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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