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)

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

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

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)

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

Few insulin-resistance genes rs2237892 11 Intronic KCNQ1 Voltage-gated potassium channel, C 1.40 2.5 x 10-40 Florez J Clin Endo Metab 93:4633 2008

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

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

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)

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)

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

CTLA-4 Cytotoxic lymphocyte antigen-4 Ueda Nature 2003

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

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

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

Beta-cell function decline delayed

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

Maniolo et al Nature 2009

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

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

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)

Carving up the diabetes pie