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How risk SNPs affect response to regular antidiabetic drugs
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Pharmacogenomic implications
of risk SNPs in type 2 diabetes mellitus
Dr Muhammad Huzaimi HaronTrainee Lecturer in Pharmacology
Pharmacology CME 28 March 2011
Introduction
T2DM revisit
What are SNPs?
Individual SNPs conferring T2DM risk
SNPs and Pharmacogenomics
What lies ahead
Take home message
Outline
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?
Introduction
Revisit: T2DM pathogenesis
T2DM
Hyper-glycaemi
a
Insulin sensitivit
y
Beta-cell dysfuncti
on
Revisit: T2DM pathogenesis
T2DM
Hyper-glycaemi
a
Insulin sensitivit
y
Beta-cell dysfuncti
on
Incretins
K+ channel
Incretins
T2DM: Global Epidemic!
Afric
an
East
Med
iterran
ean
Amer
icas
Euro
pean
Sout
h Ea
st A
sia
Wes
tern
Pac
ific
0
20000000
40000000
60000000
80000000
100000000
120000000
2000
WHO Regions
Pre
vale
nce (
million
s)
T2DM: Global Epidemic!
Afric
an
East
Med
iterran
ean
Amer
icas
Euro
pean
Sout
h Ea
st A
sia
Wes
tern
Pac
ific
0
20000000
40000000
60000000
80000000
100000000
120000000
20002030WHO Regions
Pre
vale
nce (
million
s)
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%)
T2DM: Back home…
High prevalence of undiagnosed DM in younger age group (18 – 30 years old)
Increasing prevalence despite:1. Health awareness campaigns2. Increasing education and information levels
Worrying signs in NHMS III
Need for a better screening program?
Single Nucleotide Polymorphism
A C G T C T G A
AAT
TCC
G G
T
A
DNA seq change
Coding region
mRNA seq change
Intronic
mRNA processing
altered
Exonic
AA seq change
Changes in protein
Non-coding region
mRNA transcription
alteration
Implication of SNPs
Variations in how body handles glucose
AbsorptionRate of emptying of stomach
DistributionAction of insulinMetabolism
Alteration in metabolic pathwaysDisposition
Excretion of excess
How SNPs confer risk?
Year Gene Description SNPChro-
mosome
Major / minor allele
Phenotype
Beta cell
function
Insulin action
2000 PPARGPeroxisome proliferator-activated receptor gamma
rs13081389 3 A/G Reduce
d
2003 KCNJ11Potassium inwardly-rectifying channel, subfamily J, member 11
rs5215 11 C/TReduce
d
2006 TCF7L2 Transcription factor 7-like 2 rs7903146 10 C/TReduce
d
2007 CDKAL1CDK5 regulatory subunit associated protein1-like 1
rs10440833 6 A/TReduce
d
2007HHEX/IDE
Haematopoietically expressed homeobox / insulin-degrading enzyme
rs5015480 10 C/TReduce
d
2007 SLC30A8Solute carrier family 30 (zinc transporter), member 8
rs3802177 8 C/TReduce
d
2007CDKN2A/B
Cyclin-dependent kinase inhibitor 2A/B rs10965250 9 A/GReduce
d
2007 IGF2BP2Insulin-like growth factor 2 mRNA binding protein 2
rs1470579 3 A/CReduce
d
2007 FTO Fat mass and obesity associated rs11642841 16 A/C Reduce
d
2008 KCNQ1Potassium voltage-gated channel, KQT-like subfamily, member 1
rs231362, rs163184
11A/C, G/T
Reduced
SNPs conferring risk to 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 and T2DM
Multiple SNPs in multiple population rs7903146 rs12255372 rs4506565 rs11196205 rs7901695 rs290487
Intronic
TCF7L2 SNPs
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)
TCF7L2 SNPs and T2DM
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
Impact on T2DM risk
Type 2 DM Risk AnalysisTCF7L2SNP
Subject Minor allele frequency
p-value OR [95% CI] *of wildtype vs mutant allele
rs7903146 DiabeticNon-diabetic
0.160.10
0.0061 1.73 [1.17-2.58]
rs12255372 DiabeticNon-diabetic
0.130.06
0.0010 2.14[1.35-3.40]
rs11196205 DiabeticNon-diabetic
0.810.88
0.0047 0.61[0.43-0.86]
rs4506565 DiabeticNon-diabetic
0.160.08
0.0013 2.11[1.33-3.36]
rs7901695 DiabeticNon-diabetic
0.850.92
0.0025 0.49[0.31-0.79]
* Statistical test used: chi-square test
Type 2 DM Risk AnalysisTCF7L2
SNPSubject Genotype frequency (%) OR [95% CI]*
WT vs HZ genotypeWT Ht Mt
rs7903146 DiabeticNon-diabetic
7283
2515
32 1.66
[1.13-2.44]rs12255372 Diabetic
Non-diabetic7790
208
32 2.37
[1.43-3.93]rs11196205 Diabetic
Non-diabetic74
2417
6979
0.95[0.80-1.12]
rs4506565 DiabeticNon-diabetic
7386
2311
43 2.16
[1.31-3.56]rs7901695 Diabetic
Non-diabetic43
2311
7386
1.06[0.84-1.34]
* Statistical test used: chi-square test
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?
Summary from Malaysian data
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
PPAR2 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
Other SNPs
Pharmacogenomics
Different DNA sequence, different response! Drug-metabolizing enzymes
Cytochrome-p450 family, eg CYP2C9 and sulfonylureas
Statement 1:
SNPs conferring risk affect glucose handlingStatement 2:
Glucose handling modified by drugs
Can risk SNPs alter drug response?
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
TCF7L2 SNPs and Sulfonylurea
rs7903146 rs12255372 rs11196205 rs4506565 rs79016950123456789
10
WTHZMt
TCF7L2 SNPs
HbA
1c (%
)
*
* *** *
* P<0.05, ** P<0.01
Genotypic comparison of HbA1c levels (Metformin+Sulfonylurea, n=113)
Genotypic Comparisons of Achievement of HbA1c target
Metformin + Sulfonylurea (n=29/113)
WT HZ Mt P-value(2)
rs7903146 83 10 7<0.001rs12255372 86 14 0
rs4506565 86 7 7rs7901695 7 7 86
<0.001rs11196205 10 4 86
WT: Wildtype, HZ: Heterozygous, Mt: Mutant
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 SNPs and Sulfonylurea
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
KCNJ11 SNP and Repaglinide
Kang et al (2005) Improved response to rosiglitazone in
heterozygous SNP carriers Greater drops in FPG and HbA1c
PPAR2 SNP and
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?
The future
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…
Take home message
THANK YOUfor your kind attention
Back
Incretins and GSISGlu
Pancreatic β-cells
GLP-1
GIP
GluGlu
Glu
Ins
Small intestine
lumen
Glu
Vasculature
Cell
Done
GSIS and Incretins: An Overview
• GSIS: glucose stimulated insulin secretion• Accounts for majority of postprandial insulin release• Earliest defect leading up to T2DM
• Incretins• Intestinal peptide hormones• Released upon detection of glucose in GIT• Glucagon-like peptide-1 (GLP-1)• Glucose-dependent insulinotropic polypeptide (GIP)
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