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

2. 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

3. 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 ?”

4. GENE HUNTERS AT WORK

5. Karyotype copyright©1999 Children’s Health Care System

6. SINGLE NUCLEOTIDE POLYMORPHISM...”SNP”

7. THERE ARE “AT LEAST” 15,000,000 DIFFERENT “SNPs” THAT CAN VARY BETWEEN INDIVIDUALS PROBABLY MOST HAVE NO EFFECT ON OUR BIOLOGY

8. 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

9. 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

10. 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”

11. 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

12. WHERE IT ALL STARTS

14. 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

15. LINKAGE ANALYSIS

16. GWAS!!....GEEwhat?? GENOME-WIDE ASSOCIATION STUDY THE LATEST “REVOLUTION” TO HIT GENETIC EPIDEMIOLOGY WHY IS IT IMPORTANT?

17. “GWAS” 50-100 per family 100,000 or more

18. “GWAS” 400+ SNPs Up to 2,000,000 SNPs

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 9p21 SNPs AND MI AND DIABETES!..? CLOSE BUT NO CIGAR!

26. PHARMACOGENETICS FARM...WHAT? STUDY OF HOW OUR GENES AFFECT THE WAY WE REACT TO DRUGS FIRST DOCUMENTED IN 1950s

27. PHARMACOGENETICS THERAPEUTIC “WINDOW” TOO LITTLE...NO HELP TOO MUCH...COMPLICA- TIONS DIFFERENT PEOPLE... DIFFERENT WINDOWS

28. 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

29. 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

30. 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

31. 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

32. 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 P=0.007 NS

33. 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! NS P=0.0003

34. WHAT ABOUT THE STRONG HEART STUDY GENETIC RESULTS?

35. THICK HEART WALL ON LEFT (LVH) CAUSES: –HYPERTENSION –VALVE PROBLEMS HARD FOR CORONARY ARTERIES TO PENETRATE NOT CAUSED BY EXERCISE LEFT VENTRICULAR HYPERTROPHY

36. Strong Heart Family Study: Prevalence of LVH by Age

37. 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

38. 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

39. SHS LINKAGE RESULTS Kidney Function (Glomerular filtration rate) Chromosome 12 Mottl A, in press