Diabetes T2 y Gestacional (2)
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Transcript of Diabetes T2 y Gestacional (2)
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The Genetic Interface Between Gestational
Diabetes and Type 2 Diabetes
Alan R. Shuldiner, M.D.
John Whitehurst Professor of Medicine and Physiology
Ass oci ate Dean and Direc tor , Prog ram i n Pers onal ized Medi cine
Head, Division of Endocrinology, Diabetes and Nutrition
University of Maryland School of Medicine
Telephone: 410-706-1623
Email: [email protected]
Lecture Outline
Genetics 101
Diabetes genetics
Monogenic diabetes
Type 2 di abetes (T2D)
Gestational diabetes
Type 1 di abetes (T1D)
Genetics/Genomics 101
DNA (Genes)
mRNA
Protein
Organ
function
Integrative
Physiology
(Disease)
Cell
function
Metabolic
Products
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Genetics/Genomics 101
DNA (Genes)
mRNA
Protein
3 billion chemical building blocks(base pairs)
25,000 genes
Any two humans are
99% identical genetically
Variations in 1 out of
every 1,000 base pairs
determines
Genetics/Genomics 101
Whether you are at increased risk for cancer,
diabetes, CVD, metabolic syndrome, etc.
Whether you are more likely to respond to a given medicine or
have a life-threatening adverse reaction
Whether you or more likely to have greater health benefits from an
Atk ins diet vers us an Or nish diet
Whether you will be born with a disease caused by a defect in a single
gene, e.g., cystic fibrosis or sickle cell anemia
How likely you are to live to 100
Disease With Genetic Component
Identify Gene
Diagnostics/Newborn screening
Early Prevention
rx
Pharmacogenomics
Gene Therapy
Understand Basic
Biological Defect
New Interventions for
prevention and
treatment
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T2D
T 1D
Mendelian forms of diabetes
Syndromes with diabetesOther
Genetics of Diabetes - 1990
Features of Monogenic Diabetes
Syndromes
Predictable mode of inheritance
Rare (
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Maturi ty Onset Diabetes of the
Young (MODY)
Old definition(1975, Tattersall and Fajans)
Non-insulin dependent
Autosomal dominant transmission
Onset < 25 years
Fajanset al, NEJM 2001
MODY 1,3-6
MODY 2
MODY Genes and the Beta Cell
HNF-4-alpha
HNF-1-beta
HNF-1-alpha IPF-1
Pancreatic Differentiation and
Insulin Gene Transcription
Transcript ion Factor MODY
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Transcription factor
mutationsGlucokinase
mutations
Glucokinase and Transcription Factor DiabetesRather than MODY
MODY
Onset at birth
Stable hyperglycemia
Diet treatmentComplications rare
~50% of Mutation carriers
have GDM
Ado lesc ence/youn g adul t ons et
Progressive hyperglycemia
1/3 diet, 1/3 OHA, 1/3 InsulinComplications frequent
HNF1 renal cys ts , other GU
(HNF-1HNF-1HNF-4
Adapted f rom di abetesgenes .org
Prevalence ofGCK Pathogenic Mutations in GDM
0% (0/141) GCK141 Czech women with GDMLuksovet al (2008)
2% (1/66) GCK
3% (2/66) other MODY genes
66 Swedish women with GDM and Fhxdiabetes
Wenget al (2002)
12% (2/17)17 multiethnic and with specific criteriaKoustaet al (2001)
80% (12/15)15 UK Caucasians with GDM and specificcriteria
Ellardet al (2000)
0% (0/50)50 American women with GDMAllan et al (1997)
0% (0/45)45 African American women with GDM onlyChiu et al (1994)
6% (3/50)50 Oxford, UK women with GDM andpersistent hyperglycemia (>100 mg/dl)
Sakeret al (1996)
6% (1/17)17 French women with GDM and FhxT2DM
Zoualiet al (1993)
5% (2/40)
1/18 Hispanic women
1/9 Caucasian women
40 American women with GDM + 1 st
degree relative with DMStoffelet al (1993)
PrevalenceSampleAuthors
Glucokinase DM
and Birthweight (n = 58 pairs)
3957
3378
3321
2889
2500
3000
3500
4000
Birthweight
(grams)
Infant - Infant +
Mother -
Mother +
Adapted fr om Hatters ley et al (1998): Nature Genetics 19:209-210
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Question:
Is there a place for screening for
mutations in GCK / other genes in the
OB clinic?
T2DT 1D
MODY 1 (HNF4A)
MIDD (Mitochondrial DNA)
Neonatal diabetes
(KCNJ11, ABCC8, GCK, ZAC/HYMAI)
Syndromes of
extreme insulin (INSR)
resistance
Other
MODY 2 (GCK)
MODY 3 (TCF1)
MODY 4 (IPF1)
MODY 5 (TCF2)
FPLD (LMNA, AKT2,
ZMPSTE24)CGL (BSCL, AGPAT2,PPARG, CAV1)
MODY 6 (NeuroD1)
MODY 7 (KLF11)
MODY 8 (CEL)
Genetics of Diabetes - 2006
Agi ng
Genetics of Type 2 Diabetes:
A co mpl ex in teracti on betw een geneti c su scepti bil ity,
the environment, and time
Polygenic (several genes)
The effect of any single gene
variant is modest
Genetic heterogeneity
Different or overlapping sets of
genes in different
families/populations
Environment
Genetic Susceptibilit y
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Finding Genes for Complex DiseasesCandidate Genes for Diabesity
Insulin
Act ionTypical
T2DM
(Diabesity)
Phenotype Genotype
-Cell
Obesity
CNS/Behavioral
-Ala12 is common in many populations
- Functionally has decreased activity
- A la12 - increased insulin sensitivity
- protection from diabetes
- obesity/weight gain
The PPAR Gene (Chr 3p25)
A nuclear r eceptor t hat p lays a p ivo tal r ole i n insul in s ign aling and
adipogenesis.
Sequence analysis: C to G single nucleotide polymorphism (SNP)
in 2 exon:Pro12Ala PPAR 2 [Yen, et al. (1997) BBRC]
Pro12Ala
- Pro12 is a risk allele for T2D
Meta-analysis
of Pro12Ala
PPAR2 andT2DM
[Altshuler et al.
(2000) Nat Genet]
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Molecular Basis o f Type 2 Diabetes:Candidate Gene App roach
Insulin
Act ionTypical
Type 2 DM
Phenotype Genotype
-Cell
Obesity
CNS/Behavioral
Pro12Ala PPARG
WFS1
HNF4A
E23K KCNJ11
Others ?
GenomeGenome--wide Linkagewide Linkage
Analysis/Posi tional CloningAnalysis/Posi tional Cloning
Grant et al, Nature Genet 2006
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WNT Signaling
and Pancreatic
Development(from Murtaugh,
Organogenesis, 2008)
Those with TCF7L2 variant are at increased risk of
developing diabetes.
But are super-responders to lifestyle interventions
TCF7L2 and Maternal Glucose Levels i n Pregnancy:
The HAPO Study
FreathyRM, et al Diabetes 2010
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FreathyRM, et al Diabetes 2010
TCF7L2 and Bir th Weight: The HAPI Study
Genome-wide SNP Chips
T2D GWAS
French (Sladek 2006)
Brittish (WTCCC)(Zeggini 2007)
Scandanavian (Steinthorsdottir 2007;
Scott 2007; Saxena 2007)
Japanese (Unoki 2008; Yasuda 2008) Smaller low-density GWAS
Framingham (Florez 2007) Mexican Americans (Hayes 2007)
Pima Indians (Hanson 2007) Amish (Rampersaud 2007)
Meta analysis Consortia (Zeggini 2008) DIAGRAM (Zeggini 2009) Others coming soon
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Meta GWAS of T2D: 38 Loci
Genetic Loci Associated with T ype 2 Diabetes
PROX1
ADCY5
DGKB/TMEM195
GCK
GCKR
IRS1
MTNR1B
KCNQ1
ADAMTS9
THADA
TSPAN8-LGR5
CDC123-CAMK1D
JAZF1
WFS1
TCF2
FTO
IGF2BP2
CDKN2A/B
CDKAL1
HHEX-IDE
SLC30A8
TCF7L2
KCNJ11
PPARG
NOTCH2
1 1.1 1.2 1.3 1.4 1.5
P RO X 1
ADCY5
DG K B / T M E M 195
GCK
G CK R
IRS 1
M T NR1B
K CNQ 1
NO T CH2
ADAMT S9
T HA DA
T S P A N8- LG R5
CDC123- CA M K 1D
J A Z F 1
WFS1
T CF 2
FTO
IG F 2B P 2
CDK N2A / B
CDK A L1
HHE X - IDE
S LC30A 8
T CF 7L2
K CNJ 11
P P A RG
Yearofconfirmation
Appr ox imate effec t si ze
20002001200220032004200520062007
2008
2009
2009EASD:38loci
10%ofgeneticsusceptibility
T2DT 1D
MODY 1 (HNF4A)
MIDD (Mitochondrial DNA)
Neonatal diabetes
(KCNJ11, ABCC8, GCK, ZAC/HYMAI)
Syndromes of
extreme insulin (INSR)
resistance
Other
MODY 2 (GCK)
MODY 3 (TCF1)
MODY 4 (IPF1)
MODY 5 (TCF2)
FPLD (LMNA, AKT2,ZMPSTE24)
CGL (BSCL, AGPAT2,PPARG, CAV1)
MODY 6 (NeuroD1)
MODY 7 (KLF11)
MODY 8 (CEL)
PPARG KCNJ11WFS1 CAPN10
TCF7L2 SLC30A8FTO KCNQ1
GCKR TCF2IGF2BP2 Locu s MTNR1BCDKAL1 Locus IRS1CDKN2A/2B LocusHHEX/KIF11/IDE GCK
NOTCH2 Locu s DGKB/TMEM195THADA Locu s ADCY5ADAMTS9 Locus PROX1
JAZF1 LocusCDC123/CAMK1D Locus
TSPAN-LGR5 Locus
Genetics of Diabetes - 2010
HLAINS
others Lesson 5:
People with this allele may beable to ameliorate their risk withlifestyle modifications; they may
be less responsive to
sulfonyureas
Lesson 4:This allele increases T2D riskthrough obesity. Its effect can
be attenuated by increasedphysical activity
Lesson 6:
This is a zinc transporter
expressed specifically in isletsthat may alter insulin
processing, packaging, andsecretion.
Lesson 3:
All T2D genes/loci identified todate seem to affect beta cell
function except PPARG. Whereare all the insulin resistance
genes?
Lesson 2:
This allele is much more
common in Asian populations(ethnicity-specific differences in
genetic susceptibility genes)
Lesson 1:
Risk alleles are common in thepopulation and provide only
modest increase in T2D risk(OR 1.1-1.4)
POORLY PREDICTIVE
EXPLAIN
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Association of a Common T2D Risk Variant in GCK
with GDM: The HAPO Study
Chol et al. Diabetologia, 2009
Association of T2D
Risk Alleles with
GDM in a Korean
Population
Lauenborg, J. et al. , J Clin Endocrinol Metab, 2009
Distribution of Risk Alleles of 11 T2D Risk Variants in Women withPrevious GDM (n = 244) and Glucose-Tolerant Control Women (n = 1883)
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Genetics of T1D
Concannon et al (2009), NEJM 360 (16)
HLA-DR3/4 PLUS:
Summary and Conclusions
Genetics of GDM IS the Genetics of
Diabetes
Glucokinase mutations (MODY2)
50% of carriers have GDM
May account for 5% of GDM in Caucasians
T2D Susceptibility alleles
Many genes with common variants, each with
modest effect on risk
Poorly predictive
Beginning to inform biology
Same alleles increase risk for GDM