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 Candidates

Direct Sequencing

Positional Candidates

Expressional Candidates

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 USPHSHanis 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

mLO

D

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

SNP-

57

UC

SNP-

20

14 15 VNTR-2(49136)

UC

SNP-

43,4

4,45

,46

UC

SNP-

56U

CSN

P-59

UC

SNP-

60U

CSN

P-19

UC

SNP-

48U

CSN

P-58

UC

SNP-

47

UC

SNP-

30

UC

SNP-

22,2

3,24

,25,

26

UC

SNP-

42

UC

SNP-

55U

CSN

P-54

UC

SNP-

39

UC

SNP-

32

UC

SNP-

53U

CSN

P-49

,50,

51,5

2

UC

SNP-

38,4

0

UC

SNP-

41

UC

SNP-

36,3

7

UC

SNP-

35

UC

SNP-

34

UC

SNP-

27,2

8,29

UC

SNP

-1,2

,3,4

UC

SNP-

31

UC

SNP-

33

UC

SNP-

62U

CSN

P-63

UC

SNP-

65

VNTR-1

Calpain 10 GPR35

Organization of the 31kb Calpain 10 Gene Region

1 2 3 4 5 6 7 8 9 10

11

1213

UC

SNP-

57

UC

SNP-

20

14 15

UC

SNP-

43,4

4,45

,46

UC

SNP-

56U

CSN

P-59

UC

SNP-

60U

CSN

P-19

UC

SNP-

48

UC

SNP-

58

UC

SNP-

47

UC

SNP-

30

UC

SNP-

42

UC

SNP-

32

UC

SNP-

62U

CSN

P-63

UC

SNP-

65

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 10aCalpain 10b

Calpain 10c

Calpain 10dCalpain 10eCalpain 10fCalpain 10gCalpain 10h

491

I II III TDomain

SNP 43,19,63 Haplotype and Diabetes Risk

2,86 3,06

0123456

Odd

s Rat

io

Starr 1 Starr 2Population

OGTT Glucose Response by Genotype

100

125

150

175

200

0 30 60 90 120Time (minutes)

Glu

cose

(mg/

dl)

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

01

23

4

56

Odd

s Rat

io

Starr 1 Starr 2 Botnia GermanyPopulation

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