WHAT HAVE WE LEARNED FROM GENETICS?: THE STRONG HEART STUDY 4/11/08 LYLE BEST, MD.

WHAT HAVE WE LEARNED FROM GENETICS?: THE

STRONG HEART STUDY4/11/08

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

KaryotypeKaryotype

copyright©1999copyright©1999Children’s Health Care SystemChildren’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 WORLD-

WIDE 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...COMPLICA-TIONS

• 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

• 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

-0.20

0.20.40.60.8

11.21.41.61.8

Diffe

renc

e in

BMI

TT vs AT TT vs AA

PASSIVE

SL ACTIVE

VERY ACTIVE

P=0.007

NS

GENE…ENVIRONMENT

• APOA5 gene• “T1131C” SNP• Non-coding• 7% C allele• RR 2.5 for

hyperlipidemia• Highly predictive

of FBS• BUT….look at

interaction with smoking!

00.20.40.60.8

11.21.41.61.8

2

Fast

ing

Trig

lyce

ride

(mm

ol/L

)

TT TC & CC

SMOKERS

NON-SMOKERS

NS

P=0.0003

• WHAT ABOUT THE STRONG HEART STUDY GENETIC RESULTS?

• THICK HEART WALL ON LEFT (LVH)

• CAUSES: – HYPERTENSION– VALVE PROBLEMS

• HARD FOR CORONARY ARTERIES TO PENETRATE

• NOT CAUSED BY EXERCISE

LEFT VENTRICULAR HYPERTROPHY

Strong Heart Family Study: Prevalence of LVH by Age

SHS Family Study - Decade of Age

9th8th7th6th5th4th3rd2nd

LV

H b

y L

VM

/Ht

2̂.7

(4

6.7

F o

r 4

9.2

M)(

%)

60.0

50.0

40.0

30.0

20.0

10.0

0.0

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