Importance of Race, Ethnicity and Genetics in Biomedical Research and Clinical Practice

1
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
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Flurry of Controversy

• Pharmacogenetics more than skin deep (Nature
  Genetics 2002)
• Shouldnt 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)

UCSF
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Race/ethnicity in the US
(Projected for 2010-2050)
47
53
100
80
Percent
60
40
20
0
1970
1990
2000
2010
2020
2030
2040
2050
Total
White
Black
Hispanic
API
Am Ind/AN
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3,899 SNPs in 313 genes in 4 U.S. racial groups
Common to
SNPs
5
3,899 SNPs in 313 genes in 4 U.S. racial groups
Common to
SNPs
25 of SNPs are Pan Racial
6
3,899 SNPs in 313 genes in 4 U.S. racial groups
21 of SNPs are racially specific
Common to
SNPs
7
Alzheimer's Disease and APOE e4 gene
5.6
6
5
4
Relative Risk of
3
3
Heterozygote
Allele
2
1.1
1
0
African
Japanese
Caucasian
American
UCSF
8
Alzheimer's Disease and APOE e4 gene
Allele Frequency
19
20
14
15
Relative Risk of
9
10
5.6
Heterozygote
Allele
3
5
1.1
0
Japanese
Caucasian
African
UCSF
American
9
HIV Disease and CCR5 delta 32 genetic variant
30
25
25
20
Frequency of
15
Delta32 Allele
10
5
lt1
0
Caucasian
African American
UCSF
10
Cardiac Arrhythmia SCN5A genetic variant
12
10.1
10
6.8
8
Frequency of
6
Y1102 Allele
4
0
2
0
West African /
African
Caucasian
Caribbeans
American
UCSF
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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

12
Peak Expiratory Flow Rate
Forced Expiratory Volume1 (FEV1)
Forced Vital Capacity (FVC)
Exhalation
Flow (l/s)
Volume (L)
Inspiration
13
Pharmacologic or Bronchodilator Response Delta
FEV1
PEFR
FVC
Exhalation
Flow (l/s)
Volume (L)
Inspiration
14
IL-4 PROMOTER POLYMORPHISM IS ASSOCIATED WITH
ASTHMA SEVERITY
n 682 asthmatic subjects
T mutant allele C normal or wildtype allele
UCSF
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Ethnic/Population Specific Allele?

• Mutant allele is more common among African
  American Asthmatics than Caucasian, plt1X10-23
• Inter-racial gene frequency differential 36

16
HHANES Asthma Point Prevalence
17
U.S. Asthma Mortality 1990-1995
18
Genetic Origins of Hispanic Groups
Contribution

UCSF
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GENETICS OF ASTHMAIN LATINO AMERICANS

• GALA Study

UCSF
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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
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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

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Genetic Association Studies
affected unaffected unspecified
23
Puerto Rican Volunteers
100
Percent racial admixture
Individual subjects 1-90
European
Native American
Mexican Volunteers
African
100
80
60
40
20
0
7
4
1
10
13
16
19
22
25
28
31
34
37
40
43
46
49
52
55
58
61
64
67
70
73
76
79
82
85
88
91
Individual subjects 1-93
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Phenotypes

• Procedures
• Spirometry
• Drug Resonsiveness
• Asthma Medical Questionnaire
• IgE measurements
• Genetic Testing

UCSF
25
GALA Recruitment

• January 2003
• Families Matched Controls
• San Francisco 201 200
• New York 135
• Puerto Rico 250 250
• Mexico City 100
• total 686 families 450 controls

26
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

27
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 (95CI 1.6, 4.3 plt0.001)
• Asthma-related hospitalization,
• OR of 1.94 (95CI 1.2, 3.2 p0.009)

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Baseline Spirometry
Puerto Ricans
p - value
Mexicans
Baseline spirometry
N 290
N 343
0.0001
83 (74 93)
90 (77 100)
FEV1 Predicted
0.03
94 (83 105)
97 (86 109)
FVC Predicted
0.006
92 (87 99)
90 (82 97)
FEV1/FVC Predicted
0.0004
71 (56 88)
64 (48 81)
FEF25-75 Predicted
lt0.0001
95 (81 107)
80 (67 94)
PEF Predicted
29
Bronchodilator Response to Albuterol Stratified
by Age
p0.0003
P0.0002
after albuterol
14
12
10
1
8
6
4
Reversibility in FEV
2
0
Puerto Ricans
Mexicans
Puerto Ricans
Mexicans
gt 16 years old
lt 16 years old
30
Bronchodilator Response to Albuterol Stratified
by Severity
p0.0001
plt0.0001
after albuterol
14
12
10
1
8
6
4
Reversibility in FEV
2
0
Puerto Ricans
Mexicans
Puerto Ricans
Mexicans
Moderate-severe asthma
Mild asthma
31
GALA b2AR Genotypes and Bronchodilator Response
32
IL-13 Causes b-Adrenergic Hyporesponsiveness
33
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 gt 5, 59 haplotypes
• Only one haplotype common to all three
  populations
• Private Haploypes African Americans 85
  Puerto Ricans 44 Mexcians 40

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IL-13 SNPs Asthma in Puerto Ricans
-Log P-Value
35
IL-13 Haplotypes Asthma in Puerto Ricans
36
IL-13 is Associated with Drug Response
IL-13
IL-13
IL-13
IL-13
IL-13
IL-13
IL-13
IL-4
IL-4
SNP
1
2
3
4
5
6
7
1
2
Promoter
Promoter
Intron
Intron
All
bp location
Promoter
3'UTR
Intron
Promoter
Intron
FEV1 pre percent of predicted
0.00958
n.s.
n.s.
n.s.
n.s.
0.03292
n.s.
n.s.
0.003246
0.00698
Delta FEV1
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
0.000367
Puerto Rican
FEV1 pre percent of predicted
0.038336
0.02387
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
0.029767
Delta FEV1
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
0.003089
0.053
Mexican
FEV1 pre percent of predicted
n.s.
n.s.

n.s.
n.s.
0.045495
n.s.
n.s.
Delta FEV1
n.s.
n.s.

n.s.
n.s.
0.045894
n.s.
0.08
37
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
  0.040.000003)
• 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

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Is Race a Social or Biologic Construct?

• Strict biologic construct Sex

Although these forces are not biologic in nature,
racial and ethnic categories differ from each
other genetically, which has biologic
implications
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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

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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

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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
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Thank You

• 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

• 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

• 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