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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