Genetic Testing and the Genetic Testing and the Prevention of Prevention of
Type 1 DiabetesType 1 Diabetes
Janice S. Dorman, Ph.D.Janice S. Dorman, Ph.D.
September 4, 2001September 4, 2001
Type 1 DiabetesType 1 Diabetes
One of most frequent chronic One of most frequent chronic diseases of children diseases of children - - Prevalence ~ 2 / 1000 in Allegheny Prevalence ~ 2 / 1000 in Allegheny
County, PACounty, PA
Epidemiology of type 1 diabetes has Epidemiology of type 1 diabetes has been studied at the University of been studied at the University of Pittsburgh since 1979 Pittsburgh since 1979 - Dr. Allan Drash and Dr. Lewis Kuller- Dr. Allan Drash and Dr. Lewis Kuller
Type 1 Diabetes IncidenceType 1 Diabetes IncidenceAllegheny County, PAAllegheny County, PA
0
5
10
15
20
25
30
5 10 15 20
Age in Years
per
100
,000
/yr
WM
NWM
WF
NWF
Type 1 Diabetes Incidence Type 1 Diabetes Incidence Allegheny County, PAAllegheny County, PA
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Jan-Mar Apr-Jun Jul-Sep Oct-Dec
Season
/100
,000
/yr
Type 1 Diabetes Incidence Type 1 Diabetes Incidence Allegheny County, PAAllegheny County, PA
0
5
10
15
20
25
1975-79 1980-84 1985-89
WM
NWM
WF
NWF
FIN
Type 1 Diabetes Incidence Type 1 Diabetes Incidence WorldwideWorldwide
05
10152025303540
Rat
e/10
0,0
00/y
r
Specific Environmental Specific Environmental Risk FactorsRisk Factors
Case-control studies - conflictingCase-control studies - conflicting Possible risk factorsPossible risk factors
- Infant diet or lack of breast feeding- Infant diet or lack of breast feeding- Childhood diet- Childhood diet- Viruses (exposure as early as in utero)- Viruses (exposure as early as in utero)- Hormones- Hormones- Stress- Stress
May act as initiators or precipitatorsMay act as initiators or precipitators
Evidence for GeneticEvidence for Genetic Risk Factors Risk Factors
Increased risk for 1st degree relatives Increased risk for 1st degree relatives of affected individualsof affected individuals
Concordance in MZ twins 20 - 50%Concordance in MZ twins 20 - 50% Recent genome wide screens have Recent genome wide screens have
revealed 15+ possible susceptibility revealed 15+ possible susceptibility genesgenes
Associations with HLA class II alleles Associations with HLA class II alleles in all populationsin all populations
Genome Screens for Genome Screens for Type 1 DiabetesType 1 Diabetes
IDDM1IDDM1 6p21.36p21.3
IDDM2IDDM2 11p15.511p15.5
IDDM3IDDM3 15q2615q26
IDDM4IDDM4 11q13.311q13.3
IDDM5IDDM5 6q156q15
IDDM6IDDM6 18q12-q2118q12-q21
IDDM7IDDM7 2q31-332q31-33
IDDM8IDDM8 6q25-276q25-27
IDDM9IDDM9 3q21-253q21-25
IDDM10IDDM10 10p11-10p11-q11q11
IDDM11IDDM11 14q24-14q24-q31q31
IDDM12IDDM12 2q332q33
IDDM13IDDM13 2q342q34
IDDM14IDDM14 NDND
IDDM15IDDM15 6q216q21
* Candidate Gene * Candidate Gene *Possible Candidate *Possible Candidate *No Candidate Gene*No Candidate Gene
Interpreting Linkage Interpreting Linkage Analysis for Type 1DiabetesAnalysis for Type 1Diabetes
Need to control for effect of HLANeed to control for effect of HLA Some genes confer susceptibility in Some genes confer susceptibility in
absence of high risk HLA haplotypesabsence of high risk HLA haplotypes Need model- free statistical methodsNeed model- free statistical methods Account for gender, parent-of-origin Account for gender, parent-of-origin
effects and environmental risk effects and environmental risk factorsfactors
May not be appropriate phenotypeMay not be appropriate phenotype
Genome Screens forGenome Screens for Type 1 Diabetes Type 1 Diabetes
Chromosome 6Chromosome 6
IDDM8 IDDM8 6q25-276q25-27
IDDM15 IDDM15 6q216q21
Chromosome 2Chromosome 2
IDDM7 IDDM7 2q31-33 2q31-33 HOX8, IL-1HOX8, IL-1family IDDM12 family IDDM12 2q332q33 CTLA4, CTLA4, CD28CD28 IDDM13 IDDM13 2q342q34IGFBP2, IGFBP5IGFBP2, IGFBP5
* Candidate Gene * Candidate Gene *Possible Candidate *Possible Candidate *No Candidate Gene*No Candidate Gene
Genome Screens for Genome Screens for Autoimmune DiseasesAutoimmune Diseases
Candidate Genes - Type 1 DiabetesCandidate Genes - Type 1 DiabetesIDDM1IDDM1 6p21.36p21.3 DR-DQ, 2nd loci - TNF?DR-DQ, 2nd loci - TNF?
IDDM2IDDM2 11p15.511p15.5 INS-VNTRINS-VNTR
IDDM12IDDM12 2q332q33 CTLA4, CD28CTLA4, CD28
Candidate Genes - Other DisordersCandidate Genes - Other DisordersIDDM1IDDM1 ATD, CD, RA, MS, SLEATD, CD, RA, MS, SLE
IDDM2IDDM2 SLE, ankylosing spondylitisSLE, ankylosing spondylitis
IDDM12IDDM12 ATDATD
WHO DiaMond Molecular WHO DiaMond Molecular Epidemiology StudyEpidemiology Study
Have evaluated HLA DQ Have evaluated HLA DQ Best single genetic markerBest single genetic marker
Evaluate other candidate genesEvaluate other candidate genesIDDM1IDDM1 HLA DR, DPHLA DR, DPIDDM2 IDDM2 INS-VNTRINS-VNTRIDDM12IDDM12 CTLA4CTLA4OthersOthers VDR, HLA class IVDR, HLA class I
WHO Multinational Project WHO Multinational Project for Childhood Diabetes for Childhood Diabetes
(DiaMond)(DiaMond)
What is Causing the Tremendous What is Causing the Tremendous Geographic Variation in Incidence Geographic Variation in Incidence
of Type 1 Diabetes?of Type 1 Diabetes?
Monitored Incidence WorldwideMonitored Incidence Worldwide
1990 - 20001990 - 2000
WHO Collaborating Center WHO Collaborating Center for Diabetes Registries, for Diabetes Registries, Research and TrainingResearch and Training
Ron LaPorte, Ph.D.Ron LaPorte, Ph.D. Disease Monitoring &Disease Monitoring &TelecommunicationsTelecommunications
Jan Dorman,Ph.DJan Dorman,Ph.D.. Molecular EpidemiologyMolecular Epidemiology
University of PittsburghUniversity of Pittsburgh
WHO DiaMond Molecular WHO DiaMond Molecular Epidemiology StudyEpidemiology Study
HypothesisHypothesis
Geographic differences in type 1 diabetes Geographic differences in type 1 diabetes incidence reflect population variation in incidence reflect population variation in the frequencies of disease susceptibility the frequencies of disease susceptibility genesgenes
20+ countries participating20+ countries participating Focus on 2, 1, or 0 high risk HLA-DQ Focus on 2, 1, or 0 high risk HLA-DQ
haplotypes (SS, SP, PP)haplotypes (SS, SP, PP)
Relative Increase In RiskRelative Increase In Risk
Population Population SS SS SPSP PPPP
CaucasianCaucasian†† 15.915.9 4.04.0 1.01.0**
Af AmericansAf Americans†† 44.844.8 7.37.3 1.01.0**
AsianAsian‡‡ 10.710.7 3.63.6 1.01.0**
* p < 0.05, test for trend* p < 0.05, test for trend††Allegheny Co, PA and Jefferson Co, ALAllegheny Co, PA and Jefferson Co, AL‡‡Hokkaido, Japan and Seoul, KoreaHokkaido, Japan and Seoul, Korea
Cumulative Risk Through Cumulative Risk Through Age 30 YearsAge 30 Years
Population Population SS SS SPSP PPPP
CaucasianCaucasian†† 2.6%2.6% 0.7%0.7% 0.2%0.2%
Af AmericansAf Americans†† 3.1%3.1% 0.5%0.5% 0.1%0.1%
AsianAsian‡‡ 0.2%0.2% 0.1%0.1% 0.02%0.02%
††Allegheny Co, PA and Jefferson Co, ALAllegheny Co, PA and Jefferson Co, AL‡‡Hokkaido, Japan and Seoul, KoreaHokkaido, Japan and Seoul, Korea
Population Attributable Population Attributable FractionFraction
Population Population SS SS SS or SPSS or SP
CaucasianCaucasian†† 36.2%36.2% 66.6%66.6%
Af AmericansAf Americans†† 43.5%43.5% 74.9%74.9%
AsianAsian‡‡ 18.8%18.8% 53.3%53.3%
††Allegheny Co, PA and Jefferson Co, ALAllegheny Co, PA and Jefferson Co, AL‡‡Hokkaido, Japan and Seoul, KoreaHokkaido, Japan and Seoul, Korea
What do these data tell us?What do these data tell us?
Increased risk for individuals with SS Increased risk for individuals with SS and SP genotypes, relative to PP, and SP genotypes, relative to PP, with a significant dose responsewith a significant dose response
Cumulative risk for SS individuals in Cumulative risk for SS individuals in high-moderate incidence countries high-moderate incidence countries approaches rates for first degree approaches rates for first degree relatives; relatives; 3 - 6%3 - 6%
What do these data tell us?What do these data tell us?
Contribution of the highest risk HLA-Contribution of the highest risk HLA-DQ genotypes to type 1 diabetes DQ genotypes to type 1 diabetes incidence varied from 19% - 43% incidence varied from 19% - 43% across populationsacross populations
More than 50% of the incidence of More than 50% of the incidence of type 1 diabetes is type 1 diabetes is NOTNOT explained by explained by the highest risk HLA-DQ genotypesthe highest risk HLA-DQ genotypes
Gene - Environment Gene - Environment InteractionsInteractions
Exposure Exposure increased risk by increased risk by 1/100,000 / year 1/100,000 / year among among susceptiblessusceptibles
Overall population Overall population risk would risk would increase by increase by 0.8%0.8% 0
5
10
15
20
25
30
35
Baseline AfterExposure
FinlandFinland
0
0.1
0.2
0.3
0.4
0.5
0.6
Baseline AfterExposure
ChinaChina
Gene - Environment Gene - Environment InteractionsInteractions
Exposure Exposure increased risk by increased risk by 1/100,000 / year 1/100,000 / year among among susceptiblessusceptibles
Overall population Overall population risk would risk would increase by increase by 10%10%
Molecular Epidemiology of Molecular Epidemiology of Type 1 Diabetes in ChinaType 1 Diabetes in China
What is contributing to the low overall What is contributing to the low overall incidence and large variation in risk within incidence and large variation in risk within China?China?
- Etiological heterogeneity- Etiological heterogeneity
- Susceptibility genes- Susceptibility genes
- Environmental risk factors- Environmental risk factors Project based on DiaMond registry Project based on DiaMond registry
networknetwork Model study for molecular epidemiologyModel study for molecular epidemiology
Rate (per 100,000)0 1.8
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**
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Molecular Epidemiology of Molecular Epidemiology of Type 1 Diabetes in ChinaType 1 Diabetes in China
Data collection completed in 1999 Data collection completed in 1999 - Dr. Yang Ze- Dr. Yang Ze
296 cases, 528 controls; 18 centers296 cases, 528 controls; 18 centers Molecular analyses - BeijingMolecular analyses - Beijing
- HLA DRB1, DQB1 typing- HLA DRB1, DQB1 typing Serological analyses - PittsburghSerological analyses - Pittsburgh
- GAD, IA-2, TPOAb, TGAb, C-pep- GAD, IA-2, TPOAb, TGAb, C-pep Environmental data - PittsburghEnvironmental data - Pittsburgh
- Nutrition, infections, pollution- Nutrition, infections, pollution Dissertation for Dr. Elsa StrotmeyerDissertation for Dr. Elsa Strotmeyer
Jan Alice Lew Yang Ze