Transcript Document

WHAT HAVE WE
LEARNED FROM
GENETICS?: THE
STRONG HEART
STUDY
4/11/08
LYLE BEST, MD
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
GENETIC APPROACHES
• 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 ?”
GENE HUNTERS AT WORK
Karyotype
copyright©1999
Children’s Health Care System
SINGLE NUCLEOTIDE
POLYMORPHISM...”SNP”
SINGLE NUCLEOTIDE
POLYMORPHISM...”SNP”
• THERE ARE “AT
LEAST” 15,000,000
DIFFERENT “SNPs”
THAT CAN VARY
BETWEEN
INDIVIDUALS
• PROBABLY MOST
HAVE NO EFFECT ON
OUR BIOLOGY
RECOMBINATION
• 2 SNPs CAN BE
SEPARATED DURING
THE PRODUCTION OF
SEX CELLS (eg SPERM
AND EGGS)
• THIS IS A NORMAL
PROCESS
• HAPPENS 2 OR 3
TIMES FOR EACH
CHROMOSOME
RECOMBINATION
• “ABCDEFGH” IS
CALLED THE
“HAPLOTYPE” OR A
“BLOCK” OF SNPs
• “A” AND “H” ARE
MORE LIKELY TO BE
SEPARATED THAN “A”
AND “B”
• OVER GENERATIONS
THE “BLOCKS” GET
SMALLER
RECOMBINATION
• IF “E” IS A DISEASE
CAUSING SNP
• OVER MANY
GENERATIONS, IT IS
MORE LIKELY TO
TRAVEL WITH “D” OR
“F” THAN WITH “A OR
“H”
• THE STRONG
HEART STUDY
APPROACH:
• GENOME-WIDE
LINKAGE STUDY
• FAMILY BASED
• 400+ “MARKER” SNPs
ON ALL 23 PAIRS OF
CHROMOSOMES
• DOESN’T REQUIRE
“GUESSING” WHICH
GENE TO TEST FOR
EFFECTS
WHERE IT ALL STARTS
LINKAGE STUDIES
• EACH OF THESE
PUZZLE PIECES
REPRESENTS AN
INHERITED “BLOCK”
OF SNPs
• A DISEASE-CAUSING
GENE MAY TRAVEL
WITH ONE OF OUR
“MARKER” SNPs
LINKAGE ANALYSIS
GWAS!!....GEEwhat??
• GENOME-WIDE
ASSOCIATION
STUDY
• THE LATEST
“REVOLUTION” TO
HIT GENETIC
EPIDEMIOLOGY
• WHY IS IT
IMPORTANT?
“GWAS”
50-100 per family
100,000 or more
“GWAS”
400+ SNPs
Up to 2,000,000 SNPs
GWAS
• THINK OF THE WHOLE HUMAN RACE AS A BIG
FAMILY
• INSTEAD OF HAPLOTYPE “BLOCKS” THAT ARE
10-15 MILLION BASE-PAIRS LONG
• THINK OF “BLOCKS” THAT ARE 10-15
THOUSAND BASE-PAIRS LONG
• STATISTICAL STANDARDS (p-values) much higher
• MAY MISS RARE SNPs WITH BIG EFFECTS
• GENETIC BACKGROUND MORE VARIABLE
GWAS
• NIH FUNDS MOST
BIOMEDICAL
RESEARCH IN THE US
• INCLUDING SHS
• INSIST ON WORLDWIDE SHARING OF
DATA IF THEY FUND
GWAS STUDY
• MANY TRIBES CLAIM
OWNERSHIP OF DATA
GWAS
• DR. ERIC TOPOL
REPORTED PLANS
FOR GWAS STUDY OF
TRIBES IN SAN DIEGO
AREA
• TARGET: GENETICS OF
ADDICTIVE BEHAVIOR
• TRIBAL
GOVERNMENTS SAID
TO BE SUPPORTIVE
GWAS
• PUBLIC CORPORATION
• TRADED ON NASDAQ
• AGREEMENT WITH
GOVERNMENT OF
ICELAND TO ACCESS
MEDICAL RECORDS
• ICELANDERS MUST
“OPT OUT”
• DEVELOPED DRUGS
WILL BE PROVIDED
FREE TO ICELAND
TYPE 2 DIABETES
• NOVEL GENE (TCF7L2)
DISCOVERED BY deCODE
• CONFIRMED IN OTHER
STUDIES
• 2 “T” ALLELES INCR RISK FOR
T2D 1.8X (~5 to 10% per year)
• EVEN THOSE WITH GENETIC
RISK, HELPED BY LIFESTYLE
CHANGES/MEDS
• IF YOU DIDN’T HAVE GENETIC
RISK, WOULD YOU WANT TO
IGNORE BASELINE RISK?
• $300
9p21 SNP AND MI
• ABOUT 20-25% OF
CAUCASIAN
POPULATION HAVE 2
“G” SNPs
• RISK OF MI OVER 20
YEARS INCR FROM
13% TO 17%
• NOT RELATED TO
CHOLESTEROL ETC
9p21 SNPs AND MI AND
DIABETES!..?
CLOSE BUT NO CIGAR!
PHARMACOGENETICS
• FARM...WHAT?
• STUDY OF HOW
OUR GENES
AFFECT THE WAY
WE REACT TO
DRUGS
• FIRST
DOCUMENTED IN
1950s
PHARMACOGENETICS
• THERAPEUTIC
“WINDOW”
• TOO LITTLE...NO
HELP
• TOO
MUCH...COMPLICATIONS
• DIFFERENT PEOPLE
... DIFFERENT
WINDOWS
PHARMACOGENETICS
• INH EXTREMELY IMPORTANT
FOR CONTROL OF
TUBERCULOSIS
• ABOUT 60% OF CAUCASIAN
POPULATION “SLOW
ACETYLATORS”
• REDUCED METABOLISM OF INH,
SULFA DRUGS, THEOPHYLLIN,
PROCAINAMIDE
• CAUSES TOXICITY
• DRUG INTERACTIONS
PHARMACOGENETICS
• CHEMOTHERAPY DRUGS
SUCH AS AZATHIOPRINE
AND MERCAPTOPURINE
• METABOLIZED BY TPMT
GENE
• 2 NON-FUNCTIONING
ALLELES ~ 100% RISK
OF FREQUENTLY FATAL
REACTION
• GENOTYPING NOW
AVAILABLE
PHARMACOGENETICS
• CYP2D6 GENE
STRONGLY AFFECTS
METABOLISM OF OVER
30 DIFFERENT DRUGS
• ABOUT 10% WILL NOT
DERIVE PAIN RELIEF
FROM CODEINE SINCE IT
MUST BE CONVERTED
TO MORPHINE
• GENECHIP NOW
AVAILABLE
PHARMACOGENETICS
• COUMADIN THERAPY
• VERY “NARROW
WINDOW”
• 2 GENES (CYP2C9 AND
VKORC1) SEEM TO
CONTROL ABOUT 60% OF
THE VARIATION IN
RESPONSE TO COUMADIN
• TESTS UNDER WAY TO
VERIFY THEY IMPROVE
CARE
GENE…ENVIRONMENT
Difference in BMI
P=0.007
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
-0.2
PASSIVE
SL ACTIVE
VERY ACTIVE
NS
TT vs AT
TT vs AA
• rs9939609 SNP
• FTO gene
• Associated with
type II DM
• DM not associated
if adjusted for BMI
• Effect on BMI seen
only in those with
minimal physical
activity
GENE…ENVIRONMENT
Fasting Triglyceride
(mmol/L)
P=0.0003
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
NS
SMOKERS
NONSMOKERS
TT
TC & CC
• APOA5 gene
• “T1131C” SNP
• Non-coding
• 7% C allele
• RR 2.5 for
hyperlipidemia
• Highly predictive
of FBS
• BUT….look at
interaction with
smoking!
• WHAT ABOUT THE
STRONG HEART
STUDY GENETIC
RESULTS?
LEFT VENTRICULAR
HYPERTROPHY
• THICK HEART WALL
ON LEFT (LVH)
• CAUSES:
– HYPERTENSION
– VALVE PROBLEMS
• HARD FOR
CORONARY
ARTERIES TO
PENETRATE
• NOT CAUSED BY
EXERCISE
Strong Heart Family Study:
Prevalence of LVH by Age
60.0
50.0
40.0
30.0
20.0
10.0
0.0
2nd
3rd
4th
5th
6th
7th
8th
SHS Family Study - Decade of Age
9th
SHS LINKAGE RESULTS
• LV Mass
– Chromosome 12p
– Arizona and Dakotas; but not Oklahoma
– Goring HH et al, in press
• Obesity
– Chromosome 4q35
– Goring HH et al, 2007
• Components of metabolic syndrome
– Hypertension: Chromosome 1
– Elevated lipids: Chromosome 12
– North KE et al, 2005
SHS LINKAGE RESULTS
• Systolic Blood Pressure
–
–
–
–
–
Chromosome 17q25
In women but not men
8 SNPs tested in region
UTS2R gene SNP effects kidney function
Franceschini N et al, 2006 and in press
• ? Specific to Dakotas ?
– LDL Cholesterol: Chromosome 19q13
– North KE et al, 2006
– Obesity: Chromosome 2p
– Diego V et al, 2006
SHS LINKAGE RESULTS
• Kidney Function (Glomerular filtration rate)
• Chromosome 12
• Mottl A, in press