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 SF UCSF
Race/ethnicity in the US
(Projected for 2010-2050)
100 Percent
53%
47%
80
60 40 20
0
1970
1990
2000
2010
2020
2030
2040
2050
Total
White
Black
Hispanic
API
Am Ind/AN
UCSF
3,899 SNPs in 313 genes in 4 U.S. racial groups
3000 2500 2000 1500 1000 500 0
m er ic an Ca uc as ia n A si an A m er ic an
Common to:
1 group 2 groups 3 groups 4 groups
# SNPs
A fr ic an
A
La ti no
UCSF
3000 2500 2000 1500 1000 500
3,899 SNPs in 313 genes in 4 U.S. racial groups
Common to:
1 group 2 groups 3 groups 4 groups
# SNPs
0
ca n an A si au ca si er i A m er La ti no ic an an C
A fr
ic an
A m
UCSF 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 2500 2000 1500 1000 500
Common to:
1 group 2 groups 3 groups 4 groups
# SNPs
0
ca n an A si au ca si er i A m er no ic an an C
ic an
A m
UCSF
A fr
La ti
Alzheimer's Disease and APOE e4 gene
6 5
Relative Risk of Heterozygote Allele
5.6
4 3
2 1
3
1.1
0
Japanese Caucasian
African American UCSF
Alzheimer's Disease and APOE e4 gene
20
15
Relative Risk of 10 Heterozygote Allele 5
9%
Allele Frequency
14%
19%
5.6
3
1.1
0
Japanese Caucasian African American
UC SF UCSF
HIV Disease and CCR5 delta 32 genetic variant
30 25 20
Frequency 15 of Delta32 Allele 10
25%
5 0
Caucasian
<1%
African American
UC SF UCSF
Cardiac Arrhythmia & SCN5A genetic variant
12% 10%
Frequency of Y1102 Allele
10.1%
6.8%
8% 6% 4%
2%
0%
West African / Caribbeans African American
0%
Caucasian
UC SF UCSF
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
UCSF
Peak Expiratory Flow Rate
Forced Expiratory Volume1 (FEV1) Exhalation
Forced Vital Capacity (FVC)
Volume (L) Inspiration
UCSF
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 TT CT CC
Fraction of Group
T = mutant allele C= normal or wildtype allele
108
120
FEV1 (% of Predicted)
UCSF
132
12
24
36
48
60
72
84
96
0
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% 50% 40% 30% 20% 10% 0%
54%
18%
Caucasians
African Americans
14.0%
HHANES Asthma Point Prevalence
12.0%
11.2%
10.0%
8.0% 6.0%
5.2% 3.3% 2.7%
5.9%
4.0%
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 30 20 10 0
40.75
40.9
11.3
Mexican
15
Caucasian
African Puerto Rican American UCSF
Genetic Origins of Hispanic Groups
100% 90% 80% 70%
7 24
52
Percent Ancestral Contribution Admixture
19
60% 50% 40% 30% 20% 10% 0%
African Native American European
57 41
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
Case : control
=affected
=unaffected
=unspecifiedUCSF
100%
80%
60%
40%
20%
Puerto Rican Volunteers
1
4
7
22
10
13
16
19
28
31
34
37
40
46
49
55
58
64
67
70
73
76
82
85 88
25
43
52
61
Percent racial admixture
100% 80% 60% 40%
Individual subjects 1-90
Mexican Volunteers
European Native American African
20%
7
10
13
16
19
22
25
28
31
34
37
40
43
46
52
55
58
61
64
67
70
73
76
79
82
49
85
4
Individual subjects 1-93
UCSF
91
0%
1
79
88
0%
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 Families 201 135 250 100 Matched Controls 200
250
total
686 families
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
Puerto Ricans
Baseline spirometry FVC % Predicted
FEF25-75 % Predicted
Mexicans p - value
N = 343
N = 290
90 (77: 100)
FEV1 % Predicted 83 (74: 93)
0.0001
94 (83: 105) 97 (86: 109) 64 (48: 81) 71 (56: 88) 80 (67: 94) 95 (81: 107)
0.03
0.006 0.0004
FEV1/FVC % Predicted 90 (82: 97) 92 (87: 99)
PEF % Predicted
<0.0001
UCSF
% Reversibility in FEV1 after albuterol
Bronchodilator Response to Albuterol Stratified by Age
14 12
P=0.0002
p=0.0003
10
8
6
4
2 0
Puerto Ricans Mexicans Puerto Ricans Mexicans
< 16 years old
> 16 years old UC
SF
% Reversibility in FEV1 after albuterol
Bronchodilator Response to Albuterol Stratified by Severity
p<0.0001
p=0.0001
14 12 10 8 6 4 2 0
Puerto Ricans
Mexicans
Puerto Ricans
Mexicans
Mild asthma
Moderatesevere asthma UC SF
GALA b2AR Genotypes and Bronchodilator Response
loci -709 -654 -47 46 79 252 491 523
0.02 0.012 n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Puerto Rican
FEV1 % of predicted pre albuterol FEV1 % of predicted post albuterol %Delta FEV1
* * * n.s. n.s. n.s. n.s. 0.033 n.s. 0.009 0.021 0.006 0.035
Mexican
FEV1 % of predicted pre albuterol FEV1 % of predicted post albuterol %Delta FEV1
* * * n.s. n.s. n.s. n.s. 0.025 n.s. 0.033 n.s. n.s. n.s. n.s. n.s. 0.04 0.023 0.019 n.s. n.s. n.s. 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
I
J
K
Individual SNP
UCSF
IL-13 Haplotypes & Asthma in Puerto Ricans
-Log P-Value
7 6 5
4
3 2 1 0 ABC BCD CDE DEF EFG FGH GHI HIJ IJK
Three SNP Haplotypes
UCSF
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
All
SNP # bp location % Delta FEV1
Promoter Promoter Intron Intron Promoter 3'UTR Intron Promoter Intron
0.00958
1
2
3
4
5
6
7
1
2
FEV1 pre percent of predicted
n.s.
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.
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. 0.029767 n.s. n.s. n.s. n.s. 0.0030890.053 n.s.
n.s. n.s.
Mexican
FEV1 pre percent of predicted
% Delta FEV1
n.s. n.s.
n.s. n.s.
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
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
Neil Risch
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