Interactions and the Development of Type 2 Diabetes Among Mexican Americans

NIDDM1Calpain 10

Chr. 15Calpain 3?

Nongenetic Factors - Lifestyle and Environment

Type 2 Diabetes Mellitus MODY

HNF-1αSusceptibilityLoci

The Plot Thickens

NIDDM1 Chr. 15 Chr. 7

Nongenetic Factors - Lifestyle and Environment

Type 2 Diabetes Mellitus MODY

HNF-1αChr. 11

Chr. 9 Chr. 10

Chr. 3 Chr. 21Modifier Loci

SusceptibilityLoci

Genome Scans for Type 2 DiabetesStudy Design Reference/StatusStarr County, Texas

346 Affected Sib Pairs Hanis et al., 1996/ Complete Scan

Eastern Finns 26 Pedigrees, Affected Members Mahtani et al., 1996/ Complete Scan

GENNID Affected Sib Pairs, 3 Ethnic Groups ADA/UnpublishedFUSION Affected Pairs, Pedigrees, Quantitative

TraitsGhosh et al., 1999/ Nearing Completion

San Antonio Pedigrees, Quantitative Traits Stern et al., 1996/ Near Completion

Utah Pedigrees, Affected Pairs, Quantitative Traits

Elbein et al., 1999/ Complete Scan

Pima Indians Pedigrees, Affected Pairs, Quantitative Traits

Hanson et al., 1998/ Complete Scan

Canadian Oji-Cree 49 Affected Sib Pairs Hegele et al., 1999/ 20cM Scan

Old Order Amish 27 Pedigrees, Quantitative Traits Hsueh et al., 1999 (Abstract)/ Complete Scan

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Which Chromosome Next?

• All but 4 were picked by one or more groups!

• For us --- Chromosome 15

• Must pick region with greatest chance of success in your data set– What about replication?

Complications

Type 1 Diabetes Type 2 Diabetes

HLA IDDM2 Others Cs 15 OthersCalpain 10

Comp 1

Comp 2

Comp ?

Familial Aggregation of Retinopathy by Severity

50%

60%

70%

80%

90%

100%

Ris

k in

Sib

lings

<= Mild Moderate SevereProband Retinopathy Status

Familial Aggregation of Vibratory Perception Threshold

0,0

0,1

0,2

0,3

0,4

0,5

Risk

in S

iblin

gs

< 20 20 +Proband Vibratory Perception Status

Familial Aggregation of Proteinuria among PimaPettitt et al., Diabetologia 33:438-443, 1990

0%

20%

40%

60%

80%

100%

Prot

einu

ria

in

Off

spri

ng

Neither Parent One Parent Both ParentsParents with Proteinuria

Familial Aggregation of Test-Strip Microalbuminuria

0,0

0,1

0,2

0,3

0,4

0,5

Ris

k in

Sib

lings

Negative PositiveProband Test-Strip Status

Familial Clustering of Complications

0%10%20%30%40%50%

Freq

uenc

y

VPT Micro-Alb EitherComplication

None to Mild Moderate +

Candidate Gene Association Studieswith Diabetic Retinopathy (92 References)• Positive Associations

– Aldose Reductase• Ko et al., 1995

– PAI1• Nagi et al., 1997

– HLA (in type 2)• Cruickshanks et al., 1992

– IGM• Hawrami et al., 1991

– TNF-• Hawrami et al., 1996

• Lack of Association– Aldose Reductase

• HMOs et al., 1997– PAI1

• Mansfield et al., 1991– HLA (in type 1)

• Hawrami et al., 1991 Falck et al., 1997– Angiotensinogen

• Fogarty et al., 1996, Gutierrz et al., 1997– Angiotensin I Converting Enzyme

• Marre et al., 1994,Tarnow et al., 1995• Fujisawa et al., 1995, Nagi et al., 1995

Gutierrez et al., 1997

• Positive Associations– Angiotensin I Converting

Enzyme• Hadjadj et al., 2001, Several

Others– Apo E

• Kimura et al., 1998– Glut 1

• Grzeszczak et al., 2001– Angiotensinogen

• Reviewed by Taal, 2001– NOS2

• Johannesen et al., 2000

• Lack of Association– Advanced Glycation Endproduct

• Poirier et al., 2001– Angiotensinogen

• Hadjadj, et al., 2001– Angiotensin I Converting Enzyme

• Marre et al., 1994Tarnow et al., 1995• Fujisawa et al., 1995 Nagi et al., 1995 Gutierrez et al.,

1997– Aldose Reductase

• NG et al., 2001– PON1

• Araki et al., 2001– Glutathione S Transferase

• Fujita et al., 2000– GNB3

• Zychma et al., 2000

Candidate Gene Association Studieswith Diabetic Neuropathy (14 Reports)

• Positive Associations– Aldose Reductase

• Heesom et al., 1998

• Lack of Association– Aldose Reductase

• Ng et al., 2001– Apo(a)

• Gazzaruso et al., 1998

Linkage: Diabetes vs Complications Genes

Nephropathy Linkage on Chromosome 20

Imperatore et al., Diabetes 47:821-830,

1998

Bowden et al., Diabetes 46:8882-886,

1997

Click for larger picture

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Epidemiology in the Era of Diabetes Genes

• Design– Screening followed by imposition of design– Increased power through balance

• Interaction by design– Genotype by environment– Genotype by treatment

• Risk Prediction

Barriers to Incorporating Genes

• Identifying the Genes– More Genome Scanning - including pooling– Disequilibrium-based approaches– Human Genome Project– Animal Studies

• Appropriately phenotyped samples– Remains the rate-limiting step

• Typing Technology

Which Paradigm?

• Disease Endpoints– Definable– Measurable– Analyzable

• Concordant Pairs• Discordant pairs

• Glycemic Control– Difficult to define long

term– Confounded by

Treatment– Clinical Trials

• Response– Closer to Biology (genes)?

Age Structure of Starr County, Texas and the U.S. Population

0% 2% 4% 6% 8% 10% 12%

< 5

15

30

45

60

75

Intervention in the Presence of G x E Interaction

0%

60%

1900 2025

Year

Today

William J.Schull

Terry Bertin Hilda Guerra Collaborators

Eric Boerwinkle NancyMacNaughton

Jesusa Salmon Graeme I. Bell

Charles A.Garcia

Sara Barton Alda Clarke Nancy J. Cox

Hsuan-Ho Chu David Martinez Myriam Muniz Kenneth S.Polonsky

David Hewett-Emmett

Li Li LeahHernandez

Patrick J.Concannon

WilliamMueller

Kisoo Kil Sylvia Hinojosa Richard S.Spielman

Luiz Kubrusly Charles Huber LeticiaGonzalez

Ronald Klein

DeniseKubrusly

Tommy Douglas Lisa Gonzalez Victor H.Gonzalez

Residents LocalPhysicians

CommunityLeaders

LocalPhysicians