Transcript Genetics of Diabetes - University of Pittsburgh

Genetics of Diabetes
Jan Dorman, PhD
University of Pittsburgh
School of Nursing
[email protected]
Type 1 Diabetes (T1D)
Type 1 Diabetes

Caused by the destruction of the
pancreatic beta cells
– Insulin is no longer produced
– Leads to hyperglycemia, ketoacidosis and
potentially death if not treated with insulin

Treatment goals for T1D
– Maintaining near normal levels of blood glucose
– Avoidance of long-term complications
Type 1 Diabetes

2nd most common chronic childhood disease

Peak age at onset is around puberty
– But T1D can occur at any age

Incidence is increasing worldwide by ~3%
per year
– Related to increase in T2D?
T1D Incidence Worldwide
Importance of Environmental
Risk Factors in T1D

Seasonality at diagnosis

Migrants assume risk of host country

Risk factors from case-control studies
–
–
–
–
–
–
Infant/childhood diet
Viruses – exposures as early as in utero
Hormones
Stress
Improved hygiene
Vitamin D
Importance of Genetic Risk
Factors in T1D

Concordance in identical twins greater in
MZ versus DZ twins

15-fold increased risk for 1st degree
relatives
– Risk is ~6% through age 30 years
– Risk increases in presence of susceptibility
genes
MHC Region – Chromosome 6p21
Predisposition to T1D is Better
Determined by Haplotypes

DRB1-DQB1 haplotypes more accurately
determine T1D risk

Testing for both genes is more expensive
– Most screening is based only on DQA1-DQB1

High risk T1D haplotypes
– DQA1*0501-DQB1*0201
– DQA1*0301-DQB1*0302
Relative Increase in T1D Risk by
Number of High Risk Haplotypes
Ethnicity
Number of High Risk
DQA1-DQB1 haplotypes
Two
One
Caucasians
African Americans
16
45
4
7
Asians
11
4
Absolute T1D Risk (to age 30) by
Number of High Risk Haplotypes
Ethnicity
Number of High Risk
DQA1-DQB1 Haplotypes
Two
One
Zero
Caucasians
African Americans
2.6%
3.1%
0.7%
0.5%
0.2%
0.1%
Asians
0.2%
0.1%
0.02%
Absolute T1D Risk for Siblings
of Affected Individuals
Number of High Risk
DQA1-DQB1 Haplotypes
Risk of
developing T1D
Two
One
Zero
25%
8.3%
1%
Genome Screens for T1D
IDDM1
IDDM2
6p21
11p15
IDDM13
IDDM15
2q34-q35
6q21
IDDM3
IDDM4
IDDM5
15q26
11q13
6q25-q27
IDDM17
IDDM18
PTPN22
10q25
5q31-q33
1p13
IDDM6
IDDM7
IDDM8
IDDM9
18q21
2q31
6q27-qter
3q21-q25
IDDM10
IDDM11
IDDM12
10p11-q11
14q24-q31
2q33
VDR, INFγ
TGFβ1
8q24
12q12-qter
16p11-p13
16q22-q24
17q24-qter
19p13-q13
Xp11
IDDM2

Insulin (INS) gene

Chromosome 11p15, OMIM: 176730

Variable number of tandem repeats (VNTR)

–
–
–
–
Class I: 26-63 repeats
Class II: ~80 repeats
Class III: 141-209 repeats
Relative increase in risk ~2-fold with two class I
alleles (compared to 0 class I alleles)
Class I is associated with lower mRNA in the
thymus – may reduce tolerance to insulin and
its precursors
IDDM12

Cytotoxic T Lymphocyte Associated-4 (CTLA-4)

Chromosome 2q33, OMIM: 123890
– ICOS and CD28 flank

Encodes a T cell receptor that plays are role in T
cell apoptosis
– A49G polymorphism (Thr17Ala)
– Relative increase in risk ~ 1.2

Dysfunction of CTLA-4 is consistent with
development of T1D
PTPN22

Lymphoid specific tyrosine phosphatase (LYP)

Chromosome 1p13, OMIM: 600716

Encodes a LPY that is important in negative T-cell
activation and development
– C858T polymorphism (Arg620Trp)
– Relative increase in risk ~ 1.8

May alter binding of LYP to cytoplasmic tyrosine
kinase, which regulates the T-cell receptor
signaling kinases
Intervention Trials for T1D
Study
TRIGR
DIPP
TrialNet
Intervention
Avoid CM
Insulin (N)
Immunosuppressive
agents
Target /Screen
FDR / genetic
GP / genetic
FDR / antibodies
and genetic
CM = cows milk, N = nasal,
FDR = first degree relatives, GP = general population
Natural History Studies for T1D

Conducted in the general population
– DAISY - Colorado
– PANDA - Florida
– TEDDY – US and Europe

Based on newborn genetic screening
– Concerns about proper informed consent
– Parents are notified of the results by mail
– General population at ‘high’ risk (5-8%) recruited for
follow-up
>50% of children who will develop T1D not eligible
Genetics and Prevention of T1D

Type 1 diabetes cannot be prevented

Ethical concerns regarding genetic testing for
T1D, especially in children

Education programs are need for parents who
consent to have their children involved in such
studies because risk estimation is
– Dependent on genes/autoantibodies used for assessment
– Is not sensitive or specific
Type 2 Diabetes (T2D)
Type 2 Diabetes

Is group of genetically heterogeneous metabolic
disorders that cause glucose intolerance
– Involves impaired insulin secretion and insulin action

~90% of individuals with diabetes have T2D

Considerations

Polygenic and multifactorial
– May be treated with diet / oral medications / physical
activity
– T2D individuals may be asymptomatic for many years
– Associated with long-term complications
– Caused by multiple genes that may interact
– Caused by genetic and environmental risk factors
Blood glucose
levels
Genetic effects
Insulin secretion
and
Insulin resistance
Environmental
effects
From McIntyre and Walker, 2002
Fatty acid
levels
Thrifty Genotype

Had a selective advantage

In primitive times, individuals who were
‘metabolically thrifty’ were
– Able to store a high proportion of energy as fat when
food was plentiful
– More likely to survive times of famine

In recent years, most populations have
– A continuous supply of calorie-dense processed foods
– Reduced physical activity

These changes likely explain the rise in T2D
worldwide
Revised Classification Criteria
for T2D

Fasting plasma glucose
– > 7.0 mmol/L
– > 126 mg/dl

Random blood glucose
– > 11.1 mmol/L
– > 200 mg/dl
T2D Prevalence Worldwide
Estimated Number of Adults with
Diabetes – Developing Countries
www.who.int/diabetes/actionnow/en/diabprev.pdf
Estimated Number of Adults with
Diabetes – Developed Countries
www.who.int/diabetes/actionnow/en/diabprev.pdf
Increase in T2D in Children

Most T2D children
were females from
minority populations

Mean age at onset
was around puberty

Many had a family
history of T2D
Environmental Risk Factors in T2D

Obesity
– Increases risk of developing T2D
– Defined as:
• > 120% of ideal body weight
• Body mass index (BMI) > 30 k / m2
– Likely related to the increase in T2D
• ~80% newly diagnosed cases due to obesity
– Higher association with abdominal or central
obesity
• Assessed by measuring the waist-to- hip ratio
Environmental Risk Factors in T2D

Physical Activity
– Increases risk of developing T2D
– Exercise
• Controls weight
• Improves glucose and lipid metabolism
• Is inversely related to body mass index
– Lifestyle interventions decreased risk of
progression of impaired glucose tolerance to
T2D by ~60%
Genetics and T2D

Individuals with a positive family history are about
2-6 times more likely to develop T2D than those
with a negative family history
– Risk ~40% if T2D parent; ~80% if 2 T2D parents

Higher concordance for MZ versus DZ twins

Has been difficult to find genes for T2D
– Late age at onset
– Polygenic inheritance
– Multifactorial inheritance
Finding Genes for T2D

Candidates selected because they are involved in
–
–
–
–

Pancreatic beta cell function
Insulin action / glucose metabolism
Energy intake / expenditure
Lipid metabolism
Genome wide screens
– Nothing is assumed about disease etiology

Genome wide association studies
– Current approach based on thousands of cases and
controls
Challenges in Finding Genes

Inadequate sample sizes
– Multiplex families
– Cases and controls
Difficult to define the phenotype
 Reduced penetrance

– Influence of environmental factors
– Gene-gene interactions
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

Variable age at onset
Failure to replicate findings
Genes identified have small effects
CAPN10 – NIDDM1

Chromosome 2q37.3 (OMIM 601283)
– Encodes an intracellular calcium-dependent
cytoplasmic protease that is ubiquitously
expressed
• May modulate activity of enzymes and/or apoptosis
– Likely involves insulin secretion and resistance
– Stronger influence in Mexican Americans than
other ethnic groups
• Responsible for ~40% if familial clustering
– Genetic variant: A43G, Thr50Ala, Phe200Thr
– Estimated relative risk: ~2
PPARγ

Peroxisome proliferator-activated
receptor-γ (chromosome 3p25, OMIM:
601487)
– Transcription factors that play an important
role in adipocyte differentiation and function
– Is associated with decreased insulin sensitivity
– Target for hypoglycemic drugs thiazolidinediones
– Genetic variant: Pro12Ala, Pro is risk allele
(common)
– Estimated relative risk = 1 - 3
– Variant is common
– May be responsible for ~25% of T2D cases
ABCC8 and KCNJ11

ATP-binding cassette, subfamily C member 8
(chromosome 11p15.1, OMIM 600509)

Potassium channel, inwardly rectifying, subfamily
J, member 11 (chromosome 11p15.1, OMIM
600937)
– ABCC8 encodes the sulfonylurea receptor (drug target )
– Is coupled to the Kir6.2 subunit (encoded by KCNJ11 –
4.5 kb apart & near INS )
– Part of the ATP-sensitive potassium channel
• Involved in regulating insulin and glucagon
• Mutations affect channel’s activity and insulin secretion
– Site of action of sulfonylureal drugs
– Genetic variants: Ser1369Ala & Glu23Lys, respectively
– Estimated relative risk = 2 – 4
TCF7L2

Transcription factor 7-like 2 (chromosome 10q25,
OMIM 602228)
– Related to impaired insulin release of glucagon-like
peptide-1 (islet secretagogue), reduced β-cell mass
or β-cell dysfunction
• Stronger among lean versus obese T2D
– 10% of individuals are homozygous have 2-fold
increase in risk relative to those with no copy of the
variant
– Responsive to sulfunynlureals not metformin
– Genetic variant: re7901695 and others in LD
– Estimated relative risk ~ 1.4
GWAS New Loci Identified

FTO – chr 16q12
– Fat mass and obesity associated gene
– Governs energy balance; gene expression is regulated by
feeding and fasting
– Estimated relative risk ~ 1.23

HHEX/IDE – chr 10q23-24; near TCF7L2
– HHEX - Haematopoietically expressed homeobox
• Transcription factor in liver cells
– IDE - Insulin degrading enzyme
• Has affinity for insulin; inhibits IDE-mediated degradation
of other substances
– Estimated relative risk ~ 1.14
GWAS New Loci Identified

CDKAL1 – chr 6p22
– Cyclin-dependent kinase regulatory subunit associated
protein 1-like 1
– Likely plays role in CDK5 inhibition and decreased insulin
secretion
– Estimated relative risk ~ 1.12

SLC30A8 – chr 8q24
– Solute carrier family 30 zinc transporter
– May be major autoantigen for T1D
– Estimated relative risk ~ 1.12
GWAS New Loci Identified

IGF2BP2 – chr 3q28
– Insulin-like growth factor 2 mRNA binding protein 2
– Regulates IGF2 translation; stimulates insulin action
– Estimated relative risk ~ 1.17

CDKN2A/B – chr 9p21
– Clycin dependent kinase inhibitor 2A
– Plays role in pancreatic development and islet
proliferation
– Estimated relative risk ~ 1.2
T2D Genes are Drug Targets

PPARγ, ABCC8 and KCNJ11 are the targets of
drugs used routinely in the treatment of T2D
– Pharmacogenetic implications
– Response to oral agents may be related to one’s
genotype
– Genetic testing may
• Identify individuals at high risk for T2D
• Guide treatment regimens for T2D
– Individualize therapy
Genetics and Prevention of T2D

T2D is preventable
– Maintaining age-appropriate body weight
– Physical activity

New genes will provide insight to etiology

Public health messages may have a greater
influence on genetically susceptible

Will genetic testing prevent T2D?
– Unclear whether knowledge of one’s genetic risk will lead
to behavior modifications
Genetics and Prevention of T2D

Challenges include:
– Predictive values of most test is low
– How to communicate risk information?
– Health care professionals may not be able to
interpret genetic tests
– Genetic testing may lead to distress, etc.
– Insurance and employment discrimination
– Confidentiality and stigmatization
– Direct to consumer marketing for genetic testing
Maturity Onset Diabetes
of the Young (MODY)
MODY

Account for ~ 5% of type 2 diabetes

Single gene defects
– Autosomal dominant inheritance
– Multiple generations affected

Early age at onset (< age 25 years)

Characterized by the absence of obesity, no
ketosis and no evidence of beta cell autoimmunity

Hyperglycemia often corrected by diet
MODY Genes
Type
Gene
Locus
Protein
#
Mutations
%
MODY
12
~5%
MODY1
HNF4A
20q12-q13.1
Hepatocyte nuclear
factor 4-alpha
MODY2
GCK
7p15-p13
Glucokinase
~200
~15%
MODY3
HNF1A
12q24.2
Hepatocyte nuclear
factor 1-alpha
>100
~65%
MODY4
IPF1
13q12.1
Insulin promotor
factor-1
Few
MODY5
HNF1B
17cen-q21.3
Hepatocyte nuclear
factor 1-beta
Few
MODY6
NEUROD1
2q32
Neurogenic
differentiation factor
1
Few
<3%
MODY1 is HNF4A (hepatocyte nuclear
factor 4-alpha) on 20q12-q13.1

Transcription factor
– Expressed in the liver, kidney, intestine and pancreatic
islet cells
– Has been associated with T2D

Controls genes involved in glucose, cholesterol and
fatty acid metabolism

Controls transcription of HNF1A (MODY3)

Several mutations/splicing defects identified
– Account for ~5% of all MODY cases
MODY2 is GCK (glucokinase) on
7p15-p13

Only MODY gene that is not a transcription factor

Required for glucose metabolism and insulin
secretion; acts as a glucose ‘sensor’

MODY2 is generally a mild form of diabetes

~ 200 mutations have been identified
– VNTR, nonsense and missense mutations
– Account for ~15% of all MODY cases
MODY3 is HNF1A (hepatocyte
nuclear factor 1-alpha) on 12q24.2

Regulates expression of insulin and other genes
involved in glucose transport / metabolism
– Influences expression of HNF4A (MODY1)

Results in a severe insulin secretory defect
– May contribute to abnormal islet cell development

More than 100 genetic variants have been
identified

Mutations in MODY3 are the most common cause
of MODY
– Account for ~65% of all MODY cases
– Sensitive to sulphonylureas
MODY4 is IPF1 (insulin promoter
factor-1) on 13q12.1

Transcription factor that regulates expression of
insulin, somatostatin and other genes
– Involved in the development of the pancreas
– In adults, expressed only in pancreatic cells

Mutations lead to decreased binding activity to
the insulin promoter
– Reduced activation of insulin gene in response to glucose

Genetic variants include frameshift, insertions and
missense mutations
– Accounts for a very small proportion of MODY cases
MODY5 is HNF1B (hepatocyte
nuclear factor 1-beta) on 17cen-q21.3

Transcription factor required for liver-specific
expression of a variety of genes

Is highly homologous to HNF1A (MODY3)
– Recognizes same binding site as HNF1A

HNF1A and HNF1B likely interact to regulate gene
expression

Individuals have lower renal threshold to glucose

Is a rare cause of MODY
MODY6 is NEUROD1 (neurogenic
differentiation factor 1) on 2q32

Is a transcription factor involved in the
differentiation of neurons

Regulates insulin gene expression by binding to a
critical motif on the insulin promoter

Few genetic variants identified
– Missense and nonsense mutations
– Account for ~1% of all MODY cases
Summary of MODY Genetics

All MODY genes are expressed in the pancreas,
and play a role in:
– The metabolism of glucose
– The regulation of insulin or other genes involved in
glucose transport
– The development of the fetal pancreas

MODY phenotype depends on the MODY genotype
(on next slide)

Knowing the genotype is important to determine
treatment
MODY Phenotpes
Type
Onset
Complications
Treatment
MODY1
Severe
Frequent
D, O, I
MODY2
Mild
Rare
D
MODY3
Severe
Frequent
D, O, I
MODY4
Moderate
Little data
O, I
MODY5
Severe
Renal disease
O, I
MODY6
Severe
Little Data
D, O, O
D = Diet, O = Oral agents, I = Insulin