Transcript UC SF UC SF

Importance of Race, Ethnicity and
Genetics in Biomedical Research
and Clinical Practice
Esteban González Burchard, M.D.
Assistant Professor of Medicine
Pulmonary and Critical Care Medicine
Lung Biology Center
San Francisco General Hospital
UCSF
Flurry of Controversy
• Pharmacogenetics: more than skin deep
(Nature Genetics 2002)
• Shouldn’t a Pill Be Colorblind (NY Times 2002)
• Genes, drugs and race (Nature Genetics 2002)
• Beyond Black and White in Biology and
Medicine (NY Times 2002)
• Racial Profiling in Medical Research (NEJM
2001)
• Racial Differences in the Response to Drugs
(NEJM 2001)
• Great Racial Divide (NEJM 2003)
UC
UCSF
SF
Race/ethnicity in the US
(Projected for 2010-2050)
Percent
100
47%
53%
80
60
40
20
0
White
1970
1990
Black
2000
2010
Hispanic
2020
API
2030
2040
Am Ind/AN
2050
Total
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Common to:
3000
2500
2000
1500
1000
500
0
ic
an
A
m
er
La
ti
no
A
si
an
1 group
2 groups
3 groups
4 groups
Ca
uc
as
ia
n
A
fr
ic
an
A
m
er
ic
an
# SNPs
3,899 SNPs in 313 genes in 4
U.S. racial groups
UCSF
3,899 SNPs in 313 genes in
4 U.S. racial groups
3000
2500
Common to:
2000
1 group
2 groups
3 groups
4 groups
1500
1000
500
ic
an
an
no
A
m
er
au
ca
si
C
A
si
an
La
ti
A
fr
ic
an
A
m
er
i
ca
n
# SNPs
0
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25% of SNPs are Pan Racial
3,899 SNPs in 313 genes in 4
U.S. racial groups
21% of SNPs are racially specific
3000
Common to:
2500
1 group
2 groups
3 groups
4 groups
2000
1500
1000
ic
an
La
ti
no
A
m
er
au
ca
si
an
an
C
ic
an
A
fr
A
si
er
i
ca
n
0
A
m
# SNPs
500
UCSF
Alzheimer's Disease and APOE e4 gene
6
5.6
5
Relative
Risk of
Heterozygote
Allele
4
3
3
2
1.1
1
0
Japanese
Caucasian
African
American
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Alzheimer's Disease and APOE e4 gene
20
Allele Frequency
14%
15
Relative
Risk of 10
Heterozygote
Allele
5
19%
9%
5.6
3
1.1
0
Japanese
Caucasian
African
American
UC
UCSF
SF
HIV Disease and CCR5 delta 32 genetic variant
30
25%
25
20
Frequency
15
of
Delta32
Allele 10
5
<1%
0
Caucasian
African American
UC
UCSF
SF
Cardiac Arrhythmia & SCN5A genetic variant
12%
10.1%
10%
Frequency
of
Y1102 Allele
6.8%
8%
6%
4%
0%
2%
0%
West African /
Caribbeans
African
American
Caucasian
UC
UCSF
SF
Asthma Definition
Chronic inflammatory disorder of the airways
Characterized by recurrent episodes of
wheezing, breathlessness, chest tightness,
and coughing
Widespread but variable airflow obstruction
that is often reversible either spontaneously
or with treatment.
Airflow obstruction can be measured with
Spirometry
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Peak Expiratory Flow Rate
Forced Expiratory Volume1
(FEV1)
Forced Vital Capacity
(FVC)
Exhalation
Volume (L)
Inspiration
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Pharmacologic
or
PEFR
Bronchodilator Response
Delta FEV1
FVC
Exhalation
Volume (L)
Inspiration
UCSF
IL-4 PROMOTER POLYMORPHISM IS
ASSOCIATED WITH ASTHMA SEVERITY
IL-4 Promoter Genotype vs. FEV1% of
Predicted
n = 682 asthmatic subjects
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
CT
CC
FEV1 (% of Predicted)
132
120
108
96
84
72
60
48
36
24
12
T = mutant allele
C= normal or
wildtype allele
0
Fraction of
Group
TT
UCSF
Ethnic/Population Specific Allele?
 Mutant allele is
more common
among African
American
Asthmatics than
Caucasian,
p<1X10-23
 Inter-racial gene
frequency
differential =36%
60%
54%
50%
40%
30%
20%
18%
10%
0%
Caucasians
African
Americans
HHANES Asthma Point Prevalence
14.0%
11.2%
12.0%
10.0%
8.0%
5.2%
6.0%
5.9%
3.3%
4.0%
2.7%
2.0%
0.0%
Mexican
American
African
Caucasian Cuban
American American
Puerto
Rican
U.S. Asthma Mortality 1990-1995
Average Annual Rates per Million
50
40.75
40
40.9
30
20
10
11.3
15
0
Mexican
Caucasian
African Puerto Rican
American
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Genetic Origins of Hispanic Groups
100%
90%
7
24
80%
70%
Percent
Ancestral
Contribution
Admixture
52
19
60%
50%
African
Native American
European
40%
30%
20%
57
41
10%
0%
Mexican Puerto Rican
American
UCSF
GENETICS OF ASTHMA
IN LATINO AMERICANS
GALA Study
UCSF
GALA Hypothesis & Specific Aims
Hypothesis:
• Ethnic-specific genetic risk factors for
asthma, asthma severity and drug response
Specific Aims:
• Compare Mexican and Puerto Rican asthmatic
families
• Identify ethnic specific alleles & haplotypes in
asthma candidate genes
• Perform TDT-based genetic association
studies
UCSF
GALA Hypothesis & Specific Aims
Hypothesis:
• Ethnic-specific genetic risk factors for
asthma, asthma severity and drug response
Specific Aims:
• Compare Mexican and Puerto Rican
asthmatic families
• Identify ethnic specific alleles & haplotypes
in asthma candidate genes
• Perform TDT-based genetic association
studies
Genetic Association Studies
Family - Trios
=affected
=unaffected
Case : control
=unspecifiedUCSF
Puerto Rican Volunteers
100%
80%
60%
40%
Individual subjects 1-90
88
85
82
79
European
Native American
African
Mexican Volunteers
100%
76
73
70
67
64
61
58
55
52
49
46
43
40
37
34
31
28
25
22
19
16
13
10
Percent
racial
admixture
7
1
0%
4
20%
80%
60%
40%
Individual subjects 1-93
91
88
85
82
79
76
73
70
67
64
61
58
55
52
49
46
43
40
37
34
31
28
25
22
19
16
13
10
7
1
0%
4
20%
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Phenotypes
• Procedures
• Spirometry
• Drug Resonsiveness
• Asthma & Medical Questionnaire
• IgE measurements
• Genetic Testing
UCSF
GALA Recruitment
January 2003
San Francisco
New York
Puerto Rico
Mexico City
total
Families
201
135
250
100
686 families
Matched Controls
200
250
450 controls
UCSF
GALA vs. Other Studies
• GALA is the first “head-to-head”
comparison of questionnaire and
clinical measurements among
Latino ethnic groups
• Standardized recruitment across
all sites
UCSF
Puerto Ricans have Increased
Asthma Morbidity
Strongest Predictor of Asthma Morbidity =
Ethnic Background
Puerto Rican ethnicity is associated with:
• Asthma-related ED visit in the previous 12 months,
• OR of 2.63 (95%CI: 1.6, 4.3; p<0.001)
• Asthma-related hospitalization,
• OR of 1.94 (95%CI: 1.2, 3.2; p=0.009)
UCSF
Baseline Spirometry
Baseline spirometry
Puerto
Ricans
Mexicans p - value
N = 343
N = 290
FEV1 % Predicted 83 (74: 93)
FVC % Predicted
90 (77: 100)
94 (83: 105) 97 (86: 109)
0.0001
0.03
FEF25-75 % Predicted
64 (48: 81) 71 (56: 88)
0.006
0.0004
PEF % Predicted
80 (67: 94) 95 (81: 107)
<0.0001
FEV1/FVC % Predicted 90 (82: 97) 92 (87: 99)
UCSF
% Reversibility in FEV1 after albuterol
Bronchodilator Response to Albuterol
Stratified by Age
14
P=0.0002
p=0.0003
12
10
8
6
4
2
0
Puerto Ricans Mexicans Puerto Ricans
< 16 years old
Mexicans
> 16 years old UC
SF
% Reversibility in FEV1 after albuterol
Bronchodilator Response to Albuterol
Stratified by Severity
14
12
10
8
6
4
2
0
p<0.0001
Puerto Ricans
Mexicans
Mild asthma
p=0.0001
Puerto Ricans
Mexicans
Moderatesevere asthma UC
SF
GALA b2AR Genotypes and
Bronchodilator Response
loci -709 -654 -47 46
79 252 491 523
Puerto Rican
FEV1 % of predicted pre albuterol
FEV1 % of predicted post albuterol
%Delta FEV1
*
n.s.
*
n.s.
*
n.s.
n.s.
0.02
n.s.
n.s.
n.s.
0.033 n.s.
0.012
n.s.
n.s.
n.s.
0.009 0.021 0.006 0.035
n.s.
n.s.
n.s.
Mexican
FEV1 % of predicted pre albuterol
FEV1 % of predicted post albuterol
%Delta FEV1
*
n.s.
n.s. 0.025
n.s.
0.04
n.s.
n.s.
*
n.s.
n.s. 0.033
n.s.
0.023
n.s.
n.s.
*
n.s.
n.s.
n.s.
0.019
n.s.
n.s.
n.s.
UCSF
IL-13 Causes b-Adrenergic Hyporesponsiveness
UCSF
SNP Discovery in IL-4 to IL-13 region
• Screened 72 African American, Puerto Rican,
Mexican Asthmatics
• 32 SNPs, 12 previously unreported
• 16 SNPs with allele frequency > 5%, 59 haplotypes
• Only one haplotype common to all three
populations
• Private Haploypes:
Puerto Ricans = 44%
African Americans= 85%
Mexcians = 40%
UCSF
IL-13 SNPs & Asthma in Puerto Ricans
1.5
1.25
1.0
0.75
0.5
0.25
0
A
B
C
D
E
F
G
H
Individual SNP
I
J
K
UCSF
-Log P-Value
IL-13 Haplotypes & Asthma
in Puerto Ricans
7
6
5
4
3
2
1
0
ABC BCD CDE DEF EFG FGH GHI HIJ
Three SNP Haplotypes
IJK
UCSF
IL-13 is Associated with Drug Response
IL-13 IL-13
SNP #
bp location
All
FEV1 pre percent of predicted
% Delta FEV1
IL-13 IL-13 IL-13 IL-13 IL-13 IL-4 IL-4
1
2
3
4
5
6
7
1
2
0.00958
n.s.
n.s.
n.s.
n.s.
n.s. n.s. 0.0032460.03292 n.s.
0.00698
n.s. n.s. 0.000367
n.s.
n.s.
n.s.
n.s.
n.s.
n.s. n.s. 0.029767 n.s. n.s.
n.s. n.s. 0.0030890.053 n.s.
n.s.
n.s.
Promoter
Promoter
Intron
Intron
Promoter
3'UTR
Intron
Promoter
Intron
n.s.
Puerto Rican
FEV1 pre percent of predicted 0.038336 0.02387
% Delta FEV1
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
Mexican
FEV1 pre percent of predicted
% Delta FEV1
n.s. n.s. 0.045495 n.s. n.s.
n.s. n.s. 0.045894 0.08 n.s.
UCSF
ADAM 33
Association of the ADAM 33 Gene with Asthma and
Bronchial hyperresponsiveness
• 460 Families (TDT) and controls
• 6 SNP haplotype/SNP combinations (p = P = 0.04–0.000003)
• Nature, July 25, 2002
ADAM 33 is Not Associated with Asthma in Puerto
Rican and Mexican Populations from the GALA Study
• 583 Families (TDT) and 400 controls
• 6 SNP haplotypes/SNP combinations (no association)
• AJRCCM, e-Pub Sept 4, 2003
UCSF
Is Race a Social or Biologic Construct?
Social
• Strict biologic
construct = Sex
Geographic
Race/Ethnicity
Cultural
Although these forces are not biologic in
nature, racial and ethnic categories differ from
each other genetically, which has biologic
implications
UCSF
Why Participate in Research?
• What if minorities do not participate in
Genetic and Clinical Research?
• There is great risk that disease genes in
specific populations will not be well
understood in non-participating populations
• Medical benefits to these populations will be
less than for well studied populations with
higher participation rates
UCSF
Risks of Racial Research
• History of Abuse & Misuse : WWII and
Tuskegee
• Racial Profiling : Crime, Terrorism
• Biologic Blame : Intelligence and Racial
Predisposition to Crime
• Poorly done studies of race can lead to
incorrect conclusions:
• Strive to understand the full meaning of
racial/ethnic differences including: role of
SES, cultural, environmental and dietary
differences
UCSF
Summary
• Racial & Ethnic Specific genetic differences, risk of
disease and drug response
• Can not study race in a vacuum: include SES,
environment, diet, etc.
• As of Today, the Real Answer is unknown
• Risk of Not Looking outweighs the Risks of Potential
Abuses
Racial Privacy Initiative
would have ended most state-funded
research involving race and ethnicity
UCSF
Lung Biology Center
(SFGH)
Dean Sheppard
Shweta Choudhry
Elad Ziv
Suzanne Clark
Natasha Coyle
Hank Matallana
Ngim Ung
Monica Toscano
Keyan Salari
Mike Salazar
Richard Castro
Stanford
Neil Risch
Thank You
San Francisco
Homer Boushey
Pedro Avila
MariaElena Alioto
Pui Yan Kwok
Denise Lind
Mexico
Rocio Chapela
Moises Selman
Jorge Salas
Penn State Univ.
Mark Shriver
Esteban Para
UW FHCRC
Hua Tang
Boston
Jeffrey Drazen
Ed Silverman
Scott Weiss
Puerto Rico
William
Rodriquez
Jesus Casal
Sylvette
Nazario
Alfonso Torres
Jose Rodriguez
Santana
New York
Jean Ford
Joanne Fagan