The Genetic Interface Between Gestational Diabetes and Type 2 Diabetes

Alan R. Shuldiner, M.D.

John Whitehurst Professor of Medicine and Physiology Associate Dean and Director, Program in Personalized Medicine Head, Division of Endocrinology, Diabetes and Nutrition University of Maryland School of Medicine Telephone: 410-706-1623 Email: ashuldin@medicine.umaryland.edu

Lecture Outline
Genetics 101 Diabetes genetics
Monogenic diabetes Type 2 diabetes (T2D) Gestational diabetes Type 1 diabetes (T1D)

Genetics/Genomics 101
DNA (Genes)

mRNA Cell function Protein Metabolic Products Organ function Integrative Physiology (Disease)

Genetics/Genomics 101
DNA (Genes)
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

mRNA

Protein

Genetics/Genomics 101
Whether you will be born with a disease caused by a defect in a single gene, e.g., cystic fibrosis or sickle cell anemia 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 Atkins diet versus an Ornish diet How likely you are to live to 100

Disease With Genetic Component

Identify Gene Diagnostics/Newborn screening Understand Basic Biological Defect

Early rx

Prevention Pharmacogenomics Gene Therapy New Interventions for prevention and treatment

Genetics of Diabetes - 1990

T 1D

T2D
Other

Mendelian forms of diabetes

Syndromes with diabetes

Features of Monogenic Diabetes Syndromes

Predictable mode of inheritance Rare (<5% of all diabetes cases) Diabetes may be the predominant feature or part of a syndrome Gene defects influence diverse cellular functions all leading to a common outcome: hyperglycemia Chronic complications occur as a result of hyperglycemia regardless of the primary (genetic) defect

Case
An 24 year old nonobese asymptomatic white female with a history of gestational diabetes comes for a routine check-up. Her fasting blood sugar was found to be 150 mg/dl. On follow-up, a 2 hour post-prandial blood glucose was 220 mg/dl. Patient notes that his father and a paternal aunt and uncle were diagnosed with diabetes in their late 20s and early 30s.

Maturity Onset Diabetes of the Young (MODY) Old definition

(1975, Tattersall and Fajans)

Non-insulin dependent Autosomal dominant transmission Onset < 25 years

MODY Genes and the Beta Cell

MODY 2

MODY 1,3-6

Fajans et al, NEJM 2001

Transcription Factor MODY

HNF-1-beta HNF-4-alpha HNF-1-alpha IPF-1

Pancreatic Differentiation and Insulin Gene Transcription

Glucokinase and Transcription Factor Diabetes Rather than MODY

MODY
Glucokinase mutations
Onset at birth Stable hyperglycemia Diet treatment Complications rare ~50% of Mutation carriers have GDM
Adapted from diabetesgenes.org

Transcription factor mutations (HNF-1HNF-1HNF-4

Adolescence/young adult onset Progressive hyperglycemia 1/3 diet, 1/3 OHA, 1/3 Insulin Complications frequent HNF1 renal cysts, other GU

Prevalence of GCK Pathogenic Mutations in GDM

Authors Stoffel et al (1993) Sample 40 American women with GDM + 1st degree relative with DM Prevalence 5% (2/40) 1/18 Hispanic women 1/9 Caucasian women 6% (1/17) 6% (3/50)

Zouali et al (1993) Saker et al (1996)

17 French women with GDM and Fhx T2DM 50 Oxford, UK women with GDM and persistent hyperglycemia (>100 mg/dl)

Chiu et al (1994) Allan et al (1997)

45 African American women with GDM only 50 American women with GDM

0% (0/45) 0% (0/50)

Ellard et al (2000) Kousta et al (2001) Weng et al (2002)

15 UK Caucasians with GDM and specific criteria 17 multiethnic and with specific criteria 66 Swedish women with GDM and Fhx diabetes 141 Czech women with GDM

80% (12/15) 12% (2/17) 2% (1/66) GCK 3% (2/66) other MODY genes 0% (0/141) GCK

Luksov et al (2008)

Glucokinase DM and Birthweight (n = 58 pairs)

3957 4000 3378 Birthweight (grams) 3500 3321 3000 2500 Infant Infant + Mother + 2889 Mother -

Adapted from Hattersley et al (1998): Nature Genetics 19:209-210

Question: Is there a place for screening for mutations in GCK / other genes in the OB clinic?

Genetics of Diabetes - 2006

Neonatal diabetes
(KCNJ11, ABCC8, GCK, ZAC/HYMAI) MIDD (Mitochondrial DNA)

T2D
T 1D

Other

MODY 1 (HNF4A) MODY 2 (GCK) MODY 3 (TCF1) MODY 4 (IPF1) MODY 5 (TCF2) MODY 6 (NeuroD1) MODY 7 (KLF11) MODY 8 (CEL) Syndromes of extreme insulin (INSR) resistance FPLD (LMNA, AKT2,
ZMPSTE24)

CGL (BSCL, AGPAT2,

PPARG, CAV1)

Genetics of Type 2 Diabetes:

A complex interaction between genetic susceptibility, the environment, and time
Aging

Environment Genetic Susceptibility Polygenic (several genes)

The effect of any single gene variant is modest

Genetic heterogeneity
Different or overlapping sets of genes in different families/populations

Finding Genes for Complex Diseases

Candidate Genes for Diabesity

Phenotype Typical T2DM (Diabesity)

Genotype
Obesity Insulin Action

CNS/ Behavioral

-Cell

The PPAR Gene (Chr 3p25)

Pro12Ala A nuclear receptor that plays a pivotal role in insulin signaling and adipogenesis. Sequence analysis: C to G single nucleotide polymorphism (SNP) in 2 exon:

Pro12Ala PPAR 2 [Yen, et al. (1997) BBRC]

- Ala12 is common in many populations - Functionally has decreased activity - Ala12 - increased insulin sensitivity - protection from diabetes - obesity/weight gain - Pro12 is a risk allele for T2D

Meta-analysis of Pro12Ala PPAR2 and T2DM

[Altshuler et al. (2000) Nat Genet]

Molecular Basis of Type 2 Diabetes:

Candidate Gene Approach

Phenotype
Pro12Ala PPARG

Genotype
Obesity Insulin Action

Typical Type 2 DM

E23K KCNJ11 HNF4A WFS1 Others ?

CNS/ Behavioral

-Cell

GenomeGenome-wide Linkage Analysis/Positional Cloning

Grant et al, Nature Genet 2006

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 in Pregnancy: The HAPO Study

Freathy RM, et al Diabetes 2010

TCF7L2 and Birth Weight: The HAPI Study

Freathy RM, et al Diabetes 2010

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 Type 2 Diabetes

2000 2001 2002 2003 2004 2005 2006 2007
P P A RG

PPARG KCNJ11 TCF7L2 SLC30A8 HHEX-IDE CDKAL1 CDKN2A/B IGF2BP2 FTO TCF2 WFS1 JAZF1 CDC123-CAMK1D TSPAN8-LGR5 THADA ADAMTS9 NOTCH2 KCNQ1 MTNR1B IRS1 GCKR GCK DGKB/TMEM195 ADCY5 PROX1

K CNJ 11

T CF7L2

SLC30A 8

Year of confirmation

HHE X -I DE CDK A L1 CDK N2A / B I GF2B P 2 FT O T CF2 WFS1

2008

JA ZF1

CDC123-CA M K 1D T SP A N8-LGR5 T HA DA A DA M T S9 NOT CH2 K CNQ1

2009EASD: 38loci 10%ofgenetic susceptibility

2009

M T NR1B I RS1 GCK R GCK

DGK B / T M E M 195 A DCY 5 P ROX 1

1.1

1.2

1.3

1.4

1.5

Approximate effect size

Genetics of Diabetes - 2010

Neonatal diabetes
(KCNJ11, ABCC8, GCK, ZAC/HYMAI) Lesson 1: Lesson 2: MIDD (Mitochondrial DNA) This allele is much more Risk alleles are common in the common in Asian population and provide only populations MODY 1 (HNF4A ) (ethnicity-specific differences in modest increase in T2D risk genetic susceptibility genes) MODY 2 ( GCK) (OR 1.1-1.4) Lesson 7: POORLY PREDICTIVE MODY 3 (TCF1) This gene is involved in EXPLAIN <10% of GENETIC

T2D
T 1D

PPARG KCNJ11 WFS1 CAPN10 HLA TCF7L2 SLC30A8 INS MODY 4 (IPF1) circadian a pathway RISK rhythm, FTO KCNQ1 others Lesson 5: previously implicated in T2D GCKR TCF2 MODY (TCF2) People with and this metabolism allele may5 be IGF2BP2 Locus MTNR1B able to ameliorate their risk with CDKAL1 Locus IRS1 MODY 6 (NeuroD1) lifestyle modifications; they may CDKN2A/2B Locus MODY HHEX/KIF11/IDE GCK be less responsive to 7 (KLF11) Lesson 6: NOTCH2 Locus DGKB/TMEM195 sulfonyureas This is a zinc transporter MODY 8 (CEL) THADA Locus ADCY5 Other expressed specifically in islets ADAMTS9 Locus PROX1 Syndromes of that may alter insulin JAZF1 Locus Lesson 8: extreme insulin (INSR) CDC123/CAMK1D Locus packaging, and Lessonprocessing, 3: Some Lesson 4: monogenic diabetes TSPAN-LGR5 Locus All T2D genes/loci identified to This allelesecretion. increases T2D risk

resistance genes have common variations date seem to affect beta cell more through obesity. Itsmodest effect can with effect FPLD (LMNA, AKT2, function except PPARG. Where by be attenuated increased increasing risk to typical T2D ZMPSTE24) are all the insulin resistance physical activity (and GDM?) genes? CGL (BSCL, AGPAT2, PPARG, CAV1)

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Association of a Common T2D Risk Variant in GCK with GDM: The HAPO Study

Association of T2D Risk Alleles with GDM in a Korean Population

Chol et al. Diabetologia, 2009

Distribution of Risk Alleles of 11 T2D Risk Variants in Women with Previous GDM (n = 244) and Glucose-Tolerant Control Women (n = 1883)

Lauenborg, J. et al. , J Clin Endocrinol Metab, 2009

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Genetics of T1D
HLA-DR3/4 PLUS:

Concannon et al (2009), NEJM 360 (16)

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

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