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Pharmacogenomic implications
of risk SNPs in type 2 diabetes mellitus

Dr Muhammad Huzaimi Haron
Trainee Lecturer in Pharm...
Outline
Introduction
T2DM revisit
What are SNPs?

Individual SNPs conferring T2DM risk
SNPs and Pharmacogenomics
What lies...
Introduction
Genetic component to diabetes
High concordance rate between monozygotic twins
Different prevalence between po...
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)
N...
Worrying signs in NHMS III
High prevalence of undiagnosed DM in younger age
group (18 – 30 years old)
Increasing prevalenc...
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
alter...
How SNPs confer risk?
Variations in how body handles glucose
Absorption
Rate of emptying of stomach
Distribution
Action of...
SNPs conferring risk to T2DM
Year

Gene

Description

Peroxisome proliferator-activated receptor
gamma
Potassium inwardly-...
TCF7L2 and T2DM
Protein: transcription factor 7-like-2
Gene on long arm of chromosome 10
Nuclear
Wnt pathway
Controls expr...
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...
Impact on T2DM risk
Icelandic carriers of SNPs at increased risk of T2DM
(Grant et al, 2006)

Dose-dependent
Heterozygous ...
Impact on T2DM risk
Malaysian population
No large scale data
Known data collected from UMMC 2009-2010 from
Malay, Chinese ...
Type 2 DM Risk Analysis
TCF7L2
SNP

Subject

rs7903146
rs12255372
rs11196205
rs4506565
rs7901695

Minor allele
frequency

...
Type 2 DM Risk Analysis
TCF7L2
SNP

Subject

Genotype frequency (%)

OR [95% CI]*

WT

Ht

Mt

WT vs HZ genotype

Diabetic...
Summary from Malaysian data
1. TCF7L2 SNPs increase the risk of T2DM in a
Malaysian population
2. The minor allele frequen...
Other SNPs
KCNJ11
Codes for component of ATP-sensitive K+ channels on
beta-cells (Kir6.2 subunit)
Mutations caused monogen...
Other SNPs
KCNQ1
Encodes for a voltage-gated K+ channels
needed for repolarisation phase of cardiac
action potential
This ...
Other SNPs
PPAR 2
Codes for nuclear receptor
Involved in lipid and glucose
homeostasis, differentiation of lipocytes, FA s...
Pharmacogenomics
Different DNA sequence, different response!
Drug-metabolizing enzymes
Cytochrome-p450 family, eg CYP2C9 a...
TCF7L2 SNPs and Sulfonylurea
GoDARTs study (Pearson et al, 2007)
900 patients on a sulfonylurea
Treatment failure: HbA1c >...
Genotypic comparison of
HbA1c levels (Metformin+Sulfonylurea, n=113)

HbA1c (%)

*
10
9
8
7
6
5
4
3
2
1
0

*

*

**

*

WT...
Genotypic Comparisons of
Achievement of HbA1c target
Metformin + Sulfonylurea (n=29/113)
WT

HZ

Mt

P-value

rs7903146
rs...
KCNJ11 SNPs and Sulfonylurea
Sesti et al, 2006
525 patients treated with sulfonylurea, either alone or
combination with me...
KCNJ11 SNP and Repaglinide
He et al, 2008
100 newly diagnosed Chinese patients, treated with
repaglinide over 24 weeks
SNP...
PPAR 2 SNP and
Kang et al (2005)
Improved response to rosiglitazone in heterozygous
SNP carriers
Greater drops in FPG and ...
The future
is still uncertain
Identification of risk SNPs
Need cohort studies, long term follow-up
Involvement of epigenet...
Take home message
Importance of genetic factors/variations in conferring
risk to T2DM is evident
Response to antidiabetic ...
THANK YOU
for your kind attention
Back
Incretins and GSIS
Glu
Glu

Glu

GSIS and Incretins:
An Overview

Small intestine

Pancreatic
β-cells

• GSIS: glucose sti...
Back
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Pharmacogenomics implication of risk SNPs in diabetes

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How risk SNPs affect response to regular antidiabetic drugs

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Pharmacogenomics implication of risk SNPs in diabetes

  1. 1. Pharmacogenomic implications of risk SNPs in type 2 diabetes mellitus Dr Muhammad Huzaimi Haron Trainee Lecturer in Pharmacology Pharmacology CME 28 March 2011
  2. 2. Outline Introduction T2DM revisit What are SNPs? Individual SNPs conferring T2DM risk SNPs and Pharmacogenomics What lies ahead Take home message
  3. 3. 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?
  4. 4. Revisit: T2DM pathogenesis
  5. 5. Revisit: T2DM pathogenesis Incretins K+ channel Incretins
  6. 6. T2DM: Global Epidemic! 120 100 Prevalence (millions) 80 60 40 20 0 2000 WHO Regions
  7. 7. T2DM: Global Epidemic! 120 100 Prevalence (millions) 80 60 40 20 0 WHO Regions 2000 2030
  8. 8. 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%)
  9. 9. 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?
  10. 10. Single Nucleotide Polymorphism A T C G G T C A C T T G C G A A A T
  11. 11. 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
  12. 12. 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
  13. 13. 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
  14. 14. 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)
  15. 15. TCF7L2 SNPs Multiple SNPs in multiple population rs7903146 rs12255372 rs4506565 rs11196205 rs7901695 rs290487 Intronic
  16. 16. 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)
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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?
  22. 22. 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)
  23. 23. 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)
  24. 24. 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
  25. 25. 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?
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. PPAR 2 SNP and Kang et al (2005) Improved response to rosiglitazone in heterozygous SNP carriers Greater drops in FPG and HbA1c
  32. 32. 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?
  33. 33. 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…
  34. 34. THANK YOU for your kind attention
  35. 35. Back
  36. 36. 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
  37. 37. Back

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