
(same system to run melts and endoVII assays)
>>Goal – studying unknown mutations in populations … studies in
big case collections also feasible
>>Present capacity – 10 systems – 50million base pairs scanned per week
7. Found 1 severe mutation in MC4R
in 1,100 population sample
• Khalid K. Alharbi1, Emmanuel Spanakis1,
Karen Tan2, Matt J. Smith1, Mohammed
A. Aldahmesh1, Sandra D. O'Dell1, Avan
Aihie Sayer3, Debbie A. Lawlor4, Shah
Ebrahim5, George Davey Smith4,
Stephen O’Rahilly3, Sadaf Farooqi2 ,
Cyrus Cooper3, David I.W.Phillips3 and
Ian N M Day1
Prevalence and functionality
of paucimorphic and private
MC4R mutations in a large,
unselected European British
population, scanned by
meltMADGE (Human
Mutation 2006) (cat.P114)
MC4R A87D > (Appetite++) > BMI 31.5kg/m2
Does everybody have “one worst gene”?
Can we help them (cf phenylketonuria)?
8. From RV-CD to CV-CD
• Rare variant – common disease
• Common variant – common disease
22. What Sells to the Doctors?
• Genetic information that will help clinical process
• 1. diagnosis
• 2. prognosis
• 3. monitoring
• 4. screening
• 5. Non-directive counselling /reproductive choice
• 6. !! Not the patient’s right to know
23. Some real clinical examples
(single targetted gene tests)
• TPMT / thiopurines azathioprine, 6-mercaptopurine and 6-
thioguanine / organ Tx / autoimmune disease/ leukaemias
• Her2/NEU / breast cancer drug response
• VKORC1/CYP2C9 / warfarin dosing
• UGT1A1 /Gilbert’s / irinotecan / colon cancer
• DPYD, TS / 5-fluorouracil / gastric cancer
• (ABO) – blood group 1900-1925
24. Who gets the statins?
Average prescribing cutpoint
Red genotype over-represented and blue genotype under-represented relative
to black genotype. If we know the curves, then we could just use the genotype
ratios in those getting the statin, to determine the average prescribing cutpoint
Genotype ratio treatment index (GRTI)
NHS research of service delivery?
25. What does it all cost (2009)?
• 600,000 common polymorphisms (GWAS)
• £300 from 23andMe [NB £40 200K panels imminent]
• ‘Complete’ genome sequencing (NGS)
• £50,000
• 5 year goal of 1,000 dollar genome
• The cost of making sense of it all.
• The cost of leveraging value (to whoever) of that meaning
26. Urban(e) Dog Tags? (slide modified)
• identity
• blood type and history of inoculations
• Blood group
• Statin myopathy risk
• CFTR delta508, HBB E6V
• ALDH2 status
• BCHE D70G
• LCT
• Norwalk virus resistance
• MC1R, OCA2
• What I would really like for Xmas is
my complete genome sequence!