diabetes t2 y gestacional (2)

7/27/2019 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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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


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


3/13

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)


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


9/13

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


10/13

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


11/13

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


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


12/13

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)


13/13

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

diabetes t2 y gestacional (2)

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