1. Genetics of diabetes Linkages
Vertical Genetics Module (22 April, 27 April, 6 May (Obesity))
T1D patient presentation and Diabetes Overview (29 April); Hauora Maori, Diabetes Impact (16 May); T2D patient presentation (20 May); glucose metabolism lectures
Lecture plan
Monogenic type 2 diabetes (slide 3)
Polygenic basis of common diabetes (slides 4-9)
Polygenic basis of type 1 diabetes (slides 10-16)
Precision medicine in type 2 diabetes (slides 17-22)

2. Type 2 diabetes: pathogenesis
Risk factors
Genetics
Insulin levels increase in the blood
Cells become resistant to insulin
Blood glucose and insulin levels are high
Pancreas decreases insulin production
Blood glucose levels remain high
Type 2 diabetes

3. Common variants of rare monogenic diabetes genes in T2D
KCJN11, potassium channel, regulates insulin secretion. Activating mutations cause a severe form of neonatal diabetes
WFS1, involved in insulin secretion. Mutations cause Wolfram syndrome (diabetes insipidus, juvenile diabetes)
HNF1A and HNF1B, pancreatic transcription factors. Mutations cause maturity onset diabetes of the young

4. Meta-analysis allows combination of studies to increase power eg NPT1 locus
(power = chance of detecting true positive association, at defined level of significance, >80% is optimal, power is greater for variants of stronger effect)

5. Meta-analysis of T2D GWAS ‘Impute’ 2
Meta-analysis of T2D GWAS ‘Impute’ 2.2M SNPs from genotyped SNPs Combine each of the 2.2M SNPs 8,130 cases and 38,987 controls; 8 separate GWASs

6. Few insulin-resistance genes
rs Intronic KCNQ Voltage-gated potassium channel, C x 10-40
Florez J Clin Endo Metab 93:

7. Type 2 diabetes genes highlight -cell dysfunction, less in insulin resistance
Florez
KCNQ1
CDC123
NOTCH2

8. Obesity genes and T2D risk Overweight is causal
Ahlqvist et al Clin Chem 2011

9. Where have genome-wide association studies got us ?
Not useful for risk prediction (refer obesity genetics lecture)
However they identify drug targets – modest genetic effect sizes but therapeutic modulation more dramatic
Glitazones (PPARG) improve insulin sensitivity
Sulphoylureas (KCNJ11) improve insulin release
GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve insulin release (less chance of hypoglycemia)

10. Genetics of type 1 diabetes Polychronakos and Li, Nat Rev Genet,12:781 2011
The strongest genetic effects have come from candidate gene studies
HLA-DRB1 (OR ~3)
PTPN22 (OR>1.5)
INS (OR =1.4)

11. Genome-wide association studies further emphasize that the central cause of T1D is immune system dysregulation

12. CTLA-4 Cytotoxic lymphocyte antigen-4 Ueda Nature 2003

13. The associated variants are in the 3’ UTR Do they influence isoforms?

14. Abatacept (CTLA4Ig) Co-stimulation of CTLA4 required for activation of auto-reactive T-cells

15. Patients newly diagnosed with type 1 diabetes given 27 infusions over 24 months

16. Beta-cell function decline delayed

17. Personalized medicine
The current genetic knowledge from GWAS not useful for risk prediction
However, possible in principle. E.g. high-dose sulphonylureas for KCJN11 activating mutations (cause closure of channels) in neonatal diabetes
Key is finding rarer variants of greater penetrance important for a small number of individuals

18. Maniolo et al Nature 2009

19. HNF1α (MODY3) Sulphonylureas instead of metformin
Mexican-American specific
0.2% general population; OR=5

20. Protein truncating TBC1D4 mutation in Greenland 3
Protein truncating TBC1D4 mutation in Greenland 3.8% of population; OR=10 Mediates insulin-stimulated GLUT4 glucose uptake Insulin = first-line treatment
Also known as AS160 it is a mediator of insulin-stimulated Akt-induced GLUT4 glucose uptake
Moltke et al Nature 2014

21. SLC30A8 Re-sequencing of GWAS locus Drugs to replicate reduced activity ? Flannick et al Nat Genet 2014
Inactivating protein-truncating mutations in SLC30A8 protect from diabetes. Encodes an islet zinc transporter (ZnT8) – so genetics demonstrate that reducing activity is a validated drug target in diabetes.
66% decreased risk (OR=0.34)

22. Carving up the diabetes pie