The African Diaspora: An opportunity to study geneenvironment interaction.

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The African Diaspora An opportunity to study
gene-environment interaction. The African
Society of Human Genetics
Charles N. Rotimi, Ph.D. Director, Genetic
Epidemiology National Human Genome
Center Department of Microbiology, College of
Medicine Howard University
The AFSHG Accra 12/08/03
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A young boy watching his father review his report
card What do you think the trouble with me is,
Dad? He ask with artful innocence. Heredity
or environment? Half a century ago in The New
Yorker
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Genetic Epidemiology of Complex Diseases
Genetic factors contribute to virtually every
human disease by way of increased Susceptibility
Resistance Affect the severity or
progression of disease Understanding genetic
contribution to disease will revolutionize Diagn
osis Treatment Prevention Facilitate
understanding of the role of environmental
factors
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Genetic Epidemiology
The analysis in large populations of the
interactions of gene, genetic variation and
environment. Nature 1990, 402467-8 Broad
goal To understand the complex interaction
between multiple genes and environmental factors
in the etiology of diseases in human populations
with the ultimate goal of disease control and
prevention.
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Complex Diseases
Characteristics 1. Aggregate in families but do
not segregate in mendelian fashion 2. Multiple
genes with varying genetic contributions 3. M
ultiple environmental factors 4. Complex
interplay between genetic and environmental
factors 5. Highly context dependent 6. Susceptib
ility as opposed to determinism 7. Requires
integrated approach (not reductionism) 8. Example
s hypertension, diabetes and cancer
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Consequences of complexity

• One size-fits-all strategy will have limited
  success.
• Quick and easy solutions are likely to be
  inadequate.
• Unpredictable patterns of presentation are likely
  The sum of the whole is likely to be greater
  than the sum of its parts.
  - The whole is likely to
  be different from the sum of the parts
• Interaction between pathways within the context
  of the entire system (multiple genes) under a
  variety of situations (context dependent) will be
  necessary to understanding the etiology of
  complex diseases

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Consequences of complexity

• Special challenges that make gene discovery more
  difficult for complex diseases
• Locus heterogeneity
• Epistasis
• Low penetrance
• Variable expressivity
• Pleiotrophy
• Limited statistical power

Glazier et al. Science 2002
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The African Diaspora Map

The Principal trade and slave routes
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The African Diaspora Opportunity to Study the
Thrifty Genotype hypothesis
TRADITIONAL SOCIETY
MODERNIZED SOCIETY
FEAST FAMINE
FEAST
THRIFTY GENOTYPE
MAXIMUM METABOLIC EFFICIENCY
HYPERINSULINAEMIA OBESITY BETA- CELL
EXHAUSTION
SURVIVAL
DIABETES
The interaction between the thrifty genotype
and lifestyle. Zimmet et al 1990.
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Our Culture
Our Genome
Who are we? How are we related? Why ill
health? Why differential distribution of diseases?
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Variation
Environment
Genes

• Diet (e.g., high salt intake)
• Physical activity
• social stressors (e.g., racism)
• Injuries (e.g., trauma, guns)
• Education
• income

• HbS, CF, HFE
• CARD15 gene
• NAT2 (N-aceytltransferase 2)
• APO-E
• IL-6 variant
• Factor VII gene
• CYP2C19

Complex
simpler
simpler
Phenotype Sickle cell disease Cystic
Fibrosis Hemochromatosis
Phenotype Burns
trauma
Phenotype Hypertension Diabetes Cancer
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Prevalence of Hypertension by Mean Body Mass
Index Among Populations of the African Diaspora
North America
Caribbean
West Africa
Cooper R, Rotimi C. et al. AJPH. 1997
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Prevalence of Hypertension (140/90 mmHg) by Age
in Rural and Urban Nigeria Men and Women
.6
Urban
.5
.4
Prevalence
.3
Rural
.2
.1
0
25
35
45
55
65
75
85
Age in Years
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Synergistic effect of Head Injury and APOEE4 on
the Risk of Alzheimer
Source Mayeux et al (1995) on page 398 in
Approach to Gene Mapping in Complex Human Diseases
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CHD risk by ApoE genotype and smoking
Dave Flavell PhD
Smoker
E4 163/21
E2 98/5
E3E3 367/5
Never-Smoker
apoE-smoking interaction p0.02
727/32
Smoking increases unadjusted risk in E3E3 by 68
but by gt 3 fold in E4 group
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Genetics and Environment Dave Flavell PhD

• Heart disease is a lifestyle disease
• Epidemiological studies show that e.g.
• smoking and high fat diet increases risk
• exercise protects against heart disease
• Genetics explains the indestructible granny -
  smokes Woodbines, drinks, and eats fried
  breakfasts, lives to 100

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Integrated Epidemiology
Detailed phenotypic characterization represents
the future challenge
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Pathophysiology of Hypertension Integrated
Approach
Obesity

Environmental Factors
Diet High in Sodium
Stress
Genetic Factors (Susceptible Individuals)
Intermediate Phenotypes
(eg - Angiotensinogen-ACE)
Hypertension
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Gene-Environment Interaction
BP MG AG EF ER
(SGxE) Where MG is the influence of a major
gene AG is the influence of (additive) polygenic
effects EF represents the influence of familial
environment ER is the influence of random
environment and (SGxE) is the interaction
between environmental and genetic factors.
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Gene-Environment Interaction
Freguency
0absent 1present
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Interpretations

• ORe gt 1 exposure exerts an affect even among
  persons without genotype.
• ORg risk associated with genotype in the absence
  of environment.
• If ORg 1 genotype requires the environmental
  trigger to increase disease risk.
• If ORg gt 1 genotype independent of the exposure
  increases risk
• If ORg lt 1 genotype is protective in the absence
  of the specific environmental factor.
• ORge risk associated with both genotype and
  environmental exposure.
• Additive model ORge ORg ORe - 1
• Multiplicative model ORge ORg x ORe.
• OR for susceptibility genotype compared to those
  without is
• OR(1-Pe) ORg PeORge/(1-Pe) PeORe
• Where Pe is population exposure frequency to
  the environmental factors

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Understanding genetic and environmental
determinants of complex diseases Opportunities
Presented by the African Diaspora

• One of the oldest and largest migration in
  history (founding population for modern African
  Americans).
• Graded and highly varied risk patterns exist in
  the present day populations of the African
  Diaspora. Extremes of disease distributions are
  represented.
• Broad genetic resemblance exists among
  contemporary populations. Varying degree of
  genetic admixture construction of genetic maps.
• Large family size especially in Africa and the
  Caribbean

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Opportunities Presented by the African Diaspora

• High participation rate from well defined and
  stable communities
• Low rate of treatment
• Optimum design to study gene by environment
  interaction
• Evolutionary oldest human population may provide
  higher genomic resolution of informative region
  identified from younger populations
• 9. Well-trained and highly motivated biomedical
  researchers.

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Off The Cuff What Question Would You Pose to a
Dead Scientist?
To Charles Darwin Now that you're dead and know
whether there is life after death, do you still
agree with your theory of evolution? --Marian
Blokpoel, Imperial College London
The Scientist October 6, 2003
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The surma bribe from Ethiopia wears a clay lip
plate inserted six months before marriage. The
size of the plates is an indication for the
number of cattle required for her dowry.
The bottle neck in complex disease research will
result from our inability to properly
characterize phenotypic information.