Pharmacogenomics implication of risk SNPs in diabetes
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Pharmacogenomics implication of risk SNPs in diabetes

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How risk SNPs affect response to regular antidiabetic drugs

How risk SNPs affect response to regular antidiabetic drugs

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  • Re-analyse – examine those achive hba1c target only
  • Entrance of oral glucose stimulates production of GLP-1 and GIP.These in turn will stimulate the release of insulin from the betacells – which accounts for 70% of insulin released during hyperglycemic spikes post-meals.Insulin in turn stimulates glucose uptake by cells

Pharmacogenomics implication of risk SNPs in diabetes Pharmacogenomics implication of risk SNPs in diabetes Presentation Transcript

  • Pharmacogenomic implications of risk SNPs in type 2 diabetes mellitus Dr Muhammad Huzaimi Haron Trainee Lecturer in Pharmacology Pharmacology CME 28 March 2011
  • Outline Introduction T2DM revisit What are SNPs? Individual SNPs conferring T2DM risk SNPs and Pharmacogenomics What lies ahead Take home message
  • Introduction Genetic component to diabetes High concordance rate between monozygotic twins Different prevalence between populations Different effect of traditional risk factors Single nucleotide polymorphisms (SNPs) Common Functional Heritable?
  • Revisit: T2DM pathogenesis
  • Revisit: T2DM pathogenesis Incretins K+ channel Incretins
  • T2DM: Global Epidemic! 120 100 Prevalence (millions) 80 60 40 20 0 2000 WHO Regions
  • T2DM: Global Epidemic! 120 100 Prevalence (millions) 80 60 40 20 0 WHO Regions 2000 2030
  • T2DM: Back home… Increasing prevalence 6.3% in 1986 (NHMS I) 11.0% in 2006 (MyNCDS-1) NHMS II (1996): 8.3% (>30 yrs old) NHMS III (2008): 11.6% (>18) 14.9% (>30) 39% did not know they were diabetic! 83% of 18-30yr old diabetic newly diagnosed! Ethnic discrepancy (NHMS III) Indian highest (19.9%) Malay (11.9%) and Chinese (11.4%)
  • Worrying signs in NHMS III High prevalence of undiagnosed DM in younger age group (18 – 30 years old) Increasing prevalence despite: 1. Health awareness campaigns 2. Increasing education and information levels Need for a better screening program?
  • Single Nucleotide Polymorphism A T C G G T C A C T T G C G A A A T
  • Implication of SNPs DNA seq change Coding region Non-coding region mRNA mRNA seq change Intronic transcription alteration Exonic mRNA processing altered AA seq change Changes in protein
  • How SNPs confer risk? Variations in how body handles glucose Absorption Rate of emptying of stomach Distribution Action of insulin Metabolism Alteration in metabolic pathways Disposition Excretion of excess
  • SNPs conferring risk to T2DM Year Gene Description Peroxisome proliferator-activated receptor gamma Potassium inwardly-rectifying channel, subfamily J, member 11 Phenotype Chromosome Major / minor allele rs13081389 3 A/G rs5215 11 C/T Reduced SNP Beta cell function 2000 PPARG 2003 KCNJ11 2006 TCF7L2 Transcription factor 7-like 2 rs7903146 10 C/T Reduced 2007 CDKAL1 CDK5 regulatory subunit associated protein1-like 1 rs10440833 6 A/T Reduced 2007 HHEX/IDE Haematopoietically expressed homeobox / insulin-degrading enzyme rs5015480 10 C/T Reduced 2007 SLC30A8 Solute carrier family 30 (zinc transporter), member 8 rs3802177 8 C/T Reduced 2007 CDKN2A/B Cyclin-dependent kinase inhibitor 2A/B rs10965250 9 A/G Reduced 2007 IGF2BP2 Insulin-like growth factor 2 mRNA binding protein 2 rs1470579 3 A/C Reduced 2007 FTO Fat mass and obesity associated rs11642841 16 A/C 2008 KCNQ1 Potassium voltage-gated channel, KQT-like subfamily, member 1 rs231362, rs163184 11 A/C, G/T Insulin action Reduced Reduced Reduced
  • TCF7L2 and T2DM Protein: transcription factor 7-like-2 Gene on long arm of chromosome 10 Nuclear Wnt pathway Controls expression of downstream genes Proglucagon (Ni et al, 2003) – promote expression in intestinal L-cells mRNA silencing of TCF7L2: apoptosis of beta-cells (Shu et al, 2008) proliferation, GSIS Reduced levels lead to defective insulin granule exocytosis (da Silva Xavier et al, 2009)
  • TCF7L2 SNPs Multiple SNPs in multiple population rs7903146 rs12255372 rs4506565 rs11196205 rs7901695 rs290487 Intronic
  • TCF7L2 SNPs and T2DM Effect of SNPs on: Expression of TCF7L2 gene Increased in pancreatic beta-cells (Lyssenko et al, 2007) Expression of other genes Proglucagon – reduced in pancreatic L-cells (Yi et al, 2008) Impaired GLP-1 synthesis Its protein levels: unknown Glucose handling Blunting of incretin effect (Lyssenko et al, 2007; Schafer et al, 2007) Reduction in pro-insulin conversion (Stancakova et al, 2009) Increased hepatic gluconeogenesis (Pilgaard, 2009)
  • Impact on T2DM risk Icelandic carriers of SNPs at increased risk of T2DM (Grant et al, 2006) Dose-dependent Heterozygous carrier of T allele of rs7903146: OR 1.5 Homozygous carrier: OR 2.1 Replicated in various Caucasian and Asian populations However with differing impact due to different allele frequencies
  • Impact on T2DM risk Malaysian population No large scale data Known data collected from UMMC 2009-2010 from Malay, Chinese and Indian patients and non-diabetic volunteers Case-control study of 800 people
  • Type 2 DM Risk Analysis TCF7L2 SNP Subject rs7903146 rs12255372 rs11196205 rs4506565 rs7901695 Minor allele frequency p-value Diabetic Non-diabetic 0.16 0.10 0.0061 Diabetic Non-diabetic 0.13 0.06 0.0010 Diabetic Non-diabetic 0.81 0.88 0.0047 Diabetic Non-diabetic 0.16 0.08 0.0013 Diabetic Non-diabetic 0.85 0.92 0.0025 OR [95% CI] * of wildtype vs mutant allele 1.73 [1.17-2.58] 2.14 [1.35-3.40] 0.61 [0.43-0.86] 2.11 [1.33-3.36] 0.49 [0.31-0.79] * Statistical test used: chi-square test
  • Type 2 DM Risk Analysis TCF7L2 SNP Subject Genotype frequency (%) OR [95% CI]* WT Ht Mt WT vs HZ genotype Diabetic Non-diabetic 72 83 25 15 3 2 1.66 rs12255372 Diabetic Non-diabetic 77 90 20 8 3 2 rs11196205 Diabetic Non-diabetic 7 4 24 17 69 79 0.95 [0.80-1.12] rs4506565 Diabetic Non-diabetic 73 86 23 11 4 3 2.16 Diabetic Non-diabetic 4 3 23 11 73 86 rs7903146 rs7901695 [1.13-2.44] 2.37 [1.43-3.93] [1.31-3.56] 1.06 [0.84-1.34] * Statistical test used: chi-square test
  • Summary from Malaysian data 1. TCF7L2 SNPs increase the risk of T2DM in a Malaysian population 2. The minor allele frequencies observed are: much lower than in Caucasian and Indian population (Grant et al, 2006; Chandak et al, 2007) higher than in Japanese population (Miyake et al, 2008) Impact?
  • Other SNPs KCNJ11 Codes for component of ATP-sensitive K+ channels on beta-cells (Kir6.2 subunit) Mutations caused monogenic forms of DM SNP (rs5215) cause defect to subunit K+ channels fail to open in response to rising ATP:ADP ratio Failed exocytosis of insulin granules (reviewed by Florez, 2008)
  • Other SNPs KCNQ1 Encodes for a voltage-gated K+ channels needed for repolarisation phase of cardiac action potential This channel also found on intestinal L-cells SNPs (rs231362, rs163184) cause impaired incretin effect Reduction in GLP-1 secretion by L-cells (Tan et al, 2009)
  • Other SNPs PPAR 2 Codes for nuclear receptor Involved in lipid and glucose homeostasis, differentiation of lipocytes, FA storage SNP confers protection against T2DM Increased insulin sensitivity Lower BMI Higher HDL Lower BP Reduced MI risk
  • Pharmacogenomics Different DNA sequence, different response! Drug-metabolizing enzymes Cytochrome-p450 family, eg CYP2C9 and sulfonylureas Statement 1: SNPs conferring risk affect glucose handling Statement 2: Glucose handling modified by drugs Can risk SNPs alter drug response?
  • TCF7L2 SNPs and Sulfonylurea GoDARTs study (Pearson et al, 2007) 900 patients on a sulfonylurea Treatment failure: HbA1c >7% after 3 – 12 months of initiation Adequate control of confounder SNP carrier 2 times more likely to encounter treatment failure – even after adjusting for baseline HbA1c
  • Genotypic comparison of HbA1c levels (Metformin+Sulfonylurea, n=113) HbA1c (%) * 10 9 8 7 6 5 4 3 2 1 0 * * ** * WT HZ Mt rs7903146 rs12255372 rs11196205 TCF7L2 SNPs * P<0.05, ** P<0.01 rs4506565 rs7901695
  • Genotypic Comparisons of Achievement of HbA1c target Metformin + Sulfonylurea (n=29/113) WT HZ Mt P-value rs7903146 rs12255372 83 86 10 14 7 0 <0.001 rs4506565 rs7901695 rs11196205 86 7 10 7 7 4 7 86 86 WT: Wildtype, HZ: Heterozygous, Mt: Mutant ( 2) <0.001
  • KCNJ11 SNPs and Sulfonylurea Sesti et al, 2006 525 patients treated with sulfonylurea, either alone or combination with metformin Secondary failure: those requiring insulin therapy despite combination therapy Adequate control of confounders SNP carrier more likely to get secondary failure with sulfonylurea therapy Sulfonylurea-stimulated insulin secretion lower in pancreatic islets carrying the SNP
  • KCNJ11 SNP and Repaglinide He et al, 2008 100 newly diagnosed Chinese patients, treated with repaglinide over 24 weeks SNP carriers had greater reduction in FPG and HbA1c levels SNP carriers had better improvements of HOMA-B
  • PPAR 2 SNP and Kang et al (2005) Improved response to rosiglitazone in heterozygous SNP carriers Greater drops in FPG and HbA1c
  • The future is still uncertain Identification of risk SNPs Need cohort studies, long term follow-up Involvement of epigenetics, CNVs Pharmacogenomics Better-designed clinical trials, controlling for confounder Promise of personalised medicine in DM?
  • Take home message Importance of genetic factors/variations in conferring risk to T2DM is evident Response to antidiabetic medications is heavily influenced by genetic variations as well! However, the specifics are still missing/unclear – lots of “research holes” yet to be filled…
  • THANK YOU for your kind attention
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  • Incretins and GSIS Glu Glu Glu GSIS and Incretins: An Overview Small intestine Pancreatic β-cells • GSIS: glucose stimulated insulin secretion lumen • Accounts for majority of postprandial insulin release GLP • Earliest defect leading up to T2DM -1 Ins • Incretins • Intestinal peptide hormones • Released upon detection of glucose in GIT GIP • Glucagon-like peptide-1 (GLP-1) • Glucose-dependent insulinotropic polypeptide (GIP) Cell Glu Glu Vasculature Done
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