Genomics and population health

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Genomics and population health

• David Melzer
• Epidemiology Public Health

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outline

• The promise of sequencing the genome
• Overview of findings
• Flood of discovery for common disease and traits
• Interpreting gene status
• Implications for PH
• Biological insights into population distributions
  and the need for population based approaches
• Regulatory challenge

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2005 - How the Human Genome Era Will Usher in a
Health Care Revolution -Personalized Medicine
(NHGRI)

• Prevention
• Identify those at risk before they developed
  disease
• Diagnosis
• Treatment Pharmacogenetics
• Personalising the drug and dose
• Avoiding idiosyncratic side effects
• (gene therapy)
• Prognosis

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DNA RNA protein 3 billion base pairs, 20K
genes
Mendel biography, Mawer S, Adams NY 2006
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Genetic variation between humans

• gt10 million variants in human genome databases
• Most common Single Nucleotide Polymorphisms
  (SNPs)

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Sickle cell mutation changing one amino acid
Public health genetics unit, 2006
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HeritabilityThe degree to which a characteristic
is determined by genetics (as opposed to
environment).

• stroke, diabetes, prostate cancer, cardiovascular
  disease, depression and bone degeneration
• approx 25 - 33 heritability

Sciences et Avernir, 2007
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GWA studies e.g. UK Wellcome Trust Case Control
Consortium
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WTCCC study - Type 2 diabetes - Oxford and Exeter
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FTO AA genotype is associated with a 3kg
increase in adipose tissue
P 3 x 10-35
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(No Transcript)
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FTO gene status meaning?May 27th, 2008

• Susannah said
• I was astonished, and over the moon.
• and meanwhile my fat friend here to Trinny
  I dont know what youre going to do?!
• Turning to the fat people who did not have the
  gene, Susannah said
• "So if we don't have it and we're still fat, it
  must be because we're just greedy pigs who eat
  too many pies!"

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Obesity epidemic
Mu Boyan 2009
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LDL cholesterol SNPs in the InCHIANTI study

• Frequency of respondents by LDL cholesterol
  allele count, with box-plots of the distribution
  of serum LDL cholesterol levels. Dotted lines
  indicate intervention levels of greater than 130
  mg/dl for borderline high levels and greater than
  160mg/dl for high levels.
• Murray et al European Heart Journal 2009

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population distributions
Arbitrary risk thresholds inescapable?
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Flood of SNP discoveries 300
(Melzer, BMJ Feb 08)
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Age related Macular Degeneration

• Most common risk of blindness in older people in
  developed countries
• Population attributable risk 43 for CFH
• Complement Factor H
• Plus
• 20 - smoking
• 36 for LOC387715

From Mayo Clinic website
Schmidt S, Am. J. Hum. Genet. 200678852864.
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New biologyFilaggrin mutations, dermatitis and
asthma

• Nature Genetics 38, 399 - 400 (2006) Skin barrier
  function and allergic risk
• Thomas J Hudson  Figure 1. Skin barrier function
  and allergic risk.An intact epithelial barrier
  (a) prevents allergens from reaching antigen
  presenting cells (APCs) in subepithelial tissues.
  Damage to this barrier (b) allows allergens to
  penetrate into the subepidermal layer and
  interact with APCs, leading to allergic
  sensitization and, secondarily, to allergic
  manifestations in the host.

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Regulatory issues Very little clinical
evaluation required of genetic tests (esp. for
labs)
Forbes - 12 Gene Tests That Could Change Your
LifeTCF7L2 DeCode Genetics sells a test for
500 via online test provider DNA Direct.
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TCF7H2 and Diabetes 2 reduced beta cell
(insulin) function

• Identified a hot area on 10q1, for diabetes 2,
  within transcription factor 7like 2 gene
  (TCF7L2 formerly TCF4) p value 2.1x10-9
• replicated in Danish cohort (P 4.8x103) US
  cohort (P3.3x109).
• Compared with non-carriers
• OR CC1.00
• CT1.45
• TT 2.41
• Population attributable risk of 21.

From Grant S et al, Nature Genetics 2006
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Forbes - 12 Gene Tests That Could Change Your
LifeTCF7L2 DeCode Genetics sells a test for
500 via online test provider DNA Direct.
with diabetes or Impaired Fasting Glucose by
TCF7L2 genotype aged 65 in InCHIANTI n944
ADA criteria for Impaired fasting glucose
Melzer, 2006
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Evidence requirement for clinical tests
Hogarth S, et al . Food Drug Law J.
200762(4)831-48.
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Policy issues in genetic tests

• Can balanced regulation be crafted?
• economically viable, allowing innovation etc
• Who is responsible for clinical validity (or
  utility)?
• How much clinical evidence should be required?
• How accessible should this data be (for
  systematic review etc)
• A post marketing surveillance system needed?
• off label use
• Special measures for ethnic groups?

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Defying genotype

• Incidence of Diabetes According to Treatment
  Group and Genotype at Variant rs7903146 (TCF7L2)
• Diabetes prevention programme n3548 (Florez et
  al, N Engl J Med. 2006 July 20 355(3) 241250.)

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Conclusions

• Genes and environment are inseparable
• That is how evolution works!
• Explosion of polygenic gene discovery
• Some great hits but also large number of small
  effect markers
• Provide a genetic explanation for
• trait distributions
• human, system, disease heterogeneity
• lack of natural boundaries
• (genetic) Test regulation for clinical validity
  in Europe is non-existent
• CE mark on a test is worthless!