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Integrative Medicine as Personalized Medicine
J.R. Veltmann, Jr., Ph.D., FAAIM, DCCN
The goal of any good health care professional is to personalize, customize, and individualize modalities, therapies, and treatments based on the phenotypic and genotypic uniqueness of a particular patient. Numerous methods may be used to try to capture this information. A health care professional might ask the patient to fill out an intake form, personalizing his/her signs and/or symptoms. Other providers, however, may require a more in-depth process, wherein copious amounts of information (family history, blood data, stress factors, diet, supplements, etc.) are collected and then evaluated, correlating phenotype with genotype prior to an office visit.
Sometimes, the unique phenotypic and genotypic characteristics of a patient are not revealed until after treatment when complaints about the therapy, botanical, or medication occur, or worse, when the patient experiences significant side effects. While individualizing the health care for each patient is the aim of any good health care professional, sometimes it can be overwhelming and time consuming.
Integrative Medicine as Personalized Medicine
Integrative Medicine (IM) is probably better suited for individualizing, personalizing, and customizing modalities, therapies, and treatments than conventional medicine because:
- The focus of IM is the health and vitality of the person versus attacking the disease;
- IM practices preventive medicine using conventional, complementary, and alternative approaches, working with the person to identify the best treatment(s) versus medicine of the averages;
- IM is patient-centered, wherein the person is evaluated on the physical, emotional, mental, and spiritual levels, which often takes longer than a 10-minute office visit will allow;
- IM practitioners communicate with their patients in a different way compared to conventional medicine practitioners;
- IM practitioners listen to their patients in a different way compared to conventional medicine practitioners; and
- IM practitioners view chronic disease as a multi-factorial condition versus the belief that one organism or agent results in one disease with one molecule to “kill” or “treat” it and one method of the “proof of efficacy” (double blind, placebo-controlled multi-centered trial) model of conventional medicine.
Integrative Medicine + Genomics = Personalized Integrative Medicine
To truly personalize IM, however, the IM practitioner ultimately needs to know the patient’s genotype. Until recently, this concept was left to futurists to ponder. The completion of the Human Genome Project in 2003, however, changed all that. That monumental task, one of the greatest achievements in the history of science, identified between 30,000 and 40,000 genes in the human body and revealed the sequence of over 3.5 billion chemical base pairs (nucleotides) that make up human DNA.
Matt Ridley summarized it well in his book, An Autobiography of a Species in 23 Chapters in 2000, which is paraphrased here: Imagine that the genome is a book, each chapter (chromosome) contains several stories called genes and the words making up those stories are written in four letters (A, C, G and T) corresponding to the nucleotides, adenine, cytosine, guanine, and thymine. These four letters code for every protein and every enzyme made by the human body playing important roles in cellular metabolism for every tissue and organ in the body.
Single Nucleotide Polymorphisms
More than 99% of human DNA is identical among all people. Yet, the relatively small amount of DNA that differs from person to person (less than 1%) ensures that no two humans are exactly alike (unless you are an identical twin). To create all the cells and tissues in the body, DNA must replicate itself billions and trillions of times, creating numerous opportunities for errors. When a gene sequence varies from its usual pattern (polymorphism), the normal shape and function of a protein can be altered, increasing the risk of some diseases or changing the way the body functions. The most common mistake is called a single nucleotide polymorphism or SNP (pronounced snip), where a single nucleotide in a gene is changed. For example, when comparing the same section of DNA, one person’s nucleotide “words” might read TAAA CA, whereas another’s might read TAAA GA. (Underscoring is used to indicate the single nucleotide that differs.)
Unlike Mendelian genetics, wherein phenotypic expression (trait) depends upon the dominant or recessive nature of the trait, the potential expression of an SNP depends upon whether it resides on one chromosome or both chromosomes, as well as the environment to which it is exposed.
Disease is Predetermined by Genes: NO
Most people believe that genes predetermine whether someone gets a disease or not. In some instances like cystic fibrosis, Huntington’s disease, or Tay Sachs, that is true. For almost all other human diseases, however, genes do not predetermine the disease but rather predispose a person to a disease depending on dietary and lifestyle choices and environmental factors. Genes are fluid and flexible in how they “express” themselves.
Disease: Interactions between genes and environment
The gene’s ability to promote disease depends, in almost all cases, on it being switched “on” or “off” by factors in the environment (cigarette smoke, air pollution, sun exposure, bacterial infection, toxins), dietary habits (nutritional imbalances, nutrient deficiencies), hormone imbalances, or lifestyle choices (lack of exercise). Therefore, the vast majority of SNPs only have the potential to cause health problems if exposed to the wrong “mix” of harmful agents over time. This is especially true for chronic diseases that develop with aging, such as heart disease, cancer, osteoporosis, arthritis, or Alzheimer’s disease.
Predictive Genomics, Nutrigenomics, and Pharmacogenomics
By knowing in advance what those SNPs are (predictive genomics) and what nutritional factors (nutrigenomics), environmental issues, or lifestyle choices need to change to turn these genes “on” or “off,” one can potentially decrease the risk of chronic diseases and personalize IM in a significant way. In addition, predictive genomics could empower a patient to take personal responsibility for maintaining his/her health and co-create a win-win relationship with a health care professional. Rather than a health care professional guessing what diet, supplement program, exercise program, and lifestyle choices are appropriate, and what over-the-counter medications or prescription drugs to avoid (pharmacogenomics), predictive genomics can provide clinicians pertinent genotypic information unique to an individual, permitting more effective, customized, and individualized therapies, tailored nutritional supplements, neutraceuticals, and prescription drugs to maximize health and avoid disease. Instead of relying on randomized studies involving large patient populations, epidemiological research, or ethnic tendencies, predictive genomics can allow the IM health care professional to practice true preventive medicine.
Cardiovascular, Osteoporosis, Immune, and Detoxification Platforms
More than 100,000 SNPs have been identified but less than 100 are relevant, prevalent, modifiable, and measurable by physiological tests, which can confirm whether an intervention (diet, supplements, lifestyle choices, or altering environmental factors) alters gene expression. In the two years I have been offering predictive genomics, I have evaluated more than 1,000 gene variants across four risk platforms: cardiovascular, osteoporosis, immune, and detoxification. (I will use my genome as well as others to illustrate how nutrigenomics and pharmacogenomics can maximize health and avoid disease). Within the cardiovascular platform, SNPs associated with inflammation, folic acid metabolism, blood coagulation, cholesterol regulation, and hypertension are evaluated.
SNPs associated with increased risks for developing bone loss include defects in calcium and vitamin D metabolism, parathyroid and calcitonin hormone action, abnormal collagen synthesis, and chronic inflammation. SNPs in the immune platform are associated with increased risk for asthma, rheumatoid arthritis, several types of cancers, and dermatological disorders, and include altered production and activity of cytokines (interleukins and Tumor Necrosis Factor-alpha). Within the detoxification platform, SNPs are evaluated in Phase I (Cytochrome P450 enzyme system) and Phase II (methylation, acetylation, glutathione conjugation) pathways. Defects in the detoxification pathways have been associated with increased risk of certain cancers, chronic fatigue, multiple chemical sensitivity, alcoholism, and adverse drug reactions to over-the-counter medications and prescription drugs.
Cardiovascular Platform Case History
Gene: Apolipoprotein E (Apo E)
Description: Apolipoprotein E (Apo E) is involved in dietary cholesterol and triglyceride transfer from chylomicrons and VLDL particles and is one of the genetic determinants of serum cholesterol and triglyceride levels. Accumulation of these remnants can result in premature coronary disease and peripheral vascular disease.
Gene Variants : Three allelic variants exist, Apo E2, Apo E3, and Apo E4, which are based on single nucleotide polymorphisms (SNPs) at two nucleotide sites.
Implication of SNPs : An individual’s Apo E combination (for example, Apo E2 / 3, Apo E3 / 3, Apo E3 / 4 or other combinations of 2, 3, or 4) can influence the risk of hypercholesterolemia, coronary event, and senile plaque formation. Having an E4 allele is associated with higher cholesterol, Apo B, Lipoprotein (a) and triglyceride levels along with lower HDL levels, all of which increase risk of atherosclerosis. In contrast, an E3 allele is moderately protective.
| Case History |
Family Health History |
| Male: 57 years of age |
Father- deceased (70 yr), aortic aneurysm |
| Weight: 190 pounds |
Mother- deceased (69 yr), kidney cancer |
| Height: 6’2” |
Mother’s sister-deceased (58), breast cancer |
| BMI: 24-25 |
Twin brother-good health |
| |
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| Blood Lipid Profile |
Genomics |
| Cholesterol: 198 mg/dl |
Apo E3/4 |
| HDL: 55 mg/dl |
|
| LDL: 125 mg/dl |
|
| TG: 91 mg/dl |
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| Chol/HDL ratio: 3.6 |
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| Homocysteine: 11.9 umol |
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| C-reactive protein: <0.1 mg/dl |
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| |
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Recommendations:
(In the interest of space, the suggestions provided below represent a shortened summary of those given to a person with this profile. A more detailed evaluation using the comprehensive, multi-factorial GENESIS System of Health Care is available upon request.)
- As the sum of the Apo E alleles goes up (in this case, it is 7), so too does the effect of dietary fat on serum cholesterol levels. Because of the presence of an Apo E4 allele, a very low fat, low cholesterol, high soluble fiber diet (Dean Ornish, Pritikin) is warranted.
- Individuals with an E3 allele respond well to regular aerobic exercise.
- The E4 allele dictates a front-line cholesterol lowering strategy. Those with an E4 allele respond better to probucol than to gemfibrozil or cholestyramine to lower cholesterol.
- Supplement with fish oils.
- Moderate to high doses of anti-oxidants (mixed tocopherols, ascorbic acid, and mixed carotenoids, selenomethione) may be needed to neutralize free radical production.
- Sublingual B-12 supplementation since one E4 allele increases lifetime risk for Alzheimer’s disease to 27 % at age 85.
Follow-Up
Regular monitoring of LDL, HDL, total cholesterol, triglycerides. Identify whether individual has SNP for MTHFR (Methylenetetrahydrofolate reductase), which may account for high normal homocysteine levels and another independent risk factor for Alzheimer’s disease. Be proactive in minimizing risks for Alzheimer’s disease.
Detoxification Platform-Phase I Case History
Gene: Cytochrome P450 1B1
Description: Phase I detoxification is the first line of defense against toxic substances we consume from the environment (solvents, pollution, smog), from food (pesticides, herbicides) from medicines, and from natural waste products of metabolism (steroids) that our body produces. Enzymes in the liver act on the chemical structure of a toxin to make it easier to excrete. This step is sometimes referred to a biotransformation. For some compounds, including many over-the-counter medications and prescription drugs, Phase I is all that is needed to eliminate the toxin. Other toxins are actually made more reactive after Phase I and require an additional step, Phase II. Phase II is the second line of defense against toxic substances, altering the chemical structure of a toxin by adding to or conjugating water-soluble molecules to it, to facilitate its removal from the body.
Genetic Variants: Polymorphisms (SNPs) in the genes coding for a particular enzyme can increase or more commonly decrease the activity of that enzyme. SNPs that decrease the activity of cytochrome P450 enzymes, enzymes associated with Phase I detoxification, can lead to toxic accumulation in the body. A decreased capacity for clearing drugs or steroid hormones from the system often lead to adverse drug reactions (ADRs) or can increase the risk for estrogen-induced cancer.
Implication of SNPs: Cytochrome P450 1B1 (CYP 1B1) coverts estrogen into 4-hydroxy estrogen. A SNP associated with this enzyme increases the risk of estrogen-sensitive carcinogenicity. CYP 1B1 is also partially responsible for breakdown polycyclic hydrocarbons and products related to the burning of organic material such as car exhaust, cigarette smoke, and charbroiled foods. Drugs ranging from antidepressants (Elavil, Trofranil), caffeine, acetaminophen (Tylenol), Clozaril, Naproxen, to Coumarin also are biotransformed by this enzyme. Inhibitors of this CYP enzyme include some drugs (Tagamet, Cipro, Luvox) and botanicals (grapefruit juice and possibly ginseng). This area of Phase I and Phase II detoxification can be extremely complex, discerning which drugs either induce or inhibit substrates passing through the respective cytochrome P450 enzyme system. (A detailed description of the substrates, inducers and inhibitors of the most significant cytochrome P450 enzymes can requested from the GENESIS Center for Integrative Medicine, 505.986.8835 voice or 505.982.4603 fax).
| Case History: |
Family Health History |
| Woman: 54 years of age |
Mother-Breast Cancer |
| Genomics: SNP: CYP 1B1 |
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Recommendation: Supplement with DIM Pro (75 mg DIM complex). Compare drugs that use CYP1B1 for detoxification against those taken by individual. Table below shows hormone levels and 2:16 estrone ratio before (2/2004) genomics test and 4 months after (6/2004) supplementation with DIM Pro (75 mg DIM complex).
| Hormone Levels |
2/2004 |
6/2004 |
Reference range |
| Estradiol |
56 |
33 |
20-160 pg/ml |
| Estrone |
60.5 |
28 |
20-95 pg/ml |
| Estriol |
42 |
17 |
17-63 pg/ml |
| 2-OH estrone |
139 |
258 |
112-656 pg/ml |
| 16-α-OH estrone |
525 |
283 |
213-680 pg/ml |
| 2:16 estrone ratio |
0.26 |
0.91 |
0.40-1.40 pg/ml |
Detoxification Platform-Phase II Case History
Gene: Catechol-O-methyl-transferase (COMT)
Description: Catechol-O-methyl-transferase (COMT) is a Phase II detoxification enzyme primarily responsible for the breakdown of the neurotransmitters dopamine, epinephrine, and norepinephrine. In women, COMT is associated with increased risk of breast cancer and lymph node metastasis.
Genetic Variants: Single nucleotide polymorphisms (SNPs) can exist yielding either a heterozygous or homozygous variant.
Health Implication of SNPs: With two bad genes (homozygous) for COMT, the odds ratio for breast cancer is 4 to 5 fold. The risk for breast cancer is increased also if SNPs occur in CYP1B1, GSTM1, GSTP1, GSTT1, exposure to estrogen (ERT > 30 months) or early menarche.
Case History:
Detoxification Platforms evaluated for both husband and wife
| |
Husband |
Wife |
| SNP in Phase I |
CYP 1B1 |
CYP 1B1 |
| SNPs in Phase II |
|
|
| COMT |
heterozygous |
|
| GSTM1 |
null |
null |
| GSTP1 |
heterozygous |
heterozygous |
Clinical note: 14 year-old daughter is at very high risk for breast cancer because both parents have SNPs for CYP1B1, GSTP1, GSTM1 and father has a SNP for the COMT gene.
Recommendations:
(In the interest of space, the suggestions provided below represent a shortened summary of those given to a person with this profile. A more detailed evaluation using the comprehensive, multi-factorial GENESIS System of Health Care is available upon request.)
- Support both husband and wife with DIM Pro, a dietary supplement containing a 75 mg DIM complex, known to up-regulate the conversion of estrone to 2-OH estrone and minimize the conversion of estrone to 16-α-OH estrone, a metabolite associated with estrogen sensitive cancers. In men, DIM supplementation decreases risk for prostate cancer. Support husband with SAMe, a cofactor needed by catechol-O-methyl-transferase.
- Encourage the entire family to avoid solvents and foods sprayed with pesticides, Herbicides, and insecticides because neither the husband and wife have GSTM1 (glutathione s-transferase isoform M1) genes, which detoxify many water soluble environmental toxins, and therefore have not passed this gene on to any of their kids. A defective glutathione conjugation capacity may increase toxic burden, increase oxidative stress, and can contribute to various cancers throughout the body. Support husband, wife, and teenage children with antioxidants and supplements that raise glutathione levels (n-acetylcysteine, milk thistle, selenomethione, glutathione).
- Have daughter do a Women’s Hormonal Health Assessment at 18 years of age to monitor progesterone, DHEA, testosterone, estradiol, estrone and estriol, 2-OH estrone and 16-α-OH estrone levels. Likely will recommend DIM Pro.
Summary and Conclusion
Predictive genomics, nutrigenomics, and pharmacogenomics have received lots of attention lately in the lay press, in professional journals, and in published books. Most notable was the 8-page cover article in Newsweek magazine entitled “Diet and Genes, The New Science of Nutrition and Aging,” published in January 2005. In 2003, The New York Times reported about how advances in the new science of nutrigenomics will create the ultimate personal diet.
When you “Google” nutrigenomics, there are about 44,000 citations as of May 2005. Within PubMed, there are 39 referred articles with nutrigenomic in the title, abstract, or article. And there are hundreds of thousands more citations in PubMed when pharmacogenomics, genome, or predictive genomics is included. Evidenced by the research, publications, seminars and venture capital in predictive genomic, nutrigenomics, and pharmacogenomics, this is the next sustained wave for medicine. IM has its roots in patient-centered care and management, multifactorial approaches to treatments and therapies, and an emphasis on the mind-body-spirit connections and, therefore, can more easily incorporate predictive genomics, nutrigenomics, and pharmacogenomics into its paradigm than conventional medicine. By doing this, IM can become the gold standard for personalized medicine in this country.
Resources
Books
Bishop, J.E., & Waldholz, M. (1990). Genome: The Story of the Most Astonishing Scientific Adventure of Our Time—The Attempt to Map All the Genes in the Human Body. New York: Simon & Shuster.
Bland, J.S., & Benum, S. (2000). Genetic Nutritioneering: How You Can Modify Inherited Traits and Live a Longer, Healthier Life. New York: McGraw-Hill.
Kurzweil, R., & Grossman, T. (2004). Fantastic Voyage. Emmaus, Pennsylvania: Rodale Press.
Reilly, P.S. (2004). Is It in Your Genes? The Influence of Genes on Common Disorders and Disease that Affect You and Your Family. New York: Cold Spring Harbor Laboratory Press.
Ridley. M. (2000). Genome: The Autobiography of a Species in 23 Chapters. New York: HarperCollins.
Williams, R.J. (1998). Biochemical Individuality: The Basis for the Genetrophic Concept. New York: Keats.
Magazines, Newspapers
Grierson, B. (May 4, 2003). What Your Genes Want You to Eat. The New York Times.
Underwood, A., & Adler, J. (Jan. 17, 2005). Diet and Genes. Newsweek.
Review Articles
French, M. (2004). Genomic Health Nutrigenomics: Nutrition and the Science of Optimal Genome Maintenance. Asia Pac. J. Clin. Nutr. 13 (Suppl): 515.
Loktinov, A. (2003). Common Gene Polymorphisms and Nutrition: Emerging Links with Pathogenesis of Multifactorial Chronic Diseases. J. Nutr. Biochem. 14(8): 426-451.
Milner, A. (2004). Molecular Targets for Bioactive Food Components. J. Nutr. 134(9): 492S-2498S.
Paoloni-Giacobino, A., Grumble, R., & Picharo, C. (2003). Genomic Interactions with Disease and Nutrition. Clin. Nutr. 22(6): 507-514.
Technical articles
Retrieved from http://www.genovations.com/home/clinican_overview.html.
Retrieved from http://www.genovations.com/home/patient_overview.html.
Seminars
Bland, J.S. (2005). Functional Medicine and Nutrigenomics. The Four Masters: Nutrigenomics in Practice. Tempe, Arizona: Institute for Human Individuality (April 15-17).
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