L12 Molecular epidemiology Flashcards
Define molecular epidemiology.
The branch of medical science concerned with the contribution of genetic (& epigenetic) and environmental risk factors, identified at the molecular level, to the aetiology, distribution and prevention of disease.
Why is molecular epidemiology important/of use?
It improves our understanding of the pathogenesis of disease by identifying specific pathways, molecules and genes that influence the risk of developing disease.
What is a biomarker?
Any substance, structure or process that can be measured in the human body or its products and may influence or predict the incidence or outcome of disease.
Define the criteria for evaluating biomarkers. (6)
- Easy to measure
- Add new knowledge on top of traditional risk factors
- Potential for changing patient management
- Cost-effective
- Safe
- Predictive value replicated in different populations
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Biomarkers of exposure case studies
Vitamin D and prostate cancer
- Common malignancy
- Incidence rates differ markedly between different ethnic groups and geographically, e.g.:
- African American highest, Japanese/Chinese lowest
- USA high in north, lower in south
- Vit D synthesised in response to UV exposure
- Is vitamin D protective?
Biomarkers of Vitamin D challenges:
- D3 (cholecalciferol) and D2 (ergocalciferol)
- Transported in the bloodstream covalently bound to vitamin D binding protein
- Vitamin D metabolically activated in the liver/kidney to 25-hydroxyvitamin D3 (25-OH-D3), considered to reflect bio-available vitamin D and therefore the best biomarker status
- HPLC measurement quite reliable
- Vitamin D binding protein, stable over time, so doesn’t change with exposure but may influence relationship between exposure and disease
Biomarkers of vitamin D practicalities:
- Relative time interval
- How long prior to disease should biomarker data be obtained?
- Dietary recall or dietary change
- Validate hypothesis
- If disease risk with vitamin D is through association with UV light, then seasonal changes in vitamin D status should be discernible
- Inter-assay variability
- Genetic polymorphisms
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Biomarkers of exposure case study
Phytoestrogens and health
- Linked to reduced risk of breast and prostate cancer and protection from cardiovascular disease and osteoporosis
- Excessive consumption may reduce fertility
- Food sources; nuts, oilseeds, cereals, legumes (lignans) soy products (isoflavones)
- Extensive and covert use in fast foods as soy protein to reduce high cost of true meat products
Biomarkers of phytoestrogen intake challenges:
- Food source and processing affects content significantly • Little quantitative information on food content, FFQ or dietary measures imprecise
- Diverse range of compounds
- Variety of biological effects (weak oestrogenic and anti-oestrogenic effects) How do we measure exposure
Biomarkers of phytoestrogen practicalities:
- Phytoestrogens are readily absorbed, circulate in plasma and are excreted in urine
- Only some can be detected e.g. isoflavonoids and biotransformed lignans. For many other compounds good methods are not yet available for quantification.
- Difficult analytical methodology (mass spectrometry) • Urinary isoflavonoid measurement suggests complete 48-72 hour collection gives optimal index – impractical?
- Can be used as an index of compliance with a soy-rich dietary intervention
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Biomarkers of exposure case studies
Cooked meat intake, heterocyclic amines and colorectal cancer:
- greater intake of MEAT = greater CRC risk
- Heterocyclic amines are pyrolysis products when meat is well-cooked
- HA are potent mutagens
- 2 major HA’s in the diet are
- 2-amino-1-methyl-6-phenylimiazo(4,5-b)pyridine (PhIP)
- 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx)
Biomarkers of exposure challenges:
- Not from a single dietary source
- Method of cooking has major influence on HA level
- HA are a large class of compounds so measurement of each of these in a large number of foods is impractical
- FFQ can include information on degree of cooking of meat, but still imprecise
- Urinary excretion of PhIP and MeIQx correlate well with intakes, although rapid excretion (8h) of PhIP is a limiting factor
- Excretion is also influenced by genetic polymorphisms in de-toxification enzymes
Biomarkers of biological effect:
- An alternative to measuring carcinogens or their metabolites in body fluids is to measure the binding of HA to DNA as a marker of biologically effective dose
- DNA adduct = exposure + absorption + metabolism - DNA repair
- Biomarker must be an important step in the disease pathway
- DNA adducts in target tissue (colonic mucosa)
- PhIP = compound bound to position C8 of deoxyguanosine (measured by GC-MS)
- MeIQx = measured by HPLC – Can these be applied to more accessible tissue?
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Technical considerations of molecular epidemiology
- Poor QC in collection, processing, storage and analysis of biological samples can compromise biomarker measurements
- Intra-individual variation may exist unrelated to exposure
- A single measure at one time point may not reflect typical status
- Timing of measure in relation to natural history of disease should be considered
- Disease state may affect biomarker
- Homeostatic control of certain biomarkers may lead to a poor correlation with exposure
- Genetic background will influence correlation between exposure and biomarker
- Epigenetic patterns may link environmental exposure with altered gene regulation
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Ethical considerations of molecular epidemiology
- Accessibility of tissues (in particular in children)
- Appropriate / less invasive alternatives
- Genetic / epigenetic information
- Long term sample storage
