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Genetics of Diabetes and Obesity
Terms in this set (52)
Link markers may not be the casual variant - but perhaps it could be? There are also what that change gene expression?
Epigenetic markers (e.g modifications on histones, and methylation of DNA - both of which change how accessible genes are, can essentially turn them on and off)
Marks are heritable from cell to cell, and sometimes even....?
Heritable between generations
So, there's the possibility of transgenerational epigenetics. Within the foetus there are already what kind of cells (which will become sperm and egg)?
Primordial germ cells
So, what influences a pregnant women (e.g. nutrition, exercise), will affect not just the next generation but also....?
The generation after too (due to the effect on primordial cells) - hereby some epigenetic changes go through 3 generations
Obesity and type II diabetes have strong heritability - why? The standard theory of evolution that explains this is that of....?
Genetic drift/neutral theory - that gene variants become more of less common due to chance alone ("drift")
So the idea here is that changes between DNA are not significant (most changes are neutral) - changes arise due to chance alone and drift. Such drift is affected by....?
Bottlenecks (selection) and founder effects
Thrifty genes includes certain genes that increase the efficiency of metabolism to extract energy from food and store the energy for later use. This survival trait was....?
Advantageous in our ancestors whose food supplies were scarce or unpredictable, and could help keep people alive during famine
So the idea is that such genes have been selected for in the past, despite the fact that they don't give us an advantage anymore. These genes would be for things like....?
Fundamental metabolic enzymes
So evolutionary medicine has this idea that there are current mismatches between the past, developmental and current environments, which contributes to disease. Genotype and epigenotype are affected by what?
Genotype is affected by past history of population (selection, drift etc)
Epigenotype is affected by intergenerational environmental effects
Genotype and epigenotype are influences by early developmental environments, which then together determine what?
The developmental phenotype (which then determines the adult phenotype)
Cues during development prompt predictive adaptive responses by the foetus to shift its development trajectory to match the perceived environment. If the inducing environment predicts the later environment well, then there is a match, and the individual has the appropriate....?
Physiological settings to be well prepared for the post-natal environment - so the risk of disease of disease is low
Conversely, if there is a mismatch between the predicted environment and the later environment, then....?
The risk of disease is enhanced
So basically the developmental phenotype is when all pathways are set in the foetus - if the foetus is born with a low birth weight, and goes into life with a starved/thrifty idea, then there's increased risk of....?
Becoming obese later in life (idea is that what influenced how the foetus is programmed then affects what will happen later on - undernutrition vs overnutrition later will cause disease)
Treatments have been proposed around what?
Resetting the epigenetic markers that have an effect (so that some people are not optimised for laying down fat/fuels)
For obesity, there are rare/uncommon monogenic forms of obesity - for example which ones?
- Melanocortic receptor 4 (MCR4) etc
These mutations cause obesity in children, and have a strong/what family history?
So, all the monogenic mutations implicated in obesity are involved with what?
The pituitary and hypothalamus (the hormones in the brain are the ones that are affected - not so much the metabolic pathways really)
Labrador retrievers commonly have a mutation in what that causes hunger?
Obesity is a complex disease - it's a continuous trait. The genes that mainly contribute have what kind of effect?
Additive genetic variation - each allele at the many genes that affect the trait have a small effect on phenotype (so phenotype results from cumulative effect of disease-susceptibility alleles)
So, in most cases of obesity it's multiple genes having a small effect (not one gene having a big effect). We can use a large number of these genes to predict whether people are likely to become obese or not - there was a study that used 2.1 million markers across genomes, and based on this came up with a...?
Polygenic score decile (where people in the top decile had a 45% chance of become obese)
So, with enough markers we can predict the risk of obesity from....?
Birth (where at birth some babies that were only 0.06kg heavier than others can by middle age be 13kg heavier)
The environment can shift curves and increase.....?
Penetrance of obesity (given the predisposing genetic variants)
So shifting the curve means more are over the threshold.
What is penetrance?
Those with the genotype that are exhibiting the phenotype
What we can see here is that there's lots of common variants that are associated with obesity and type II diabetes. There are genes associated with many different measures of obesity (e.g. BMI, waist circumference) and also diabetes (e.g. insulin and fasting glucose). There are some that....?
overlap/are in common to both conditions (and also overlap within each condition)
What have variant-disease association studies achieved?
They are individually not useful for risk prediction (e.g. obesity), however is important for pathophysiology
Most genes for common obesity that are identified act through what pathways?
Hunger/satiation pathways (more involved with neuroendocrine control of appetite rather than the metabolic enzymes themselves)
What is the European descent "gene" which has the largest effect on obesity?
A common variant in the FTO gene (which is a non-coding variant)
The FTO gene is associated with BMI and predisposes to....?
Childhood and adult obesity
The variant is rs9939609 T>A (T -> A), which is a non-coding variant but on average adds what per risk ("A") allele?
So, this is dominant, and has an additive effect with....?
Other risk genes
The variant is found in 40% of European chromosomes (and 16% of people have two copies). So, it's quite frequent and therefore contributes a lot in the population. There are lower proportions of it in what ethnicities?
- 52% in Yorubans (Africans)
- 14% in Chinese and Japanese
The fat mass and obesity (FTO) gene acts through what?
Higher levels of the "hunger hormone" ghrelin - through gene regulatory and epigenetic pathways
This again illustrates that most genes involved in obesity act....?
In the brain (through hunger/satiation pathways)
There are different obesity associated genes in different ethnicities. E.g. some genes are in common say between Asian and African populations (whereas there are some that are unique). What is a variant that is quite high in Samoans, but not other populations?
The CREBRF variant was likely increased in the Samoan population through what?
Founder effect + selection
The CREBRF is a classic example of a thrifty gene - which was quite likely selected for as a....?
Survival advantage (natural selection favoured the Samoans that could store fat effectively - and so now has become quite common in the Samoan population)
Obesity has a heritability of about 70% in Samoa - there are again many genes each with a minor contribution. However the largest contributor is variation in what?
CREBRF gene (but still only 2% of the 70% heritability)
We don't really know how this gene works (we don't know the pathophysiology) - but the association is....?
The effect of this variant is dominant - 7% of Samoans have two copies and 38% have one copy. People with 2 copies are on average....?
The variation of the CREBRF promotes what?
Glucose being converted to fat, by regulation gene expression (so basically it codes for a transcription factor that is involved in regulating other transcription factors - in a way that promotes fat storage)
But paradoxically because of this, this variant is protective against....?
High blood glucose and type II diabetes (as this gene involves more efficient uptake of glucose from the bloodstream and storage into fat - so increases obesity and decreases diabetes)
Is this variant just as common in Maori populations in NZ?
Yes - leads to similar risk (discordant association between Maori and Pacific people living in NZ)
Again though there is a reduction in Maori with this for....?
Risk of type II diabetes (OR is down to 0.59 for it)
This variant was also very protective against what in obese pregnant women?
Gestation diabetes (and perhaps against extra gestational obesity??? - lecture contradiction)
So this thrifty gene that helped store fat was an advantage in the past but a liability now. Avoid however what?
Genetic determinism (that there's no solution for what your genes have set you up for) - avoid not taking responsibility for health due to this
For type II diabetes there are also many gene variants each with a modest effect:
- Some of these mutations are intronic/non-coding (some are to do with promoters etc)
- Some are associated with transcription factors/regulation - more so than actual enzymes involved in the pathway
- OR is quite small for each one - so again most genes involved have a small effect
Gene association studies and polygenic scores can be useful - but due to the modest genetic effect sizes, they are not usually useful for....?
Risk prediction (e.g. obesity)
However, gene association studies can identify what?
Drug targets - and make therapeutic modulation more dramatic
For example you can develop drugs such as what that improve insulin sensitivity in peripheral tissues (for type II diabetes)?
Glitazones (which target PPARG)
What improve insulin release (for MODY)?
Sulphonylureas (which target KCNJ11)
So we have found these targets based on what pathways we have....?
Found to contribute (through knowing what mutations increase risk where)
Something about association with obesity (of BMI) not involving a....?
Height association - ????
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