Download Genetics and Strong Heart Study

GENETICS AND STRONG
HEART STUDY
• WHAT IS
GENETICS?
• WHY DO I CARE?
• HOW DOES DNA
WORK?
• WHAT GOOD IS A
GENETICS
RESEARCH
PROJECT?
WHAT IS GENETICS?
• THE STUDY OF
HOW WE PASS
BIOLOGIC
INFORMATION
FROM ONE
GENERATION TO
ANOTHER.
• CULTURAL
INFORMATION IS
DIFFERENT
FINDING DIFFERENCES
•
•
•
•
•
•
•
•
LOOK, TOUCH
STETHOSCOPE
SIMPLE LAB TESTS
CULTURES
X-RAYS
ENDOSCOPES
ULTRASOUND/MRI
GENETIC TESTS
DIFFERENCES IN OUR
ENVIRONMENT
•
•
•
•
CLIMATE
DIET
HABITS
INSECTS AND
ANIMALS THAT WE
LIVE WITH
• TOXINS
DIFFERENCES IN OUR
GENES
• WITHIN FAMILIES
• BETWEEN
FAMILIES
• BETWEEN ETHNIC
GROUPS AND
RACES
• CAN LEAD TO
DIFFERENCES IN
DISEASES
DNA TELLS HOW TO BUILD
A BODY
• HOLDS
INSTRUCTIONS
FOR HOW CELLS
WORK TOGETHER
• OUR CULTURE
AND WHAT WE
THINK AND FEEL
IS DIFFERENT
WHAT IS DNA?
• A CHEMICAL, JUST
LIKE MANY OF
THE OTHER
BUILDING BLOCKS
OF YOUR BODY
• MADE UP OF
SIMILAR UNITS,
LIKE NECKLACE
BEADS
DNA, UP CLOSE
DNA-YOUR BODY’S
ENCYCLOPEDIA
• LIKE LETTERS SPELL
WORDS, FORM IDEAS
• DNA HAS FOUR
LETTERS TO SPELL
WITH, A, T, G, AND C
• INFORMATION
ORGANIZED INTO
CHROMOSOMES
CHROMOSOMES
• LIKE THE BOOKS
IN AN
ENCYCLOPEDIA
• 23 PAIRS IN EACH
CELL
• LOOK LIKE PIECES
OF YARN
• DNA WOULD BE 8
MILES LONG
WHAT IS A GENE LIKE?
F
G
H I
• THE SECTION
ABOUT HORSES
IN THE
ENCYCLOPEDIA
• FOUND IN THE
SAME PLACE
• CAN BE
DIFFERENCES IN
DESCRIPTION
LITTLE CHANGES…..
BIG DIFFERENCE
• ONE LETTER IN
A WORD
• MICE
• RICE
• DICE
• LICE
• ICE
SICKLE CELL ANEMIA
PKU….AN EXAMPLE
NORMAL GENE FOR
DIGESTION
MOM
NORMAL
DIET WITH
JUST
ENOUGH
PROTEIN NORMAL
LEARNING
BABY
DAD
NORMAL
LACKS
GENES TO
DIGEST
PROTEINS
LEARNING HANDICAP
CHROMOSOMES SHUFFLED DURING
EACH MEIOSIS
GENE HUNTERS AT WORK
WHERE IT ALL STARTS
1
2
3
4
5
6
7
8
9
10
11
12
WHO IS THE CULPRIT?
WHO IS THE CULPRIT?
SOMETIMES THEY WORK IN
TEAMS
SOMETIMES THEY WORK IN
TEAMS
THE CULPRIT DOESN’T CAUSE
TROUBLE EVERY TIME
THE CULPRIT DOESN’T CAUSE
TROUBLE EVERY TIME
SOMETIMES THE CUPRITS ONLY ACT
WHEN THE POLICE AREN’T THERE
SOMETIMES THE CUPRITS ONLY ACT
WHEN THE POLICE AREN’T THERE
SOMETIMES THERE IS TROUBLE
AND NO CULPRIT
SOMETIMES THERE IS TROUBLE
AND NO CULPRIT
A TALE OF MICE AND MEN
• EXERCISE IS GOOD
FOR YOU....RIGHT!
• EXERCISE MAKES
HEART AND
MUSCLES
STRONGER....RIGHT!
• SOME KINDS OF
ABNORMAL
EXERCISE CAN
CAUSE INJURY
A TALE OF MICE AND MEN
• THE LEFT HEART
SHOWS CARDIAC
HYPERTROPHY (LVH)
• CAUSES:
– HYPERTENSION
– VALVE PROBLEMS
– GENETIC PROBLEMS
• RIGHT HEART IS
NORMAL
A TALE OF MICE AND MEN
• THE DNA OF MICE
CAN BE
“ENGINEERED”:
– TO MAKE MORE OF A
PARTICULAR GENE
– TO MAKE LESS, OR
NONE OF A GENE
– SOMETIMES IN JUST
ONE TISSUE OF THE
BODY
A TALE OF MICE AND MEN
NORMAL
• AN EXTRA GENE
FOR THE PROTEIN
“CALCINEURIN” IS
ADDED TO THE
MOUSE
• IT IS ONLY
EXPRESSED IN
HEART TISSUE
ADDED
• HEARTS ENLARGE
CALCINEURIN
AND FAIL
GENE
A TALE OF MICE AND MEN
NORMAL
ADDED MCIP
GENE
• AN EXTRA GENE,
“MCIP” ADDED TO A
NORMAL MOUSE
• IT CONTROLS THE
EXPRESSION OF
CALCINEURIN
• HEARTS ARE 10%
SMALLER, BUT
ANIMALS ARE
HEALTHY
A TALE OF MICE AND MEN
NORMAL
• WHEN AN EXTRA
MCIP GENE IS
PRESENT:
• HEARTS DON’T
ENLARGE FROM AN
EXTRA
CALCINEURIN GENE
CALCINEURIN
AND MCIP
• MICE LIVE NORMAL
GENES ADDED
LIVES
A TALE OF MICE AND MEN
• ULTRASOUND
IMAGES OF MOUSE
HEARTS AT WORK
• LOOK AT THE BIG
SPACE BETWEEN
THE TWO SIDES OF
THE HEART IN THE
MIDDLE PICTURE
• THAT MOUSE HAS
AN ENLARGED
HEART
A TALE OF MICE AND MEN
• MOUSE HEARTS CAN
ALSO ENLARGE AND
FAIL WHEN “GIVEN”:
– HYPERTENSION
– STIMULATING
MEDICINES
– ABNORMAL VALVES
• AN EXTRA MCIP GENE
PREVENTS THIS AND
GIVES NORMAL LIFE
A TALE OF MICE AND MEN
• ENLARGEMENT OF THE
HEART (LVH) IS A RISK
FACTOR FOR HEART
DISEASE
• SOME ANTIHYPERTENSIVES
PREVENT LVH
• CAN WE FIND
MEDICINES THAT MIMIC
THE EFFECT OF MCIP
GENE?
THE PROBLEM
• At least 30,000 genes
• Among 3 BILLION base-pairs of
the human genome.
• Genes interact with the
environment
• Genes interact with each other
• Environmental influences alone
can cause disease
• Chance plays a role
SHS GENETIC RESULTS
• Heritability
– “Does genetics play a role in
this situation? If so, how big a
role?”
• Linkage
– “Can we find small pieces of
chromosomes that are strongly
influencing an effect?”
• Candidate gene
– “We think it is a good bet that
this particular gene is a factor
in X condition. Are these
variations in this particular
gene associated with X ?”
HERITABILITY
• There are a series of church
fires in Ohio. Why?
• Could they all be accidents?
– All are heated with natural gas
– There seem to be twice as
many church fires as there are
in other buildings heated with
gas
– Seems like some fraction of
these fires are not just due to
gas leaks
LINKAGE
• At three of the fires the
police found a wallet
containing IDs
– Conclusion: Clumsy
Criminals
– None of the IDs belonged to
people in the town or the
church
– On questioning, all three
admitted to arson
– None of the three knew
each other
CANDIDATE GENE
• Police were also aware
of a local Neo-Nazi
group that had sent
threats to many of these
churches
– The leader and a couple
adherents were brought
in for questioning
– 2 of them confessed to
arson, 1 had a verified
alibi
HERITABILITY
• HERITABILITY IS THE
PROPORTION OF
VARIANCE DUE TO
GENETICS
• SHARED
ENVIRONMENT
EXPLAINS A
PROPORTION OF
VARIANCE
• CHANCE THE REST
SELECTED HERITABILITIES
• Aortic Root diameter=51%
– Bella JN et al, 2002
• Carotid artery diameter=44%
– North KE et al, 2002
• Various CVD risk factors: following slide
– North KE et al, 2003
• LV mass=17%, LV end diast diameter=33%
– Bella JN et al, 2004
• CRP=46%
– Best LG et al, 2004
Heritabilities for CVD Risk
Factors
Strong Heart Family Study
Phenotype
BMI
WHR
LDL-C
HDL-C
lnTG
SBP
F Glu
ln Ins
ln Fibrinogen
Proportion of Variance
Due to Genes
%
SE
44
54
39
50
40
23
29
44
23
0.07
0.07
0.06
0.07
0.07
0.06
0.08
0.08
0.06
HERITABILITY: CAUTION
• Heritability is the fraction of
the TOTAL variation in the
population that is due to
genetic factors
• SO....If there is less
environmental variance, the
proportion due to genetics will
be increased
• If there is less genetic
variance, the environmental
proportion will be increased
• What if the population
consisted of identical twins??
HERITABILITY: CAUTION
• Heritability is the fraction of the
TOTAL variation in the population
that is due to genetic factors
• SO....If there is less
environmental variance, the
proportion due to genetics will be
increased
• If there is less genetic variance,
the environmental proportion will
be increased
• What if available food for the
population was severely
restricted?
SHS LINKAGE RESULTS
• Components of metabolic syndrome
–
–
–
–
Obesity, insulin etc: Chromosome 4
Hypertension: Chromosome 1
Elevated lipids: Chromosome 12
North KE et al, 2005
• LV Mass
– Chromosome 12p
– Arizona and Dakotas; but not Oklahoma
– Goring HH et al, in press
SHS CANDIDATE GENE
Mannose Binding Lectin
•
•
•
•
•
•
•
SERUM PROTEIN, PRODUCED BY LIVER
OPSONIZES BACTERIA, YEAST ETC
ACTIVATES COMPLEMENT
“INNATE” IMMUNE SYSTEM
ASSOCIATED WITH INCR INFECTIONS IN CERTAIN GROUPS
DECREASED INFECTION WITH MYCOBACTERIA
1998 LANCET: REL RISK 4.9 FOR CABG WITH
HOMOZYGOUS MBL LOWERING ALLELES
• TWO ADDITIONAL CASE/CONTROL STUDIES, + AND –
• WORLD WIDE, APPROX 20% GENOTYPES FOR LOW-MBL
• SHS COHORT: 15.7% GENOTYPES FOR LOW-MBL
MANNOSE BINDING LECTIN
CARBOHYDRATE
BINDING
AREA
THREE
IDENTICAL
CHAINS
FROM 2 TO 6 SUBUNITS
IN FUNCTIONAL
PROTEIN
MANNOSE BINDING LECTIN
COMPARING LOW-MBL GENOTYPE WITH
HIGH-MBL GENOTYPE, ALL P<0.006
4
3
ODDS
2
RATIO
1
0
CVD
UNADJUST
CVD MORT
MULTIVARIATE
NOTE: MY FORMAL PRESENTATION ENDED HERE
IN OKLAHOMA CITY AT THE SHS ORIENTATION
PROGRAM. I HAVE SOME OTHER SLIDES THAT
FOLLOW WHICH MAY OR MAY NOT BE OF USE
TO FOLKS.
ONE STRAND OF DNA STRETCHED FROM
SEATTLE TO WASHINGTON, DC
(Nucleotide letters as big as 12 point font)
STRETCHED THROUGH NORTH
DAKOTA
STRETCHED THROUGH
JAMESTOWN, N.DAKOTA
RIGHT DOWN THIS COUNTRY
ROAD
RIGHT AROUND THIS CORNER
NOW WE CAN JUST START TO
SEE THE LETTERS
THE CHROMOSOMES ARE LAID END
TO END
GENES FROM SEATTLE TO
DC
• NORMAL PRINT:
ABOUT 16 LETTERS
PER INCH
• AVERAGE GENE IS
ABOUT 25 FEET
LONG
• SHORTEST ABOUT 2
FEET
• LONGEST ABOUT 2
MILES
ADDRESS: GENE
HOUSE: ALLELE
RECOMBINATION:
SEISMIC EVENTS
RECOMBINATION:
AFTER THE QUAKE
HOW DOES GENETICS
HELP?
• DIFFERENT DISEASES,
DIFFERENT DEGREES OF
HELP
• SICKLE CELL ANEMIA:
• THE DISORDER IS VERY
WELL UNDERSTOOD
• NEW TREATMENTS, BUT
NO CURE
• MORE ACCURATE
DIAGNOSIS
• SCREENING FOR
CARRIERS AVAILABLE
HOW DOES GENETICS
HELP?
PKU…AN EXAMPLE
• DIFFERENT
DISEASES,
DIFFERENT DEGREES
OF HELP
• PKU
• VERY GOOD
UNDERSTANDING OF
THE CONDITION
• VERY GOOD
TREATMENT
HOW DOES GENETICS
HELP?
• DIFFERENT DISEASES,
DIFFERENT DEGREES OF
HELP
• HIGH CHOLESTEROL
• 4-5 GENETIC CONDITIONS
• SOME WELL UNDERSTOOD,
SOME NOT
• TREATMENT FAIR
• GENETIC KNOWLEDGE
HELPED DESIGN DRUGS
• DIET PLAYS A ROLE
HOW DOES GENETICS
HELP?
• DIFFERENT DISEASES,
DIFFERENT DEGREES OF
HELP
• BREAST CANCER
• MOST CASES NOT INHERITED
• IN SOME FAMILIES TESTING
CAN DETECT HIGH RISK
• CAN ALLOW WOMEN TO BE
MORE ALERT, TAKE
PREVENTIVE STEPS
• BETTER UNDERSTANDING OF
DISEASE, NEW TREATMENTS
HOW DOES GENETICS
HELP?
• DIFFERENT DISEASES,
DIFFERENT DEGREES OF
HELP
• HUNTINGTON’S CHOREA
• TESTING AVAILABLE, VERY
ACCURATE
• DIAGNOSIS MUCH IMPROVED
• NO TREATMENT
• PREDICTIVE TESTING USED
BY SOME TO PLAN FAMILY,
OTHERS DON’T WANT TO
KNOW
2
(h )
Heritability
of LV Mass
and Geometry in SHS-FS
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
0
LV Mass
LVIDd
RWTd
Overall*
Center*
* Heritability for QTL needed for power = 80% in SHS