Framingham meets genomics William P Castelli MD Director Framingham Cardiovascular Institute Adjunct-Associate Professor of Medicine Boston University School of Medicine Boston, MA

The Framingham genomics group plans to use the genomics data to search for gene connections to disease. For example, there are 5 genetic diseases or connections associated with the long QT syndrome  2 affect the potassium channels  2 affect the sodium channel  the mechanism of 1 is unknown Congenital long QT syndrome is genetically heterogeneous: different genes may be responsible for the same phenotype. A fix for the potassium channel won't help people with the sodium-channel problem. The genomics group Framingham

Framingham experience Framingham has been collecting data for more than 50 years, and research on the data began with things like cholesterol and BP. The first generation: data have been collected from healthy people every 2 years for more than 50 years The second generation: data have been collected every 4 years for 30 years Data collection on the third and forth generations is now underway. This data from healthy people can be used to establish risk of future disease. Long-term data collection

Genome complexity  There are 23 chromosomes  There are between and genes  There are ~5 million combinations of base pairs Very few places are equipped to handle such complex analysis. The Framingham genomics group at Boston University will specialize in such analysis. The collaboration between Framingham and the National Heart, Lung, and Blood Institute will remain. Making genomic connections

Access to data All of the Framingham data have eventually entered the public domain. Anyone in the world can use these data to search for disease connections; however very few places in the world are capable of making base pair connections. There's no other place where basic data collected are available to the public in the way the Framingham data are. The uniqueness of Framingham

Commercial endeavors Framingham data collection has been conducted under the direction of the National Heart Lung and Blood Institute. Pharmaceutical companies are developing genomic divisions and are willing to invest the large amounts of money that will be required to find these disease connections, which eventually will lead to gene therapies. Profiting from Framingham

Patenting genes From the time of his first HIV test in 1988, which was negative, one patient repeatedly asked AIDS researchers to look into why he seemed to be immune to the virus. In 1994, researchers at the Aaron Diamond AIDS Research Center in New York agreed to study him. The scientists discovered an inherited gene that results in a blocked porthole into white blood cells, preventing the virus from entering. Investigators went on to isolate the gene, discover how it worked and establish how many other people have it. On May 2, 2000, the research center was awarded a patent for a test to identify people who have the HIV-resistance gene, allowing it to share in any profits from the test; the patient receives nothing. Kolata G. Who owns your genes? New York Times 2000 May 15

Who owns what? Patients whose cells provided the genes that have been patented are almost never compensated. Without such patients, who approach scientists, provide blood, and participate in research projects, research centers would not be making the advances that they have. Patents are owned for the use of the more than 700 human genes for which there are currently laboratory tests. Most academic research and researchers currently have some commercial interest.

Protecting identities Framingham has done a good job so far of protecting the identity of the people from whom they collect data. When the social security administration used Framingham data to examine qualifications for disability, they identified some people who were on disability yet didn't meet the qualification criteria. They demanded the names of these people, and Framingham did not provide them. Genomic information is especially in demand by employers and insurance companies. Ethical issues

Cholesterol genes Of people with the type 2A hypercholesterolemia gene  20% have a heart attack before the age of 40  50% have a heart attack by the age of 50  85% have a heart attack by the age of 65 Fewer than 10% of people with a cholesterol problem reach their target goal with therapy. Fewer than 10% of people with hypertension reach target BP of 130/85 mm Hg with therapy; only 20% achieve a BP of 140/90 mm Hg (NHANES target). Half the strokes and heart attacks occur at BP between 120 and 140 systolic and 80 and 90 diastolic. Identification of the gene for familial hypercholesterolemia will allow people in high-risk groups to be treated with preventive therapy. Managing risk

Hypercholesterolemia Heterozygous familial hypercholesterolemia is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of the statins. Based on the study by Stein and colleagues, students from 2 Framingham high schools are currently being studied. Preventive therapy

Hypercholesterolemia Adolescent boys aged 10 to 17 years from 14 pediatric outpatient clinics in the United States and Finland who followed the AHA pediatric diet for at least 4 months, and had  an LDL-C value between 4.9 mmol/L (189 mg/dL) and 13.0 mmol/L (503 mg/dL) with at least 1 parent who had an LDL-C value of at least 4.9 mmol/L (189 mg/dL) not associated with a disorder known to cause secondary LDL-C elevation or  an LDL-C value between 5.7 mmol/L (220 mg/dL) and 13.0 mmol/L (503 mg/dL) and a parent who had died of CAD Stein EA, et al. JAMA 1999;281(2): Participants

Hypercholesterolemia A double-blind, placebo- controlled randomized trial was conducted to assess the lipid-lowering efficacy of lovastatin in adolescent boys with familial hypercholesterolemia Both treatment arms followed the American Heart Association (AHA) pediatric diet throughout the study period Study design Stein EA, et al. JAMA 1999;281(2): Active treatment arm DosageWeeks Period 1 10 mg/d1–8 20 mg/d9–16 40 mg/d17–24 Period 2 40 mg/d25–48

Hypercholesterolemia Change from baseline (%) LDL-CTotal cholesterol Active treatmentweeks 1–8–17*–13 weeks 9–16–24*–19 weeks 17–24–27*–21 weeks 24–48–25*–20 Placeboweeks 1–811 weeks 9–1622 weeks 17–24–3–2 weeks 24–48–4–3 *p<0.001 vs placebo Results Stein EA, et al. JAMA 1999;281(2):

INTERSALT study INTERSALT is a cross-sectional epidemiologic study of more than individuals, aged 20 to 59 years, in 52 population samples from 32 countries. 4 population samples were found to have very low sodium excretion, low BP levels, and little or no rise in blood pressure with age. In 48 population samples, sodium was significantly related to the slope of blood pressure with age. Intersalt Cooperative Research Group. BMJ 1988;297: International Study of Salt and Blood Pressure

INTERSALT study Among individuals, a difference of 100 mmol/day in sodium excretion was associated with an average difference of 3 to 6 mm Hg in systolic BP Across the 52 populations, median 24-hour sodium excretion higher by 100 mmol was associated with median BP higher on average by 5–7/2–4 mm Hg, and an estimated mean difference in BP at age 55 compared with age 25 greater by 10–11/6 mm Hg. Sodium and BP Elliott P, et al. BMJ 1996;312:

Legislation Legislation will have to be passed to ensure that genomic data will not be used to discriminate against people Genomic data presents only a partial picture; a genotype leads to a phenotype, and the same gene doesn’t always lead to the same phenotype. With a better understanding of disease connections, we may be able to predict disease more precisely This information will also lead to far better therapies than are available today; those specific to a particular genome. Protecting patient privacy