Genetics of Diabetes and Its Complications: Layers of Complexity

University of Pittsburgh

October 23, 2001

Craig L. Hanis, Ph.D.Human Genetics Center

The University of Texas Health Science Center at Houston

A Brief History of the Genetics of Diabetes

Nightmare

Headache

Heterogeneity

Complexity

Interactions

Linkage

Disequilibrium

Genetics of Diabetes Complications

Headaches from the Nightmares

&

Nightmares from the Headaches

Rising Interest in the Genetics of Diabetes and Its Complications

0

50

100

150

200

250

300

350Publications

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Complex Inheritance

• Model Free Linkage Approaches– Affected Pairs

• Concordant Sib Pairs• Discordant Sib Pairs

• Association Based Mapping– Transmission Disequilibrium Testing

• Parent - Offspring Trios (pairs)

– Traditional Associations• SNP-based mapping

Fine Mapping

• Ultimately a Search for Association

• Criteria for selecting samples– Affected/Unaffected

– Segregating/Non-segregating

– Haplotype Determination• enhanced by pedigrees?

Candidate Genes to Functional Variation

Biological CandidatesBiological Candidates

Direct S

equ

encin

gPositional CandidatesPositional Candidates

Expressional

Candidates

Expressional

Candidates

Functional

Studies

Functional

Studies

Diabetes Mortality in Texas

Type 2 Diabetes Among Mexican Americans in Starr County, Texas

4%1%1%

10%

4%2%

17%

4%4%

15%

6%6%

12%

6%5%

0%

5%

10%

15%

20%

25%

30%Prevalence

35-44 45-54 55-64 65-74 75+

Age Category

Starr County Rancho Bernardo USPHS

Hanis et al. (1983). Am J Epidemiol 118:659-672

Type 2 Diabetes in 3 Ethnic Groups

0%10%20%30%40%50%60%70%

Prevalence

35-44 45-54 55-64 65-74 75+

Age Category

Pima Indians Starr County USPHS

Genome Scan Results – Chromosome 2

-18-15-12

-9-6-3036

0 0,5 1 1,5 2 2,5 3

Position

mL

OD

1,6 1,2 2,8

Narrowing the NIDDM1 Region on Chromosome 2

300 cM – 300+ million base pairs

NIDDM1 maps near

D2S1405 – 10 million base pairs

150,000 base pairs

Direct Sequencing of 65,000 base pairs

Organization of the NIDDM1 Region

1 2 3 4 5 6 7 8 9 1011

1213

UC

SN

P-5

7

UC

SN

P-2

0

14 15 VNTR-2

(49136)

UC

SN

P-4

3,44

,45,

46U

CS

NP

-56

UC

SN

P-5

9U

CS

NP

-60

UC

SN

P-1

9

UC

SN

P-4

8

UC

SN

P-5

8

UC

SN

P-4

7

UC

SN

P-3

0

UC

SN

P-2

2,23

,24,

25,2

6

UC

SN

P-4

2

UC

SN

P-5

5U

CS

NP

-54

UC

SN

P-3

9

UC

SN

P-3

2

UC

SN

P-5

3U

CS

NP

-49,

50,5

1,52

UC

SN

P-3

8,40

UC

SN

P-4

1

UC

SN

P-3

6,37

UC

SN

P-3

5

UC

SN

P-3

4

UC

SN

P-2

7,28

,29

UC

SN

P-1

,2,3

,4

UC

SN

P-3

1

UC

SN

P-3

3

UC

SN

P-6

2U

CS

NP

-63

UC

SN

P-6

5

VNTR-1

Calpain 10 GPR35

Organization of the 31kb Calpain 10 Gene Region

1 2 3 4 5 6 7 8 9 10

11

12

13

UC

SN

P-5

7

UC

SN

P-2

0

14 15

UC

SN

P-4

3,44

,45,

46

UC

SN

P-5

6

UC

SN

P-5

9

UC

SN

P-6

0U

CS

NP

-19

UC

SN

P-4

8

UC

SN

P-5

8

UC

SN

P-4

7

UC

SN

P-3

0

UC

SN

P-4

2

UC

SN

P-3

2

UC

SN

P-6

2U

CS

NP

-63

UC

SN

P-6

5

Click for larger picture

Alternative Splicing of Calpain 10

ATG

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

TAAATG

Exon

6721 41 304Protease

544TGAag

517ATG TAA

513TGAATG

444ATG TGA ag

274ATG TGAgt

139TGAATG

138ATG TAA

Calpain 10a

Calpain 10b

Calpain 10c

Calpain 10d

Calpain 10e

Calpain 10f

Calpain 10g

Calpain 10h

491

I II III T

Domain

SNP 43,19,63 Haplotype and Diabetes Risk

2,86 3,06

0

1

2

3

4

5

6

Odd

s R

atio

Starr 1 Starr 2

Population

OGTT Glucose Response by Genotype

100

125

150

175

200

0 30 60 90 120Time (minutes)

Glu

cose

(m

g/d

l)

G

AA

GG

AGAA

Mouse Pancreatic Islets in the Presence of Calpain Inhibitors

have an approximate 2-fold increased

Insulin Secretory Response

Sreenen et al. (2000). Diabetes 49 suppl 1:A62

Insulin and Glucose by Calpain 10 Genotype

Insulin

Glucose

Insulin

Glucose

St. Louis - N = 29 Utah - N = 38 Seattle - N = 29

Chicago - N = 32 Colorado - N = 44 Los Angeles - N = 8

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0 30 60 90 120

80.00

100.00

120.00

140.00

160.00

180.00

200.00

0 30 60 90 120

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0 30 60 90 120

80.00

100.00

120.00

140.00

160.00

180.00

200.00

0 30 60 90 120

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0 30 60 90 120

80.00

100.00

120.00

140.00

160.00

180.00

200.00

0 30 60 90 120

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0 30 60 90 120

80.00

100.00

120.00

140.00

160.00

180.00

200.00

0 30 60 90 120

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0 30 60 90 120

80.00

100.00

120.00

140.00

160.00

180.00

200.00

0 30 60 90 120

0.00

20.00

40.00

60.00

80.00

100.00

120.00

0 30 60 90 120

80.00

100.00

120.00

140.00

160.00

180.00

200.00

0 30 60 90 120

FSIVGTT Insulin by Calpain 10 Genotype

Insulin - FSIVGTT

020

40

60

80

100

120

140

160

0 20 40 60 80 100 120 140 160

Time (minutes)

Insu

lin

(u

U/m

L)

SNP 43,19,63 Haplotype and Diabetes Risk

2,86 3,062,57

5,52

0

1

2

3

4

5

6

Odd

s R

atio

Starr 1 Starr 2 Botnia Germany

Population

Genome Scan Results – Chromosome 15

-18-15-12

-9-6-3036

0 0,2 0,4 0,6 0,8 1 1,2 1,4

Position

mL

OD

1,2 1,6 2,8