Age-Adjusted Death Rates for Coronary Heart Disease, U.S., 1950-2004 Deaths/100,000 Population 600 500 400 300 200 100 Risk Factors U.S. Actual U.S. "Could Be" (Based on Japan Actual) 0 1950 1960 1970 1980 1990 2000 2010 Year
Framingham Heart Study Downtown Framingham, MA Risk Factors for Heart Attack and Stroke High blood pressure High cholesterol Cigarette smoking Diabetes mellitus Parental or sibling history Obesity
Framingham Heart Study: Population-Based Family Study 1948 1958 1968 1978 1988 1998 2008 1948 2008 Original cohort: n=5209 men and women (ages 28-62) 1644 spouse pairs, 596 extended families 1972 2008 Offspring study: n=5124 men and women (ages 5-70) 1576 spouse pairs, 3514 biological offspring Third Generation study: n=3500 men and women 2002
Contributions to Change in Life Expectancy, U.S., 1970-2000 Cardiovascular Disease Perinatal Disease Injuries Cancer COPD Increase Due to CVD = 3.9 Years CHD Stroke Other CVD Net Increase = 6.0 Years HIV/AIDS Other causes -1 0 1 2 3 4 5 Change in Life Expectancy (Years)
Age-Adjusted Death Rates for Coronary Heart Disease, U.S., 1950-2004 Deaths/100,000 Population 600 500 400 300 200 100 0 Risk Factors defined 1961 NHBPEP 1972 BHAT 1981 HDFP 1979 Risk Factors Primary and Secondary Prevention CASS Physical Intervention 1983 TIMI 1985 CPPT 1984 NCEP 1985 ALLHAT 2002 1950 1960 1970 1980 1990 2000 2010 Year
Survival from age 35 for continuing cigarette smokers and lifelong non-smokers among UK male doctors born 1900-1930, with percentages alive at each decade of age Doll, R. et al. BMJ 2004;328:1519 Copyright 2004 BMJ Publishing Group Ltd.
Effects on survival of stopping smoking cigarettes at age 25-34 (effect from age 35), age 35-44 (effect from age 40), age 45-54 (effect from age 50), and age 55-64 (effect from age 60) Doll, R. et al. BMJ 2004;328:1519 Copyright 2004 BMJ Publishing Group Ltd.
Relationship: LDL-Cholesterol & CHD Risk 50 CHD Deaths (per 1000/10y) 40 30 20 10 China 60 0 70 120 170 220 USA LDL (mg/dl) Source: Helen H. Hobbs, UT Southwestern Med Center
Genes and Environment Initiative
Combinatorial Complexity of CHD
Principles of whole-genome association mapping and finding complex disease genes
Characteristics of complex diseases Multiple genes Common variants Low penetrance Genetic interactions Epigenetic effects :
Complex inheritance: An Hypothesis Complex (non-mendelian) inheritance arises from the accumulation of common polymorphisms with small-to-modest allelic effects at multiple genes Common variants underlying disease can be identified a priori!
Whenever a mutation has a single origin it can be identified individually or through its association with nearby markers surrogates by virtue of being associated in the population through shared genetic history linkage disequilibrium (LD) mapping
Haplotype Map of the Human Genome Goals: provide genotyping information to support efficient and well-powered genetic association studies of human disease Define patterns of genetic variation across human genome Guide selection of SNPs efficiently to tag common variants Public release of all data (assays, genotypes): www.hapmap.org Phase I: 1.3 M markers in 269 people (1SNP/5kb at 5% +) Phase II: +3.1 M markers in 270 people(1snp/1kb at 5% +) The remarkable feature learnt is the pervasive nature of
Framingham SNP Health Association Resource (SHARe) Genotypes: ~10,000 Caucasians from 3 generations - Affymetrix 500,000 SNP chip Phenotypes: >1,000 risk factor, subclinical and clinical CV phenotypes, from 60 years of exams Genotypes and phenotypes placed in a webbased dataset, called dbgap, maintained at the NIH Framingham SHARe dataset contains 5.5 billion genotypes, >5.5 trillion association tests Available to biomedical researchers October 1, 2007
database Genotype and Phenotype (dbgap)
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QuickTimeª and a decompressor are needed to see this picture. * Take full advantage of new next-generation sequencing technologies. * Target only customer defined genetic elements. * Eliminate the time, cost, and performance limitations of multiplexed PCR.
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