Jeffrey Dach MD

Understanding Online Genetic Testing by Jeffrey Dach MD

Jeffrey Dach MD — Fri, 09 May 2008 07:21:30 GMT

Understanding Online Genetic Testing,
Current and Future.

DNA DIRECT

DNA Direct is one of many online genetic testing services which offers a reasonable list of tests which are useful because each test actually corresponds with a known genetic disease or clinical abnormality.(7)

List of tests offered by DNA Direct:(7)

Alpha-1 Antitrypsin Deficiency, Asthma and Lung Disease

Alpha-1 Antitrypsin is a protein in the lung tissue, and deficiency leads to a tissue breakdown in the lung causing pulmonary emphysema.(1)

Alpha-1 Carrier Status

About 1 in every 10-30 Americans are Alpha-1 carriers. While carriers are usually asymptomatic, they may be more susceptible to lung injury from toxins such as cigarette smoke, or susceptible to liver injury from toxins such as acetaminophen (tylenol). Preventive measures include avoidance of lung and liver toxins. Most Alpha-1 carriers have enough protein production to remain disease free.

Image at left: structure of alpha-1-anti-trypsin protein courtesy of wikipedi.

Severe Alpha-1 Deficiency

An estimated 100,000 people in the U.S. (1 in 2500) and a similar number in Europe have severe Alpha-1 antitrypsin deficiency. Since the symptoms of asthma are common in the general population, Alpha-1 patients are most often misdiagnosed as having asthma. On average it takes seven years and three doctors to make the correct diagnosis of alpha-1 which causes 3 percent of all cases of emphysema, and COPD (chronic obstructive pulmonary diseases) in the U.S.

Treatment with Prolastin (Bayer), which is purified alpha-1-anti-trypsin protein, is available.(8)

Ancestry and Ethnicity Test Panel

Ashkenazi Jewish Carrier Screening Panel (in Alphabetical Order)

Bloom Syndrome: The carrier frequency in individuals of Eastern European ancestry is about 1/100. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child.

Bloom syndrome is caused by mutations in the BLM gene responsible for the DNA helicase, an enzyme that unwinds the two spiral strands of a DNA molecule so that they can be copied. The chromosome copying mechanism is faulty causing a high risk for early cancer in affected individuals.

Canavan Disease: One in 40 individuals of Ashkenazi Jewish ancestry is a carrier of Canavan disease.

Canavan disease is a leukodystrophies, characterized by degeneration of myelin, which is the fatty covering that insulates nerve fibers in the brain causing abnormal neurological development, and poor survival of the affected child. The American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology (ACOG) recommend Canavan carrier screening for all Ashkenazi Jewish individuals.

Cystic Fibrosis: One in 25 Ashkenazi Jewish individuals are CF carriers. The American College of Obstetrics and Gynecology (ACOG) recommends that all couples who are pregnant or planning a pregnancy be offered CF carrier screening.

Familial Dysautonomia: Autosomal recessive, and almost exclusively in Ashkenazi Jews. Both parents must be carriers in order for the child to be affected. The carrier frequency in Jewish individuals of Eastern European (Ashkenazi) ancestry is about 1/30, while the carrier frequency in non-Jewish individuals is about 1/3000. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of familial dysautonomia.(2)

Fanconi Anemia: One in 89 Ashkenazi Jewish individuals is a carrier of Fanconi anemia Type C.

Gaucher Disease: About 1 in 100 people in the U.S. population are carriers, and about 1 in 15 Ashkenazi Jews are carriers for Gaucher's disease.

Gaucher's disease is the most common of the storage diseases caused by a deficiency of the lysosomal enzyme glucocerebrosidase, which breaks down glucocebrosides, found in red and white blood cell membranes. This leads to an accumulation a fatty substance in various RE and filtering organs such as the spleen, liver, kidneys, lungs, as well as brain and bone marrow. Symptoms may include hepatosplenomegaly, skeletal disorders and severe neurologic abnormalities.

There is an effective treatment with enzyme replacement with recombinant glucocerebrosidase given intravenously every two weeks which can dramatically reverse the symptoms. However, this treatment with Cerezyme costs $500,000 annually for the lifetime of the patient.

Mucolipidosis IV: About 1 in 100 Ashkenazi Jewish individuals is a carrier. Mucolipidosis is a neurodegenerative lysosomal storage disorder. Symptoms include agenesis of the corpus callosum, neurological and opthalmic abnormalities.

Niemann-Pick Disease: Caused by the deficiency of the enzyme, acid sphingomyelinase, leading to accumulation of sphingomyelin in the liver and spleen (hepatosplenomegaly), progressive deterioration of the nervous system, and poor survival in the severe form of the genetic disease. One in 90 people with Ashkenazi Jewish ancestry is a carrier of Niemann-Pick Type A (severe) or Type B (less severe form).(3)

Tay-Sachs Disease: One in 30 people with Ashkenazi Jewish ancestry is a carrier of Tay-Sachs disease. Because of the high carrier rate, the American College of Medical Genetics (ACMG) and the American College of Obstetrics and Gynecology (ACOG) recommend screening for Ashkenazi Jewish individuals. ACOG recommends that couples in which only one member is Ashkenazi Jewish also consider carrier testing for Tay-Sachs disease.

Tay-Sachs disease is a severe progressive disorder that causes deterioration of the central nervous system, resulting in poor muscle tone, loss of motor skills, seizures, blindness, and difficulties with swallowing and breathing. On eye exam, people with Tay-Sachs disease have an unusual appearance to the retina, known as a cherry-red spot. Children born with Tay-Sachs disease appear normal at birth, however symptoms begin as early as 3 months of age and death usually occurs by age 4. There is no cure for Tay-Sachs disease.

Blood Clotting Disorders (Factor V Leiden, Prothrombin)

This genetic test looks for a mutation in two genes which increase risk for blood clots, factor V Leiden, and prothrombin mutation. These lead to increase risk for deep venous thrombosis in the calf veins, and associated pulmonary embolism. Once identified as a carrier, one can take precautions to prevent deep venous thrombosis.

Factor V Leiden

Factor V Leiden is found in 1 in 20 Caucasians, and is rare in Hispanic Americans, African Americans, and not often found in people from Africa or Asia. A mutation increases the risk of blood clot formation.

Factor V Leiden is also found in 10% to 20% of people of all ages with first-time venous blood clots, 40% of people younger than 50 with first-time venous clots, and 60% of pregnant women with venous thrombosis.

Factor V Leiden has been associated with an increased risk of recurrent pregnancy loss, severe preëclampsia, fetal growth retardation, stillbirth, and placental problems (infarction and abruption).

Prothrombin (Factor II) G2021A

SImnilar to Leiden, the Prothrombin mutation is found in about 1% to 2% of the Caucasian population. It is rare in the African and Asian populations. Prothrombin G2021A is found in 6% to 8% of people with a first-time venous clot, has been associated with myocardial infarction (heart attack) in young women and cerebral (brain) venous thrombosis.

Breast & Ovarian Cancer Risk-BRCA1 and BRCA2

Hereditary cancer has general features that include: Cancer diagnosed at a young age (earlier than 50 years old), multiple primary cancers in the same person, a combination of certain cancers in a family, such as breast and ovarian or colon and uterine.

Key features in history suggesting hereditary breast and ovarian cancer are:

1) Breast cancer before age 50
2) Ovarian cancer at any age
3) Breast cancer in both breasts
4) Breast cancer and ovarian cancer in the same person.
5) Male breast cancer
6) Ashkenazi Jewish ancestry

Genetic testing for breast and ovarian cancer deals with two extremely large genes — called BRCA1 and BRCA2 — and hundreds of possible mutations.

Ashkenazi Jews, however, present a simplified pattern, mostly involving one of three specific BRCA mutations. This test, called multisite analysis, looks exclusively for three mutations in the BRCA1 and BRCA2.

Colon Cancer Screening. The DNA Stool Test examines a stool sample for 23 DNA markers that are associated with colorectal cancer and pre-cancerous polyps.

Cystic Fibrosis- CFTR gene.

Cystic fibrosis (CF) is a disease of thick mucous affecting lungs, liver, and pancreas, charaterized by repeatd and frequent lung infections, digestive problems with decreased pancreatic enzyme production (growth retardation and deficiency in fat-soluble vitamins A, D, and E). The diagnosis of CF can be made with sweat test. There is no cure for CF. Life expectancy is shortened with most succumbing to lung infection in their 20s and 30s. CF is a common genetic disorder with   5% of people of European descent carriers for CF (one gene affected).

CF is caused by a mutation in CFTR gene, making an abnormal chloride ion channel. This is the mechanism for making sweat, digestive juices, and mucus.

Professional medical groups including the NIH, ACUG, and ACOG recommend that CF carrier screening be offered to all couples who are planning a pregnancy or are currently pregnant.

Drug Response Testing

Three genes are responsible for enzymes that metabolize medications. Mutations in these genes can produce '"poor metabolizers" who nee lower doses of medication to avoid overdose. This information is useful in personalizing drug treatment.

Hemochromatosis

Hemochromatosis (iron accumulation) is the most common genetic disorder in Caucasians, with an estimated prevalence of 1/4 to 1/2 per cent having both genes affected (homozygotes) and 10-12 per cent carriers (one gene).

Iron accumulation of heochromatosis is an example of a common genetic disorder whiich has a curative treatment if diagnosed early. This treatment is bleeding or phlebotomy which removes the iron from the body. Those 18th century bleeding treatments weren't so ridiculous after all.

The disease causes iron accumulation in the liver, adrenals, heart and pancreas, causing cirrhosis, adrenal insufficiency, heart failure and diabetes. The cirrhosis is associated with increased risk of liver cancer. The more common clinical presentations are malaise, liver cirrhosis, insulin resistance, diabetes mellitus type 2 (due to pancreatic damage), erectile dysfunction, decreased libido, congestive heart failure, arrhythmias, arthritis, adrenal insufficiency, deafness, parkinsonian symptoms, hypothyroidism, a darkish colour to the skin (Diabetes bronze), etc.

Males are usually diagnosed after their forties and fifties, and women several decade later owing to regular iron loss through menstruation (which ceases in menopause). Many patients who have the full blown genetic mutation (homozygous) may be asymptomatic, or have minimal symptoms, showing only an elevated ferritin or saturation. Diagnosis is commonly made with elevated LFT's (liver enzymes), elevated ferritin, and increased iron binding saturation. DNA testing for two mutations in the HFE gene, C282Y and H63D, makes the diagnosis (available at Quest and Labcorp). (9)(10)

Imaging features: The increased iron stores in the liver and pancreas result in characteristic findings on unenhanced CT and a decreased signal intensity at MR imaging.

Routine screening of population for haemochromatosis is generally not done, since serum ferritin is a more practical and less expensive marker. Serum ferritin above 1000 ng/mL suggests iron overload.

Left image: ferritin protein structure courtesy of wikipedia

Early diagnosis allows prompt curative treatment with phlebotomy (discarded blood donation) which removes iron from the body.  Treatment is usually started with ferritin above 200-300 mg/L.

Warfarin Response Testing

Warfarin response testing looks at two genes, called CYP2C9 and VKORC1 which determine our response to coumadin. CYP2C9 is a gene involved in warfarin metabolism. CYP2C9 variants have reduced metabolism and generally require lower warfarin doses. VKORC1 is involved in vitamin K epoxide reductase, or VKOR which makes the blood-clotting proteins. Warfarin works by reducing this enzyme's activity. A common VKORC1 gene variant (called -1639G>A) also reduces the enzyme’s activit. If one has low enzyme levels to start with, an average warfarin dose may be too much, and cause excessive bleeding.

Cardiovascular Disease

The most common inherited cardiovascular diseases are:

Hypertrophic cardiomyopathy (HCM) causes muscle thickening in the ventricles (the heart’s pumping chambers). It is the most common inherited cardiovascular disorder, affecting one in every thousand people. Many people with HCM show no symptoms; when present, however, symptoms may include shortness of breath, tiredness, chest pain, fainting or near-fainting, and/or heart palpitations. Learn more about HCM.

Dilated Cardiomyopathy (DCM): In DCM, the heart is enlarged, grows weaker, and is less able to pump blood throughout the body. When the heart does not pump properly individuals develop symptoms of heart failure, including shortness of breath, swelling of the ankles and feet, and fatigue. In addition, abnormal heart rhythms (arrhythmias) may develop. Learn more about DCM.

Inherited Arrhythmias are abnormal heart beats or rhythms caused by gene mutations. Inherited arrhythmias affect the electrical signaling of the heart and can cause symptoms such as faintness, dizziness, and heart palpitations. Learn more about inherited arrhythmias.

Marfan Syndrome is a genetic disorder of the connective tissue. Because connective tissue is throughout the body, a variety of organs can be involved, including the eyes, skin, bone, and heart. Sometimes people with Marfan syndrome show no symptoms. As the disease progresses, symptoms – which range from nearsightedness to arrhythmias – may become noticeable. Learn more about Marfan syndrome.

Familial Aortic Aneurysm (FAA) is an inherited disorder in which a section of the aorta starts to stretch and bulge. The aorta is a large blood vessel that carries blood from the heart to the rest of the body. The bulging is called an aneurysm and may occur along the aorta in the abdomen or the chest. Most people with FAA show no symptoms; when present, however, symptoms may include general abdominal pain or discomfort, or pain in the chest or lower back. Learn more about FAA.

http://www.genetichealth.com/HD_Genetics_of_Coronary_Artery_Disease.shtml
Genetics of Heart Disease - Inheritance Patterns - Review Article

So far, there are 250 genes involved in heart disease producing a blended effects. This makes things complicated. A person may have some mutations that increase risk and other mutations decrease risk. On average, a person's risk level is approximately midway between those of the parents.

LDL Metabolism,  LDL Receptor. 1985, Michael Brown and Joseph Goldstein Nobel prize for gene for familial hypercholesterolemia, or FH. FH is inherited in a dominant manner.

Apolipoprotein E. More than 30 mutant forms of apo E. the e4 version of the gene tend to have higher cholesterol levels than the general population, but levels in people with the e2 version are significantly lower. The apo E gene has also been implicated in Alzheimer's disease.

Apolipoprotein(a). Apo(a) combines with LDL to form Lp(a) often found as a part of plaques . High Lp(a) levels (over 30 mg/dL) indicates higher risk of developing CAD. Lp(a) levels may be reduced with the vitamin niacin, or by hormone replacement therapy in postmenopausal women.

Homocysteine Metabolism, (hyperhomocystinemia) is known to be a risk factor for CAD.  In the US, about one in eight people have a mutation for MTHFR, with elevation in homocysteine, treatable with folate, B6 B12 vitamins.

Apolipoprotein A1 is a protein found in the HDL particle, the "good cholesterol". Some mutations in the apo A1 gene result are bad causing early heart attacks, and strokes.

A particular mutation in Apo A1 found in some residents of Milan, Italy, called the "Milano" mutation results in very low levels of HDL. Although these people have very low levels of HDL, they also have a low incidence of Heart Disease.

Genetic testing

In general, tests for specific genetic mutations are not performed in CAD. Indirect tests are much easier and less expensive. For example, blood homocysteine levels are useful. If elevated, treatment is B6 B12 and folate vitamins.

Conclusion

In conclusion, genetic testing can be complicated. In some cases it is useful to confirm a diagnosis, or to predict future disease risk so that preventive measures can be taken. In some cases it is useful for family planning. When parents have knowledge of their carrier status, they may take precautions to prevent expression of severe a genetic disease in the child. In some cases, it is not useful, since less expensive screening tests are available for routine use. This is a rapidly evolving field and the above information may become outdated within a few years, to be replaced by newer information. Very soon, the cost for routine whole human genome sequencing will become cheaper, and will be offered during routine clinical testing along with the CBC, blood count and chemistry panel. Also, we will very soon have a greater understanding of gene variation and disease risk, which will hopefully allow intelligent and useful interpretation of the routine clinical sequencing of the entire human genome. We are not quite there yet.

Jeffrey Dach MD
4700 Sheridan SuiteT
Hollywood Fl 33021
954-983-1443
http://www.jeffreydach.com
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References

(1) http://en.wikipedia.org/wiki/Alpha_1-antitrypsin
Alpha 1 anti trypsin wikipedia

(2) http://en.wikipedia.org/wiki/Familial_dysautonomia
Familial Dysautonomia

(3) http://en.wikipedia.org/wiki/Niemann-Pick_disease
Niemann Pick

(4) http://en.wikipedia.org/wiki/Gaucher's_disease
Gaucher's

(5) http://en.wikipedia.org/wiki/Mucolipidosis_IV

(6) http://www.labcorp.com/genetics/genetic_disorders/index.html
Common Genetic Disorders LAbcorp

(7) http://www.dnadirect.com/
DNA Direct WEb Site

(8) http://www.rxlist.com/cgi/generic/aprotein.htm
Information on Prolastin treatment for alpha -1-antitryin deficiency
alpha1-Proteinase Inhibitor (Human), Prolastin is a sterile, stable, lyophilized preparation of purified human Alpha1-Proteinase Inhibitor (alpha1-PI) also known as alpha1-antitrypsin. Prolastin is intended for use in therapy of congenital alpha1-antitrypsin deficiency.

(9) http://www.questdiagnostics.com/hcp/files/02winter_newsletter.pdf
Quet NEwletter dealing with hemochromatosis. Approximately 85-90% of patients with typical clinical features of HFHC are homozygous for the C282Y mutation. However, only 40-50% of homozygous patients demonstrate clinical disease.

(10) http://cas2.questdiagnostics.com/scripts/webdos.wls?MGWLPN=QDCIAP22&wlapp=DOS&OrderCode=10249&SITE=32&SearchString=HEMOCHROMATOSIS&tmradio=alias
Quest LAB DNA test for hemochromatosis Chantilly Lab
Code: 10249 Hereditary Hemochromatosis DNA Mutation Analysis [35079X]
This assay detects the two mutations in the HFE gene, C282Y (NM_000410.2: c.845G>A) and H63D (NM_000410.2: c.187C>G), that are commonly associated with HH. The mutations are detected by multiplex-polymerase chain reaction (PCR) amplification, followed by digestion of the amplification products with the restriction enzymes RsaI and NlaIII, for the detection of the C282Y and H63D mutations respectively. Fluorescent-labeled restriction fragments are detected by capillary electrophoresis.

Code: 141661 Hereditary Hemochromatosis DNA MutationAnalysis,NY [36193X]

http://en.wikipedia.org/wiki/Niemann-Pick_disease
Niemann Pick

http://en.wikipedia.org/wiki/Gaucher's_disease
Gaucher's disease

http://www.labcorp.com/genetics/genetic_disorders/index.html
Common Genetic Disorders LAbcorp

http://www.clinchem.org/cgi/content/full/47/7/1147
Clinical Chemistry. 2001;47:1147-1156.
Hereditary Hemochromatosis Since Discovery of the HFE Gene
Elaine Lyona1 and Elizabeth L. Frank Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84132.

http://www.geneclinics.org/
http://www.geneclinics.org/servlet/access?id=8888891&key=ymv3mRXKyXAA1&fcn=y&fw=Y5Xo&filename=/concepts/teachtool/teachintro.html

http://www.geneclinics.org/img/teachtool/TestingMethods.pdf
PowerPoint review of genetic testing techniques…
Nuclear Sequencing is latest…Pagon

http://www.kumc.edu/gec/support/
Genetic Conditions

http://www.geneticstesting.com/patient_info/jewish_diseases.htm

http://content.nejm.org/cgi/content/full/347/23/1867
Volume 347:1867-1875 December 5, 2002 Number 23
Genetic Testing ylie Burke, M.D., Ph.D.

Genetic testing can provide dramatic clinical benefits. A child known to have multiple endocrine neoplasia type 2 (MEN-2) can be spared medullary carcinoma by undergoing prophylactic thyroidectomy (Figure 1),1 and an adult with hereditary hemochromatosis can be spared cirrhosis by the early initiation of phlebotomy treatment.2 Genetic testing can also provide diagnostic and prognostic information that aids in difficult clinical decision making. For example, a test for a deletion in the dystrophin gene, the cause of Duchenne's muscular dystrophy, can be used to identify women who are carriers of this condition (Figure 2).3 A carrier may avoid having an affected child by avoiding pregnancy or by undergoing prenatal testing for Duchenne's muscular dystrophy, with possible pregnancy termination if the fetus is found to be affected.

http://talk.dnadirect.com/2007/11/27/media-round-up-personal-genome-services-23andme-decodeme-navigenics/
Media Round-Up: Personal Genome Services 23andMe, deCODEme, Navigenics
As promised, here’s a round-up of media on the new personal genome services.

http://news.yahoo.com/s/ap/20080424/ap_on_he_me/genetic_discrimination;_ylt=AmxJrC5Cz23gK4TKhFsb332s0NUE
By JIM ABRAMS, Associated Press Writer Thu Apr 24, 2008
Senate passes genetic discrimination bill WASHINGTON - People learning through genetic testing that they might be susceptible to devastating diseases wouldn't also have to worry about losing their jobs or their health insurance under anti-discrimination legislation the Senate passed Thursday.

http://www.thegeneticgenealogist.com/2008/04/07/genetic-testing-under-the-microscope/
Genetic Testing Under the Microscope

Cardiovascular Disease

http://www.medscape.com/viewarticle/543910?rss

From Nature Clinical Practice Cardiovascular Medicine
Genetic Testing in Cardiac Disease: From Bench to Bedside
Posted 10/09/2006 Allison L Cirino; Carolyn Y Ho Author Information

http://www.brighamandwomens.org/cvcenter/Patient/FAQ/FAQcvgenetics.aspx
What types of heart disease may be caused by inherited traits?
The most common inherited cardiovascular diseases are:
Hypertrophic cardiomyopathy (HCM)
Dilated Cardiomyopathy (DCM)
Inherited Arrhythmias
Marfan Syndrome
Familial Aortic Aneurysm (FAA)

http://blog.wired.com/wiredscience/2007/10/genetic-tests-f.html
Biotech Firm Identifies Five Genes Associated with Heart Disease

http://www.genengnews.com/news/bnitem.aspx?name=24733875
Oct 15 2007, Celera and Collaborators Identify a Five-Gene Genetic Risk Score(TM) That Predicts Risk of Coronary Heart Disease

Genetic Risk Score(TM) (GRS) based on five gene variants that predicts risk for coronary heart disease (CHD). These variant genes were KIF6, MYH15, PALLD, SNX19, and VAMP8. The GRS of each ARIC participant depended on how many of these risk variants an individual had. After adjusting for traditional risk factors, those individuals with a high risk GRS had a 57% increased risk of incident CHD, which is similar to the magnitude of risk for CHD associated with smoking, hypertension, hypercholesterolemia, or obesity.

http://www.londonideas.org/internet/public/over_counter_tests/genetic_tests_pet.pdf
Heart Disease

Apo-E And Heart Disease

http://www.biomedcentral.com/1471-2350/4/8
Genetic study of common variants at the Apo E, Apo AI, Apo CIII, Apo B, lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes and coronary artery disease (CAD): variation in LIPC gene associates with clinical outcomes in patients with established CAD

http://mostgene.org/gd/gdvol14d.htm
Apo E genotype DNA test to identify the apo E2/E2 genotype. This genotype is diagnostic for broad beta disease when associated with combined elevation of cholesterol and TG. The test is typically performed by polymerase chain reaction followed by restriction enzyme cleavage and gel electrophoresis. Accuracy of E2/E2 detection is >99%.

http://www.genetichealth.com/HD_Genetics_of_Coronary_Artery_Disease.shtml
Genetics of Heart Disease - Inheritance Patterns - Review Article
Researchers have identified more than 250 genes that may play a role in CAD.

http://www.mdl-labs.com/testing/

Thrombosis Testing
Prothrombin Gene Mutation
PAI-1 Gene Mutation
Factor V Leiden Mutation
MTHFR C677T and A1298C Mutations
Glycoprotein IIIA (A1 vs A2)
Stromelysin-1 5A/6A Polymorphism
Endothelial Nitric Oxide Synthase (eNOS) T-786C Mutation
Apolipoprotein E Genotyping (Apo E)
Pharmacogenetic Testing

Warfarin (coumadin) Metabolism Panel
DPD Enzyme Deficiency (Dihydropyrimidine Dehydrogenase)
UGT1A1 Camptosar (irinotecan) Metabolism

CYP2D6, CYP2C9, CYP2C19 Drug Metabolism Panel
CYP2D6 only
CYP2C9 only
CYP2C19 only
Vitamin B12 Deficiency

----------------------------------------
Vitamin B12 deficiency by uMMA

http://www.genome.gov/Pages/News/webcasts/Personalized_Medicine_files/Default.htm#nopreload=1
video presentation Personalized Medicine:
How the Human Genome Era Will Usher in a Health Care Revolution
Francis S. Collins, M.D., Ph.D. Personalized Medicine Coalition February 10, 2005

http://www.genome.gov/Pages/News/webcasts/Personalized_Medicine_files/0Media.asx

risk prediction
colon cancer- offer colonoscopy
drug metabolism
develope new therapies..drugs or gene therapy

JAMA January Sodium channell gen atrial fibrillation, cardiomyopathy
SCN5A Olsen etal JAMA JAn 2005

LAncet Cly2019Ser LRRK2 common in familial Parkinson's disease
this is 7th gene associated with PArkinson's Disease
Identify who is at risk for Pakinsons in family where gene is identified.

Individualized preventive medicine, prevention.
BEst possible window for developing drug thereapy.
Experiment of nature which tells you the a gene and protein product is involved in pathogenesis.
Away from small molecule reseah into thsi direction.
That kind of discovery os gpoing to accelerate dramatically over the next few years. In past, most variants were discovered in wknown diseases.

We now have ability to look at all the genes there is only about 25,000 of them.
Hap.map progect www.hapmap.org
understand genetic variation, all data goes into public domain.
Generate MAp of incredible richness. View genetic variation of greater depth than we had imagined. High density genotyping.

Crohn's disease tends to run infamilies. tested 248,000 snps. Postitve controils, another 10 or so.
Drug target approach. thats an example.

NEJM 2004 351 2817-26
Tamoxifen node neg breast cancer multigene assay.
gene expression risk for distant recurrance. compelling correlation.
Multi-genew Assay predicts recurrance of Tamoxiphen treated node neg breast cancer.
80% cured and dont need chemo. This identifies high risk group that need chemo.

Roche product Amplichip CYP450 NEJM Caraco 2004 Predict drug metabolism

Iressa (gefinitib) genome based drug that blocks EGF receptor kinase

NEJM 2004 350 2129-39 Some patients had dramatic response. Restricted ito individuals who have mutastions in kinase domain of EGF receptor. Kinase inhibitor sensistve.

NEJM 2005 352, 441 -9 I131 Tositumomab Therapy sustained remission.

PCR analysis of BCL2 gene follicular lymphoma predicts clinical response genome based drug.

http://www.nutrienergetics.com/The_Coming_Medical_Revolution-Peter_Fraser(1-0)uk.pdf
The coming Revolution in Physics, Biochemisty and Medicine, Peter Fraser, Milo WOlf ideas.

(c) 2008 All rights reserved Jeffrey Dach MD www.drdach.com disclaimer

Interview with Naomi Wolf, Author of the End of America by Jeffrey Dach MD

Jeffrey Dach MD — Thu, 08 May 2008 07:07:32 GMT

Naomi Wolf's, End of America

Is the world speeding inevitably towards a world totalitarian government as Aldous Huxley predicted in his 1958 interview with Mike Walkace? Watch this Interview with Naomi Wolf, author of the End of America, and find out.

Wolf attended Yale University and was a Rhodes Scholar at New College, Oxford. She was a consultant to former Vice President Al Gore during his bid for president.

http://www.you tube.com/watch?v=i0LvtQAQ6sc

This is a fascinating interview with renowned author Naomi Wolf, perhaps best known for her early 1990s feminist classic "The Beauty Myth", considered by many to be one of the most important works of the 20th century.

Wolf discusses her new book "The End of America", already on the New York Times bestseller list. The book identifies ten classic steps common to all dictatorships -- including those of Mussolini, Hitler and Stalin. Alarmingly, Wolf makes the case that each of these ten steps is occurring in post 9/11 America today. The book is a call to action for young and concerned Americans and this interview intimately frames this important discussion.

See : Naomi Wolf The Guardian, Tuesday April 24 2007

Fascist America, in 10 easy steps from Hitler to Pinochet and beyond, history shows there are certain steps that any would-be dictator must take to destroy constitutional freedoms. And, argues Naomi Wolf, George Bush and his administration seem to be taking them all

10 Steps Already Invoked by the Bush Administration:

1. Invoke a terrifying internal and external enemy.

2. Create a gulag, a prison system outside the rule of law

3. Develop a thug caste

4. Set up an internal surveillance system

5. Harass citizens' groups

6. Engage in arbitrary detention and release

7. Target key individuals

8. Control the press

9. Dissent equals treason

10. Suspend the rule of law

In 1958, 50 years ago, Aldous Huxley foresaw the End of America, replaced by a totalitarian state, in this interview with Mike Wallce. see the trranscript and the video.

Quoted from Mark Groubert at from Crooks and Liars :

The End of America: Letter of Warning to a Young Patriot A Citizen’s Call To Action By Naomi Wolf

Fascism: Fast and furious in ten historic steps.

1. Invoke a terrifying internal and external enemy
2. Create a gulag
3. Develop a thug caste
4. Set up an internal surveillance system
5. Harass citizens’ groups
6. Engage in arbitrary detention and release
7. Target key individuals
8. Control the press
9. Dissent equals treason
10. Suspend the rule of law

Naomi Wolf says: Recent history has profound lessons for us in the U.S. today about how fascist, totalitarian, and other repressive leaders seize and maintain power, especially in what were once democracies. The secret is that these leaders all tend to take very similar, parallel steps.In the true spirit of Thomas Paine, Wolf takes her slender pamphlet/book (155 pages) to the streets of America. Our job is to read it, write about it and Revere it. Ride through the towns across the land yelling: “The fascists are coming. The fascists are coming.”

That is, if it isn’t too late.

Wolf’s previous books have mostly centered on women’s issues. The Beauty Myth, Fire With Fire, Misconceptions, Promiscuities: The Secret Struggle for Womanhood and The Treehouse. This work, The End of America is completely out of left field. A radical departure, if you will. While not trying to minimize the importance of her previous progressive books, this tome is a major historical piece of non-fiction. I say so because of its simplicity, minimalism, brevity, cohesion and importance.

I’ll tell you what it’s not.

It is not highbrow. It is not pompous. It is not longwinded. It is not complicated.

It is simply, the truth.

At once a brilliant indictment of the Bush administration, The End of America, explains in blunt terms how the last 7 years have paralleled the same steps taken during the 20th century that led to the dictatorships of Italy, Russia, China, Germany, and Chile.

Believe me, folks. It can happen here.

The book is not partisan. It is historical. It starts with the premise that ten steps, ten small changes are all that is necessary to move a country from democracy to fascism.

The work demonstrates how the massive escalation of executive power in the White House has eroded the core values that surround our personal freedoms. In her citizen’s call to action, Wolf demonstrates the very real threats that exist to our civil liberties and explains how we can deal with this growing threat. You can start by reading this book.

In the 2006 military coup in Thailand, the leaders of the coup took a number of systematic steps. Within days, the coup leaders declared martial law, sent soldiers into residential areas, took over radio and TV stations, issued press restrictions, tightened travel and rounded up the usual suspects. They weren’t winging it. They knew exactly what they were doing. Veteran campers know how to make a fire. There are certain steps you take. The U.S. has already initiated the 10 steps to fascism and they are spelled out above. Wolf illuminates them all clearly and precisely. From the USA Patriot Act to the John Warner Defense Authorization Act of 2007, we have seen a breathtaking passage of laws that its own signers now admit they didn’t even bother to read.

By the way, in case you are wondering, the Defense Authorization Act allows the President (or his surrogates) vast new powers over the National Guard. He can send Michigan’s militia to enforce what he decides is a “state of emergency” in California over the objections of the state’s governor and its people.

This is a clear violation of the Posse Comitatus Act, which was meant to stop the federal government from using the military as police force. So much for state’s rights. Having seen its citizens beaten by a foreign king’s army, the founding fathers wanted to prevent our own government turning on its own citizens. Apparently the Bush administration finds that to be a restriction on the executive branch and an unconstitutional check on his powers. Question is, what are you gonna do about it? Vote him out? Okay, what about the next president?

As Americans follow the latest turn of events regarding Britney Spears or Miley Cyrus, the people who crave power consolidate it quietly and aggressively. They don’t have time to watch the latest episode of American Idol. They are in the business of creating their own.

Germans still went to the movies in Berlin in 1931.

The Chinese will soon have the Olympics as the Germans did in 1936. The outward structures always appear the same. The point is that fascism doesn’t come as a black and white newsreel any longer. Today, it comes in fuschia and pastels with a yellow smiley face. It is Disneyfied. It wears the same clothing as you do. The hair styles are the same. The shoes are the same. Remember the crazed thuggish gang of Republican operatives banging at the door while the Florida recount was occurring? They all wore white starched shirts and tan khaki slacks, yet they were dressed to kill. Democracy, that is.

This democracy business is a lot of work. Freedom makes you fat and lazy. I mean that in a good way. We used to be able to sit back and let our elected officials take care of business. Well, apparently business has taken care of our elected officials. Now we gotta do it. Ugh. Time to get off the couch. Well, let’s get it on. I guess we do have to fight for our right to party.

The End of America by Naomi Wolf serves as a companion piece to her sister-in-arms, Naomi Klein’s work, The Shock Doctrine. Read them both and you will understand everything you need to know about today’s threats to democracy. But read them quick. The clock is ticking, we’re in the 4th quarter of the Super bowl with no time outs.

A WGA screenwriter/producer/journalist based in Hollywood, California, Mark Groubert is the Senior Film and Book Reviewer for CrooksandLiars.com. As a filmmaker he has produced numerous documentaries for HBO. Groubert is also the former editor of National Lampoon Magazine, MTV Magazine and The Weekly World News. In addition, he currently writes for the L.A. Weekly, L.A. City Beat, Penthouse, High Times and other publications.

Links:

http://www.americanfreedomcampaign.org/
American Fredom Campaign Web Site
According to Naomi Wolf, A National Uprising to restore democracy, appointment of a special prosecutor, and impeachment/criminal prosecution for treason is required to save America from shift into fascism.

http://www.guardian.co.uk/world/2007/apr/24/usa.comment

http://www.huffingtonpost.com/naomi-wolf/ten-steps-to-close-down-a_b_46695.html

http://www.youtube.com/watch?v=RjALf12PAWc

http://www.youtube.com/watch?v=aW9PulYpjGs
Interview - The End of America

http://www.crooksandliars.com/2008/04/30/book-review-the-end-of-america-a-letter-of-warning-to-a-young-patriot/

http://www.huffingtonpost.com/naomi-wolf/why-barack-obama-got-my-v_b_89017.html
Why Barack Obama Got My Vote Naomi Wolf Posted February 28, 2008

http://www.hrc.utexas.edu/multimedia/video/2008/wallace/huxley_aldous_t.html
http://www.hrc.utexas.edu/multimedia/video/2008/wallace/huxley_aldous.html

50 years ago, Huxley predicts end of democracy in America. Mentions Orwell's 1984 Dictatorship based on terror.
In 1958, Mike Wallace interviews with Aldous Huxley author of brave new world. Huxley predicts the end of democracy, because of overpopulation , and advanced propaganda media. He predicts a Dictatorship with consent of the "ruled" with new techniques of propaganda, bypassing the rational mind of man, appealing to the unconscious so that man will love his slavery.

His Series of essays, enemies of freedom. He outlines enemies of freedom in the US.
First one is overpopulation, first 1500 years, the population doubled. Current doubling time 50 years.
We have practiced Death control without birth control. Increasing longevcity.

http://www.youtube.com/watch?v=SaiWCS10C5s
Video of college student Andrew Meyer brutally arrested and tasered for asking Kerry a question at a college forum at University of Florida. He asks questions about 2004 election, voters prevented from voting as mentioned in Greg Palast book, Armed Madhouse. Kerry would have won if all people were allowed to vote. Wolf says this kind of suppression of dissent is typical for early "fascist shift". Think about it. College forums for students are there for the exact reason to allow students to ask difficult questions.

Jeffrey Dach MD
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