W8L1 Non communicable disease Flashcards
What is non-commutable disease
refers to a group of conditions that are not mainly caused by an acute infection, result in long-term health consequences and often create a need for long-term treatment and care. These conditions include cancers, cardiovascular disease, diabetes and chronic lung illnesses.
Why do non-communicable diseases occur
- Some conditions result from environmental factors which are evolutionarily novel (e.g. asbestos) or affect fundamental aspects of cell function (e.g. arsenic poisoning)
- Some genetic disorders may have benefits which offset selective pressure against the disease
- Some diseases occur mostly in the post-reproductive period, or occur very rarely in the absence of additional environmental factors
Case study #1 - cancer
- Cancer is a highly heterogenous condition
- Cancer is itself an evolutionary process, with distinct selective pressures on cancer cells driving higher cell division rates, capacity for migration, resistance to pro-apoptotic signals etc.
- Development of cancer requires multiple mutations, meaning it becomes far more common late in life
How heritable is cancer risk
- Many cancers, especially in old age, occur without clear familial history
- A minority of cancer types seem to be almost entirely sporadic, with no detectable genetic contribution
- Cancers for which smoking is the main risk factor are over-represented among cancers with low heritability
Environment-genome interactions Of cancer
- Risk of esophageal cancer is strongly increased by tobacco and alcohol consumption
- However, the extent to which an environmental agent increases cancer risk can itself be affected by genetic factors (in this case, a CYP26B1 variant)
- The definition of a cancer risk allele is not straightforward!
Familial cancer syndromes
- Various familial cancer syndromes involve some risk of mortality before the end of the reproductive period
- Caputo et al. (2012) analysed French families carrying BRCA mutations -slightly more than half of the families possessed unique alleles, but a small number of variants were widespread (one in 138 families, one in 137)
other explanation of high-frequency cancer risk alleles be other than inefficient selection?
- Elevated frequencies of risk alleles in some populations (e.g. BRCA1 risk alleles among east Greenlandic Inuit) may reflect founder effects
- Possible benefits of risk alleles have also been suggested:
- Increased reproductive success
- Greater female embryonic survival
Detecting selection on cancer risk alleles
- Risk of prostate cancer is greatly elevated in African populations
- As prostate cancer risk is highly heritable, a genetic contribution to this disparity is likely
- Most risk alleles found to evolve neutrally across all studied populations
- However, ‘hitchhiking’ with nearby beneficial alleles is sometimes seen
Accidental cancer protection
- rs7584330 - 47% higher frequency of risk allele in African populations, evidence of positive selection for protective allele in European populations
- rs7584330 occurs close to the melanophilin gene, variants of which result in reduced skin and hair pigmentation
- Lower prostate cancer risk in European vs. African populations in part a side-effect of selection for reduced skin pigmentation!
Genetics of cancer outcomes
- Most cancer research has focused on variation in incidence of cancer, rather than survival rates
- How might we use this information in cancer screening and treatment?
Case study #2 - Alzheimer’s disease
- Decline on some measures of cognitive function is common in old age, but far from invariable
- Alzheimer’s disease is usually diagnosed by analysis of cognitive function (memory, judgement, sociality), but formally requires neuronal biomarkers, i.e. deposition of β-amyloid and tau
Inheritance of Alzheimer’s disease
- Alzheimer’s disease is largely a post-reproductive disease; even early-onset Alzheimer’s is usually diagnosed after the age of 45
- Alzheimer’s disease is highly heritable, especially in early-onset cases, though environmental effects (e.g. history of traumatic brain injury) can slow or accelerate onset
- Mutations in APP, PSEN1 and PSEN2 were associated with Alzheimer’s disease in the 1980s and 1990s
Amyloid precursor protein and presenilins
The normal function of β-amyloid is not well understood, despite the importance of formation of β-amyloid plaques in the brain in Alzheimer’s disease
* Presenilins have important developmental roles, and also interact with the amyloid precursor protein
* Therapies which reduce β-amyloid level have had little success in reversing the progression of Alzheimer’s disease
APOE genotype and Alzheimer’s risk
- Mutations in APP or presenilins explains a fairly small portion of Alzheimer’s disease risk
- Variation at apolipoprotein E (which transports cholesterol and lipids in the central nervous system) is the biggest single contributor to Alzheimer’s disease risk
- APOE genotype has been linked to many other aspects of Alzheimer’s pathology, perhaps through effects on cholesterol, but the mechanisms involved are far from fully understood
Alzheimer’s disease and APOE
- Individuals with one or two copies of the APOE ε4 allele are at higher risk of developing Alzheimer’s disease in old age; the increase in risk may vary substantially with genetic background
- In contrast, the APOE ε2 allele seems to have a weak protective effect
- Analysis of chimpanzees suggests that APOE ε4 is the ancestral form, with APOE ε3 having arisen about 200000 years ago
