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The Genetics of Type 2
Diabetes
Learning the Right Lessons
NCHPEG
12th Annual Meeting
Jim Evans MD, Ph.D
University of NC at Chapel Hill
The Promise of Genetic Medicine
“But remember throughout that no external cause is
efficient without a predisposition of the body itself.
Otherwise, external causes which affect one would
affect all…”
We now have the ability to analyze the individual’s
genome deeply and define medically important variation
Diabetes is an Environmental
Disorder
Worldwide Prevalence of Diabetes for 2000 and 2010
Zimmet et al. Nature 414:782.2001
Environmental Causation of
Diabetes
Obesity = BMI > 30
Mokdad et al., 2001, JAMA, 286: 1195-1200
Diabetes is an Evolutionary Disease
• Neel’s “Thrifty Gene Hypothesis”
– Certain human alleles were selected for which maximize
metabolic efficiency & food searching behavior
• In times of abundance these alleles predispose
their carriers to diseases caused by excess
nutritional intake, such as obesity & DM
• Populations with a history of food scarcity harbor
more such thrifty alleles than other populations
– Accounting for the more rapid rise in T2DM incidence in
societies undergoing “Westernization”
Calories are Dangerously Cheap
– The average citizen of NC earns
$30,553/yr
– The price of a Hardee’s Monster
Thickburger© is $5.59
– It takes 21 minutes to earn one
1417 calories
• It supplies almost a day’s worth of calories
• Never in the history of our species have
calories been so cheap
• It is engineered to appeal to our evolutionarily
derived compulsion to seek concentrated fat,
salt, carbohydrates and protein
• And we don’t even have to leave our car to
get it
T2DM results from rapid environmental changes superimposed upon an underlying
evolutionarily sculpted genome
Diabetes is a Genetic Disorder
• A number of single-gene mutations have been shown to
cause T2DM
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Insulin receptor gene
PPAR, HNFs and other transcription factors
Mutant insulin
Mitochondrial mutations in a tRNA gene
Mutations in glucokinase
– While of interest, these forms of diabetes are rare and relatively
unimportant from a public health standpoint
• Twin studies have highlighted the large genetic component
in T2DM
– MZ concordance for T2DM approaches 100% in some studies
– Concordance has increased as mean weight and inactivity have
increased
Estimates of Heritability From Twin Studies
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•
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•
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Obesity
Type 2 Diabetes
Schizophrenia
Hypertension
Alcholism
Cirrhosis
Atherosclerosis
Breast Cancer
Type 1 Diabetes
0.80
0.75
0.65
0.55
0.55
0.50
0.40
0.35
0.25
We now have the ability to analyze the genome and define individual
variation
Robust Genomic Analysis
• At the heart of the concept of
“personalized medicine”
• Massively parallel genotyping now is
widely available
– Delineation of the individual’s genome at ~1
million sites
– for << $500
• Affordable* complete sequencing of all
3 billion bases of the individual’s
genome will likely be a reality within the
next 1-3 years
– For ~$1,000
What Can We Do With Such Information?
• An avalanche of
Genome Wide
Association
Studies (GWAS)
in common
diseases
• Shedding light on
the genetic
underpinnings of
every disease
imaginable
GWAS-Implicated T2DM Loci
McCarthy et al. Current Diabetes Reports 2009, 9:164–171
There is Great Potential in Harnessing
Genomic Information
• Delineation of novel
genes and
pathways in the
genesis of disease
– Allowing
identification of
genes without
underlying
biochemical/physiol
ogical knowledge
– Identification of
novel drug targets
The Promise of Individualized Medicine
Screening & Treatment
• The current status of screening in
medicine
– Relatively little benefit
– Actual harm to some
– Tremendous waste of resources
• Current drug therapy in medicine
– Efficacy varies widely
– Adverse effects are common and
unpredictable
– Wasted resources and time
• Can we directly apply genetic
advances in diabetes to care of the
individual?
Clinical Medicine is Messy
The application of good ideas to the care of the individual
is difficult and fraught with hazard
How might we apply new genetic
knowledge directly to T2DM patients?
• Pharmacogenomic applications
– PGx is often touted as the “low hanging fruit”
of the genetics revolution
– Predicated upon the idea that knowledge of
one’s genome will be a useful tool to guide
drug therapy
• Assessment of individual risk
– To enable prevention
Genotype & Sulfonylurea Response
• Genotype at
TCF7L2 may be
associated with
response to
sulfonylurea
agents
• Carriers of the risk
allele (TT) were
less likely to
respond to
sulfonylureas
– As assessed by
reaching target
A1C <7% after
initiation
• Odds ratio for
failure = 1.95
Pearson et al. 2007, Diabetes;56:2178
OCT1 & Metformin
• The organic cation
transporter 1
(OCT1) is involved
in controlling
intracellular
metformin
concentration
• Could
polymorphisms in
OCT1 influence
metformin
efficacy?
OCT1 & Metformin
• In one small study
of 20 healthy
volunteers given a
glucose challenge
following metformin
dosing, genotype at
OCT1 influenced
metformin response
PGx and T2DM
Not Ready for Prime Time
• Such results are evident at an
aggregate level, not the
individual level
• The discriminatory capabilities
of genotype to assess
response are very weak
– 35% of the sulfonylurea “nonresponder” genotype never-theless respond to the agent
– There is dramatic overlap in
metformin glucose concentrations
between the two genotype
groups
• A lack of clinical outcome data
Applying Genomic Information to the Individual
The Problem of Relative Risk
• Numerous risk alleles for
T2DM have been identified
– The vast majority of RR
defined by GWAS are between
1-2
• What do I do with such
information?
– From a clinical standpoint the
information is so lacking in
robustness that it is of
questionable utility
Frayling T; Nature Reviews 8:657.2007
Applying Genetic Risk Information
to the Individual
• Most genotyping may soon be performed
outside of the traditional medical setting
• Numerous companies are now offering
“boutique” genotyping
– Most include estimates of T2DM risk
• Heavily covered by the media
• Is such information useful towards the
goal of improving health?
• “Buying is more American than thinking”
Aggregate Risk Scores
• One purveyor of such testing (deCODE Genetics; $370)
offers a T2DM risk score using one’s genotype at 4 loci
– ~40% of population have increased relative risk (RR >1)
– 8% have RR 1.5-2.2
– ~3% have RR 1.8-2.2
• Calculation of aggregate risks assumes no interactions
• But the real problem is how little useful clinical information
is provided
Multiple Genetic Variants
How Much Added Value?
Shifting Knowledge
• We are rapidly discovering more genes that
influence the risk of T2DM
• We have yet to define the majority of T2DM’s the
genetic component
• Thus future discoveries, like the discovery of
modifiers and novel loci may dramatically shift
risk assessments
– It may eventually make genetic prediction more
robust
– Today’s “low risk” genotype may well be tomorrow’s
“high risk” genotype, and vice versa
• Proceed cautiously in the midst of a data
avalanche
Good Ideas That Weren’t
• Hormone Replacement Therapy
• Sleeping Babies & prevention of
SIDS
• Anti-arrhythmics for PVCs
• PSAs may cause more harm than
help
• Good ideas are not enough to
guide medical care
– We have the power to harm
– Even through “non-invasive” testing
• Such information has the potential to put
our patients on a trajectory that leads to
dangerous and harmful interventions
We must demand outcome data before embracing
good ideas
The Paradox of Risk Information
• “Knowledge is Power”…or is it?
• It is often maintained that knowledge of one’s
genetic risk will benefit patients
• Does knowledge of increased risk of obesity,
diabetes, CVD lead to improved lifestyle?
– We’re all at “increased risk” for these maladies
– We already strongly recommend healthy lifestyles
• Little evidence that genetic information per se
is more effective than other types of
information in getting people to change their
long-term behavior
• And for everyone I find who is at increased
risk, I’ll find those at decreased risk
– Will such information give such individuals license to
not pursue healthy lifestyles?
The Coming Deluge
• The $1,000 genome is coming
• We will be awash with new highly complex
genetic information
• It will often be touted as ready to revolutionize
healthcare
• It does hold great promise
– Especially for drug development and laying bare the
molecular foundation of disease
• But the rules of medicine haven't changed
– There’s nothing magical about genetic information
– Take a good family history!
– Insist on actual outcome data before embracing
attractive ideas
You Know You’re a Genetics Nerd When…
Google News Alert for: genetics
From: Google Alerts [mailto:[email protected]]
Sent: Thursday, September 10, 2009 6:29 AM
To: Evans, Jim
Subject: Google Alert - genetics
Toward Personalized Diabetes Treatment
Pharmaceutical Technology Magazine
These are the types of breakthroughs the industry has been waiting
for; the links between genetics, biology, and medicine are solidifying.
...
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• How might we apply new genetic knowledge
directly to T2DM patients?
• Pharmacogenomic applications
• Estimate Disease Predisposition
The Need for Clinical Outcome Data
• The history of medicine is riddled with the corpses of
good ideas that didn’t pan out
– EC/IC bypass to prevent stroke
– HRT to prevent every possible bad outcome of female aging
– PSA?
• Good ideas are not enough to guide medical care
– We have the power to harm
– Even through “non-invasive” testing
• Such information has the potential to put our patients on a trajectory
that leads to dangerous and harmful interventions
• We need to insist on data to prove that our good ideas
actually result in improved outcomes
• We have to be leery of shortcuts and attractive theories
Genotype Adds Little to
Conventional Risk
Estimation
C Statistic
Model
Parameters
No
Genotype
With
Genotype
P Value
Sex & FHx
0.595
0.615
0.11
Age, Sex, FHx,
BMI, FBS, BP,
HDL, TG
0.900
0.901
0.49
Meigs; N Engl J Med 2008;359:2208-19
What Else Can We Do With Such
Information?
• Make money!!!
– After all, this is the
USA
• Several companies
are now offering
“boutique”
genotyping
• Their success
threatens to prove
Andy Warhol’s
adage that “buying
is more American
than thinking”
Worldwide Prevalence of Diabetes
for 2000 and 2010: An Epidemic
ZIMMET P, ALBERTI KGMM & SHAW J. Nature 414, 782 - 787 (2001)
Published Genome-Wide Associations through 3/2009,
398 published GWA at p < 5 x 10-8
NHGRI GWA Catalog
www.genome.gov/GWAStudies
Controlling the Genetic Genie
•
Genetic Discrimination
– There is no federal legislative protection…yet
•
Gene Patenting
– Most of our genes have patent claims on them
– BRCA1/2 are under restrictive patents
•
Privacy Issues
– “Privacy is dead. Get over it.”
– What happens when 23andMe is subpoenaed?
– Problems compounded by the acceleration of
Information Technology and the World Wide Web
– Corporate, government and public genetic databases
are being formed all over the world
•
Who will control this information?
– Do you want to know ?
– Do you want others to know?
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Your insurance / managed care plan
Your employer
Your family
Dick Cheney
Your neighbor who surfs the web