Complex genetic diseases Flashcards
What affects polygenic disease development?
- Low genetic risk and strong environmental trigger
- High genetic risk and weak environmental trigger
- High genetic risk and strong environmental
What does genetic variation affect?
- Normal variation e.g eye colour
- Differences in response to diet/medication e.g obesity
- Influence likelihood of disease e.g diabetes
- Directly results in genetic condition e.g PKU
What are the differences between type 1 and type 2 diabetes?
Type 1:
- Presents as any age
- Autoimmune system destroys pancreatic bet cells
- Need insulin fron diagnosis so insulin replacement needed
Type 2:
- Older age - increasing with youth
- Resistance to insulin action
- Increase in insulin production
- Pancreatic exhaustion and reduced secretion
- Treat by diet excerise and orl hypoglycaemic agents
What are the types of monogenic diabetes?
- Single gene defects
- Maturity onset diabetes of the young (MODY)
- Permanent neonatal diabetes (PND) - diabetes in first 6 months of age
- Mitochondrial diabetes: mit DNA different to genomic DNA - MIDD and MELAS
What is MODY?
AD collection of monogenic disorders affecting beta cell glucose sensing and insulin secretion
Which gene is mutated in MODY?
Most common HNF-4-alpha and glucokinase
What occurs during HNF-4alpha MODY?
- Insulin production reduced
- Only manifests in adulthood when beta cell function starts to naturally delcine
- Haploinsuffucient NOT insulin insensitivity
○ Haploinsufiency: Not enough normal gene present to job it has to do - Often incorrectly diagnosed with T1DM
- Uncommon 2-4% of all diabetes
How is MODY managed?
- Sulphonylurea is best management
- May eventually end up reusing insulin therapy
What occurs during Glucokinase (MODY 2)?
- Beta cell glucose sensing
- Changes set point at which you start secreting enzyme (normally fasting sugar 5.5-8 mmol/L)
- Often misdiagnosed
- Stable mild hyperglycaemia
Why should we study genes in diabetes?
- Investigate underlying pathophysioogy
- Define and predict genetic risk
- Identify monogenic causes
- Precision medicine (currently not being achieved in diabetes)
Define heritability?
- Study of genetic contribution to inc risk of disease
What is the problem with heritability in polygenic diseases?
- Difficult to differentiate genetic from non genetic
○ Study mono, dizygotic twins, first and second degree relative - Estimates vary between populations, across ages, baseline risk of disease in population, sampling variance
○ Should be viewed as benchmarks to indicate evidence for low, moderate high contributions of genetic effects
What is the Genome Wide Association Study?
- Looks for 6 million markers across genome
- Common disease, common variant
- See is disease statistically associated within single nucleotide polymorphisms (SNPs)
- Hypothesis free
- Look at sequence variation not mutations
What has GWAS found about Type 2 diabetes?
- 100 loci associated with inc. Risk
- Observed effect size is small
- Collective SNAP account only for 6% of type 2 risk
- Most loci affect beta cell function not insulin resistance
What to do with this?
- Genetic risk score
- Personalize treatment
What is a copy number variant?
- Deletions, duplications, insertions in genome
- Few bp-more than a million
- May increase risk of polygenic disease
- More common in obesity
- Most risk in single nucleotide changes
What are the challenges of diagnosis in monogenic diabetes?
- Incomplete understanding
- Access to genetic testing
- Interpret variants of unknown significance
