Genetics of Diabetes: What do we know and what can we do?

Genetics of Diabetes: What do we know and what can we do? Toni I. Pollin, MS, PhD Associate Professor of Medicine and Epidemiology & Public Health Div...
Author: Eustacia Davis
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Genetics of Diabetes: What do we know and what can we do? Toni I. Pollin, MS, PhD Associate Professor of Medicine and Epidemiology & Public Health Division of Endocrinology, Diabetes & Nutrition University of Maryland School of Medicine

March 13, 2012

Overview „ „ „ „ „ „

Why genetics? DNA Mutations Inheritance Genetics of diabetes subtypes Genetic testing/ services/ resources

Molecular medicine comes to the rescue Targeted therapy turns life around for child with neonatal diabetes On Monday, August 14, Lilly Jaffe, a six-year-old North Shore suburban girl who had been diagnosed with type 1 diabetes when she was one month old, checked into the Clinical Research Center at the University of Chicago Medical Center. On Friday, August 18, she checked out, starting to make her own insulin, well on her way to insulin independence and ready to get in a few days of beach time in Michigan before starting first grade.

http://www.uchospitals.edu/news/2006/20060911-diabetes.html

DNA in Context

(Not to scale!)

DNA is a Blueprint for Protein

www.genome.gov

DNA Replicates During Cell Division

www.genome.gov

Nuclear DNA at Metaphase

www.pathology.washington.edu

Chromosome Ideogram pter

2 1 1 2 3 qter

www.pathology.washington.edu

cen

Protein Coding Genes Comprise ~1% of Genome (About 20,000 Genes on 46 Chromosomes in Humans)

www.genome.gov

Mitochondria Also Contain DNA „

Circular double stranded DNA

„

Codes for 13 proteins

„

Maternal transmission

www.genome.gov

The Genetic Code

www.genome.gov

Amino Acids

www.cm.utexas.edu

Coding Mutations

CCG TCA CCG TTA TTG CGT Proline

Serine

Proline

Leucine

Leucine

Arginine

CCG TCC CCG TTA TTG CGT Proline

Serine

Proline

Leucine

Leucine

Arginine

CCG ACA CCG TTA TTG CGT Proline

Threonine

Proline

Leucine

Leucine

Arginine

CCG CCA CCG TTA TTG CGT Proline

Proline

Proline

Leucine

Leucine

Stop

Proline

Leucine

Leucine

Serine

Threonine

Valine

Isoleucine

Nonconservative Missense

Nonsense

Arginine

CCG TCG ACC GTT ATT GCG T.. Proline

Conservative Missense

Arginine

CCG TAA CCG TTA TTG CGT Proline

Silent

Alanine

Frameshift

Gene Regulation

www.accessexcellence.org

Family History Uncovers Classic Inheritance Patterns

Autosomal Dominant

Autosomal Recessive?

X-linked

…And Other Inheritance Patterns Maternal (Mitochondrial) ►Maternally inherited diabetes and deafness

Imprinting ►Transient neonatal diabetes

One gene

Two genes

04_11.jpg

Three genes

Many genes

Liability Threshold Model

http://www.uic.edu/classes/bms/bms655/lesson11.html

Diabetes Classification (ADA/WHO*) • • • •

Type 1 Diabetes (T1DM) Type 2 Diabetes (T2DM) Other specific types (known etiology) Gestational diabetes mellitus (GDM, ~4% of pregnancies)

Type 2

*ADA = American Diabetes Association WHO = World Health Organization

Type 1

Other specific types

Diabetes Genetics “The genetics of diabetes is a confused subject in which almost every possible mode of inheritance has been proposed. It is apparent, however, that no simple genetic hypothesis is compatible with the data gathered from large groups of diabetics. One reason . . . may be that diabetes is not homogeneous but rather consists of a number of different diseases in which carbohydrate intolerance is the common factor.” R. B. Tattersall (1974). Mild familial diabetes with dominant inheritance. QJM 170:339

% Risk

Type 1 Diabetes: Familial Aggregation 100 90 80 70 60 50 40 30 20 10 0 Gen. Pop. MZ Twin

DZ Twin

Sibling

Genetics of Type 1 (Autoimmune) Diabetes Insulin (Chr 11) 10%

HLA (Chr 6) 45%

(IDDM2)

’s w Co Other 45%

(IDDM 3 – 24)

(IDDM1) Genes

M

il k

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To x

Vi

in

Vaccin es? ru s

s?

es

?

?? ? ?

Environmental Factors

Type 1 Diabetes

Non-HLA Genetics of T1DM 2009

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

% Risk

Type 2 Diabetes: Familial Aggregation 100 90 80 70 60 50 40 30 20 10 0 Gen. Pop. MZ Twin

DZ Twin

Sibling

Genetics of Type 2 Diabetes J11 N 2 7L KC PP F C ARG T

Type 2 Diabetes

Genes

Obesity Medication

Physical Activity

Diet

Complications

Courtesy J.C. Florez 2010

Fajans et al, NEJM 2001

Maturity Onset Diabetes of the Young (MODY) Transcription Factor/ Glucokinase Diabetes „

Definition: „ „ „

„ „

Obesity not required Several different single gene forms „ „ „

„

Early onset hyperglycemia (

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