Transcript Epigenetic correlates of human socioeconomic status

Epigenetic correlates of human
socioeconomic status
Clyde Hertzman
Gradient in all Cause Mortality:
UK Whitehall Study (1980s)
CHD Mortality - UK Whitehall Study
The Challenge of the Gradient
• ubiquitous in wealthy and majority world countries
by income, education, or occupation
• cuts across a wide range of disease processes
• not explained by traditional risk factors
• replicates itself on new conditions as they emerge
• occurs among males and females
• ‘flattens up’
• begins life as gradient in ‘developmental health’
Sensitive Periods in Early Brain
Development
Pre-school years
High
School years
Numbers
Peer social skills
Language
Symbol
Habitual ways of responding
Emotional control
Vision
Hearing
Low
0
1
2
3
4
Years
5
6
7
Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.)
% Vulnerable
Canada: % vulnerable by SES
Source: NLSCY/UEY 1999-2000; EDI 1999-2000
% Vulnerable
% Vulnerable
Jamaica: % vulnerable by SES
SES
% Vulnerable
Kosovo: % vulnerable by SES
Life Course Impacts of Early
Experiences
2nd
Decade
• School Failure
3rd/4th
Decade
• Obesity
5th/6th
Decade
Old Age
• Coronary Heart • Premature
Disease
Aging
• Teen Pregnancy • Elevated Blood
Pressure
• Diabetes
• Criminality
• Depression
• Memory Loss
Hypothesis: Biological
embedding
Biological embedding occurs when
• experience gets under the skin and alters human
biodevelopment;
• systematic differences in experience in different
social environments lead to different
biodevelopmental states;
• the differences are stable and long-term;
they influence health, well-being, learning, and/or
behaviour over the life course.
Archeology of Biological Embedding
Quic kTime™ and a
GIF dec ompres sor
are needed to s ee this pic ture.
Experience/Behavior
Neural Circuitry
Cell/Synapse
Gene Expression
Shallow Archeology
Candidate Systems
• HPA axis --- cortisol
• ANS system --- epinephrine/ne
• Prefrontal cortex
• Social affiliation --amygdala/locus cereleus
• Immune function -- the ‘peripheral
brain’
Candidate System: Prefrontal Cortex
SES Differences by School Age
Deep Archeology
‘Social Epigenesis’ and other
processes that can influence
gene expression.
Biological Embedding: The ‘MeaneySzyf Paradigm’
• rat pups from high and low licking/suckling
mothers cross-fostered to remove genetic
effect
• differential qualities of nurturance occurs
during sensitive period of brain
development
• differential nurturance leads to epigenetic
modification of key DNA regulatory loci
through methylation
The ‘Meaney-Szyf Paradigm’ (cont’d)
• epigenetic modification leads to lifelong
change in HPA axis response to stress
• this change affects learning and behaviour
across the rat life course
• inter-generational transmission (high licked
female pups become high licking mothers,
and vice versa)
The Opportunity
If early experience really does ‘get under the skin’ to
influence brain and biological development
through epigenetic processes, then:
• similar environments & experiences should leave a
consistent set of epigenetic ‘marks’ on different
populations, and/or create great opportunities for
understanding gene-environment-epigenetic
interplay.
• the variation in epigenetic marks in children from
diverse environments (& experiences) globally
should teach us a great deal about biological
embedding.
SES, Life Course and Epigenesis: An
Hypothesis Generating Study
• The opportunity: 1958 British Birth Cohort (>17,000
members at birth), with >4000 phenotypic variables
collected at birth and 7 follow-ups, with fresh
lymphocytes collected at age 45.
• The goal: to identify a full range of gene loci where
experience may have become ‘biologically embedded’
through methylation.
• Done to date: examined >20,000 regulatory regions of
40 cohort members, sampled according to a factorial
design, based upon extremes of SES in childhood
and adulthood (also, abuse and maternal smoking)
The Team
• Population health/life course epidemiology:
Clyde Hertzman, Chris Power
• Epigenetics: Moshe Szyf, Marcus Pembry
• Bio-informatics: Michael Hallett, Matt
Suderman
• Laboratory: Nada Borghol
So far:
• 1252 loci differentially methylated
according to childhood SES (smaller
signatures for adult SES and social
mobility)
• 794 loci differentially methylated by
maternal smoking
• Approx. 4000 loci differentially
methylated by retrospective reports
of abuse in childhood
1958 Cohort
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Replication
Expression??
Gene analysis
Exploit 4000 phenotypes with larger
sample sizes
Consistency in different
populations?
The Wisconsin Study of Families and Work
The BC GECKO Study: ‘On and Off-diagonal
children’ in ‘On and Off-diagonal
neighbourhoods’
Developing country studies
Is this the way forward?
Exposure
Endophenotype
Abuse
Mid- Brain
affiliation/attachment
PFC
executive function/
impulsivity
Epigenome
Phenotype
Health behaviors
Mental health
HPA
stress response
Chronic diseases
Exposure
(Prenatal)
Maternal
Smoking
Epigenome
Biochemical Phenotype
/Biophysical
Pathway
Exposure Specific
Pathways
Common Pathways
Childhood
Abuse
Childhood
SES
Exposure Specific
Pathways
Exposure Specific
Pathways
Outcome(s)
www.earlylearning.ubc.ca