Genetics 6 Flashcards
(32 cards)
What are the typical characteristics of diabetes
Chronic hyperglycaemia
Beta cell dysfunction and/or insulin resistance
Classification determines treatment
Polygenic or monogenic
Describe the characteristics of type 1 diabetes
Can present at any age
Autoimmune system destroys pancreatic beta cells
Diminished or absent endogenous beta cell function→ Need insulin from diagnosis
Treatment
Insulin replacement
Describe the characteristics of type 2 diabetes
Usually starts in middle age or older, but increasing in youth
Incidence changes in different ethnic groups
Resistance to insulin action → Increase in insulin production → Ultimately ‘pancreatic exhaustion’ and reduced secretion
Treated:
Initially by diet & exercise & oral hypoglycaemic agents (relies on endogenous insulin production)
Insulin eventually
Describe monogenic diabetes
Single gene defect
Maturity onset diabetes of the young (MODY)
Permanent neonatal diabetes (PND)
(Mitochondrial diabetes)
What is MODY
Collection of autosomal dominant monogenic disorders affecting genes involved in beta-cell glucose sensing and insulin secretion.
Treatment depends on the affected gene
Why do we need to study genes in diabetes
Investigate underlying pathophysiology
Define and predict genetic risk
Identify monogenic causes
Determine if genotype influence treatment choices / outcomes
precision medicine
What do we mean by heritability
Study of genetic contribution to increased risk of a disease
Difficult to disentangle genetic from non-genetic factors
How do estimates of heritability vary and how do we categorise them
Estimates vary between populations Across ages Baseline risk of disease in population Sampling variance
In reality, heritability estimates should be viewed as pragmatic benchmarks representing evidence for low, moderate or high contributions of genetic effects.
Describe the threshold theory
Although diseases are dichotomous, however for complex, polygenic diseases, there is underlying continuous susceptibility to the disease, only people whose susceptibility exceeds a certain threshold develop the disease. Relatives of an affected individual are more likely to have the susceptible genes than the general population, but the tendency is much weaker than mendelian inheritance
Describe the differences between monogenic and polygenic diseases in terms of inheritance
Polygenic
Not born with it but may develop later
Low genetic risk + strong environmental
High genetic risk + weak environmental
High genetic risk + strong environmental
Monogenic
‘Born with it, always going to develop diabetes’
Describe the mutations that occur in each region of the gene.
One end- normal variation- what makes us different
Other side- needs to be consistent- changes lead to disease.
Grey zones in the middle- changes do not cause disease but can increase risk (SNPs)- responsible for different responses to diet and medication.
Describe polygenic diabetes
A compilation of genetic changes that increase predisposition to developing
type 2 diabetes
type 1 diabetes
Unlike monogenic diabetes, there has to be a second hit to develop diabetes
environmental
lifestyle
Describe the role of GWAS
GWAS increased our understanding
Hypothesis-free
“Common disease, common variant”
See if disease is statistically associated with Single Nucleotide Polymorphisms (SNPs)
Requires data from lots of people.
What is a SNP
Change in nucleotide which is common within the population > 1%
What does a high score on the Manhattan plot show
Significant SNP that is linked with disease.
What does GWAS in diabetes show
90 loci associated with increased risk
Observed effect size is small
TCF7L2 has the largest effect size, odds ratio of 1.4
Collectively all SNPs account for 6% of type 2 diabetes risk observed
Most loci affect beta cell function not insulin resistance
What is the importance of GWAS in type 2 diabetes
It shows that the environment plays a greater role than genetics in the development of the disease.
What are copy number variants
Copy Number Variants (CNVs)
deletions, duplications, insertions present in the genome
range from a few bp to >1Mb
Can increase risk of polygenic disease
Which is more likely to have a sever effect rare of more common alleles
Rare alleles.
Describe the role of HNF-1 alpha mutations in type 1 diabetes
Hepatic nuclear factor 1 α
Transcription factor normally stimulating insulin production
Accounts for most cases in the UK
In absence, insulin production reduced, but only manifests in adulthood when beta- cell function starts to naturally decline
History of HNF-1 alphas
Usually best-managed with sulphonylureas
Often stop insulin in patients who have been incorrectly diagnosed as T1DM
At risk of future microvascular and macrovascular complications
May eventually end up requiring insulin therapy
These people have no problem with insulin resistance.
Characteristics of HNF-1 alpha deficiency
Uncommon 2-4% of all diabetes
May lead to treatment changes
Improve over all control
Genetic test - £400
Strategies to identify potential cases from type 2 diabetes and type 1 diabetes
Clinical features
Biomarkers
No ATP production, hence k+ channels cannot open, no insulin secretion. Sulphonylureas open K+ channels independent of ATP.
Sensitivity (hypoglycaemia) to low-dose sulphonylureas
Young age at onset
Generational family history
Non-insulin requiring
Atypical for type 1 or type 2
Why is making a genetic diagnosis important
Make genetic diagnosis
Understand pathophysiology
Predict clinical features
Monitor response to treatments
What is the role of glucokinase in MODY 2
Enzyme converting glucose to glucose-6-phosphate
Beta-cell glucose sensing
Mutations result in a higher set-point at which insulin secretion is triggered
Often misdiagnosed as T2DM, IFG or GDM
