How Psychogenetics &
Nutrigenomics Began
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Nutrigenomics and Pharmacogenomics : A new Era in therapeutic Targets.
Kenneth Blum, PhD
Chairman of the Board & CSO
LifeGen, Inc.
San Diego, California
INTRODUCTION
In this article we are suggesting that in this era genes and nutrition will be the target of ongoing research. Currently, the nutraceutical world has seen only limited research in this wonderland of potential. However, the concept of gene -based response especially in the pharamaceutical world is growing and billions of research dollars are being poured into the field known by the pharmaceutical world as pharmacogenomics. In this paper our purpose is to show how one's genome is ever important in a response to any biologically active substance such as drugs and more importantly nutrients. If as a partner in the health industry we begin to focus our attention on the principals laid down here we will survive and scientifically develop potential treatments for many naturally based dysfunctions. As our knowledge of genomics continues to grow so will nutrigenomics in all of its facets, especially to help us understand the basis of individual differences in response to dietary patterns and targeted supplementation. It is my opinion that gene mapping , especially of brain based genes associated with neurochemistry and function, will be the new target of not only ongoing research but actual practice. Journey with me into the wonderland of genes and nutrition.
THE ADVENT OF GENOMIC MEDICINE
The recent completion of the draft sequence of the human genome and related developments have increased interest in genetics, but confusion remains among health professionals and the public at large. Inaccurate beliefs about genetics persist, including the view that in the past it had no effect on the practice of medicine and that its influence today is pervasive. We have recently entered a transition period in which specific genetic knowledge is becoming critical to the delivery of effective health care for everyone ( Uhl & Crow 2004). While we do not know precisely how many genes the human genome contains, current data indicate that the human genome includes approximately 30,000 to 35,000 genes- a number that is substantially smaller than was previously thought ( Guttmatcher, Alan & Francis , 2002).
Genetics vs. Genomics
If genetics has been misunderstood, genomics is even more mysterious-what exactly, is the difference? Genetics is the study of single genes and their effects. "Genomics" , a term coined only 17 years ago, is the study not just of single genes, but of the functions and interactions of all the genes in the genome. Genomics has a broader and more ambitious reach than does genetics. The science of genomics rests on direct experimental access to the entire genome and applies to common conditions, such as breast cancer, colorectal cancer, human immunodeficiency, cardiovascular, Parkinson's disease and certain brain and neurological disorders such as Alzheimer's, bipolar disorder, Reward Deficiency Syndrome, and even Attention Deficit Disorder (ADHD) and related behaviors. These common disorders are also all due to the interactions of multiple genes and environmental factors
Genes 101
Only about half these genes have recognizable DNA sequence patterns that suggest possible functions. Mutations known to cause disease have been identified in approximately 1000 genes. However, it is likely that nearly all human genes are capable of causing disease if they are altered substantially. Whereas it was dogma that one gene makes one protein , it now appears that, through the mechanism of alternative splicing, more than 100,000 proteins can be derived from these 30,000 to 35,000 genes. Once thought that DNA expression is fixed in stone new evidence now suggests that DNA expression is a dynamic process. In addition to alternative splicing, a number of "epigenetic" phenomena, such as methylation and histone modification, can alter the effect of a gene. Furthermore, a complex array of molecular mandates allows specific genes to be "turned on" ( expressed) or "turned off" in specific tissues and at specific times. Genes are distributed unevenly across the human genome. Certain chromosomes particularly 17,19, 22 are relatively gene dense as compared with others , such as 4,8,13, 18, Y. ( Evans, William, Mcleod & Howard, 2003)
Interestingly, gene density varies within each chromosome, being highest in areas rich in the bases cytosine and quanine, rather than adenine and thymine. Moreover, not all genes reside on nuclear chromosomes, several dozen involved with energy metabolism are on the mitochondrial chromosome. Since ova are rich in mitochondria and sperm are not, mitochondrial DNA is usually inherited from the mother. Therefore, mitochondrial genes- and diseases due to DNA sequence variants in them -are transmitted in a matrilineal pattern that is distinctly different from the pattern of inheritance of nuclear genes ( Evans & Relling, 1999)
Variation in Human Genome
One characteristic of the human genome with medical and social relevance is that, on average, two unrelated persons share over 99.9 percent of their DNA sequences. However, given the more than 3 billion base pairs that constitute the human genome, this also means that the DNA sequences of two unrelated humans vary at millions of bases. Since a person's genotype represents the blending of parental genotypes, we are each thus heterozygous at about 3 million bases. Many efforts are currently under way, in both the academic and commercial sectors, to catalogue these variants, commonly referred to as " single-nucleotide polymorphisms" (SNPs), and to correlate these specific genotype variations with specific genotypic variations relevant to health. Some SNP-phenotype correlations occur as a direct result of the influence of the SNP on health. More commonly, however, the SNP is merely a marker of biologic diversity that happens to correlate with health because of its proximity to the genetic factor that is actually the cause. In the case of mood there are multiple genes (polygenic inheritance) involved and thus potentially 100's of SNPs. In general terms, the SNP and the actual genetic factor are said to be in linkage disequilibrium ( Cascorbi et al. 2001).
PHARMACOGENOMICS/NUTRIGENOMICS
The convergence of Pharmacogenetics and rapid advances in human genomics has resulted in pharmacogenomics and/or nutrigenomics, terms used here to mean influence of DNA-sequence variation on the effect of a drug and/or a natural substance or nutrient. With the completion of the Human Genome Project, and the ongoing annotation of its data , the time is rapidly approaching when the sequences of virtually all genes encoding enzymes that catalyze phase 1 and phase 11 drug metabolism will be known including genes that encode drug (nutrient) -transporters, drug (nutrient ) receptors, and other drug (nutrient) targets.
Genome -Based Response
It is well know that individuals respond differently to medications and certain nutraceuticals in terms of both toxicity and treatment efficacy. Potential causes for such variability in drug (nutrient) effects include the pathogenesis and severity of the disease being treated: drug (nutrient) interactions; the individual's age, nutritional status; kidney and liver function; and concomitant illnesses. Despite the potential importance of these clinical variables in determining drug/nutrient effects, it is now recognized that inherited differences in the metabolism and disposition of drugs/nutrients, and genetic variants (polymorphisms) in the targets of drug/nutrient therapy (such as receptors like the dopamine D2 receptor), can have even greater influence on the efficacy and toxicity of either medications or nutraceuticals.
Historical Wonderland
Clinical observations of such inherited differences in drug effects were first documented in the 1950's, exemplified by the prolonged muscle relaxation after the drug known as suxamethonium ( an inhibitor of the breakdown of acetylcholine) and an inherited deficiency in the genes that encode the enzyme responsible for the breakdown of this drug as marked by plasma cholinesterase ( the enzyme which breaks down acetylcholine). The second gene -based drug response was observed when researchers found that certain patients bled to death after they were treated with an anti-malarial therapy because they carried a gene variant which lowered their blood cell glucose 6-phosphate dehydrogenase activity. Such observations gave rise to the field of "pharmacogenetics" the antecedent to pharmacogenomics, the current topic. However, we now know that individual differences in response to drugs and or nutrients are not due to single gene variants but rather they are determined by the interplay of several genes encoding proteins ( enzymes, receptors, transporters) involved in multiple pathways of drug/nutrient metabolism, disposition and effects ( Otani, Koichi, Aoshima & Toshiaki 2000). We are embarking on new era where efficacy of any substance is governed by an individual's inherited genotype to a greater degree than even other non-genetic factors. Understanding structure/function normal physiology and certain observable dysfunctions may indeed lead to promising nutrient based targets, but without the knowledge afforded by accurate DNA based prescreening ( genotyping) subsequent supplementation becomes nothing more than a crap shoot. Similar to the pharmaceutical industry the nutraceutical industry can become an equal opportunity player and begin to initiate ongoing research and development by incorporating these genomic based doctrines as described herein. It is literally a Nutrigenomics wonderland of opportunity ( Kalow , 2001).
The first US patent ever awarded in the area of Nutrigenomics occurred in 2000 when Dr. Kenneth Blum was issued US 6,955,873B1.
GENE VARIANTS AND INDIVIDUAL RESPONSE TO TARGETS
Out of the 3 million unshared DNA bases, individuals could carry gene variants ( polymorphisms) that might lead to either an increase or a decrease of a certain important drug/nutrient response related proteins such as receptors, enzymes, cell cycle control, chemical messenger synthesis or catabolism ( breakdown) or many other cellular events. As stared earlier while there is a paucity of molecular studies involving genome -based response in the nutrition field ( see below), a plethora of molecular studies have revealed that many genes encoding drug targets exhibit genetic polymorphism ( variants), which in many cases alters their sensitivity to specific medications and /or offer specific targeted therapy ( Ma et al ,2002, Ordovos, Jose , Mooser & Vincent, 2002,.Cadman , Peter, O'Connor, Daniel, 2003,Weinhilboum , 2003, Stephen et al 2003, Sellers 1997, Sui & Wang, 1998, Yoshioka et al 1999, Ordovas 1999, Singh & Niaz 1999,
Such examples include the following:
" Asthma- Polymorphisms in Beta -adrenergic receptors ( adrenalin -like) impart differential sensitivity to substances that stimulate these receptors ( beta -agonists) in asthmatics.
" Renal function and Blood pressure -angiotensin converting enzyme (ACE) gene polymorphisms impart differential sensitivity to inhibitors of ACE .
" Cardiovascular - angiotensin 11 T1 receptor gene polymorphisms impart differential sensitivity to the substance phenylalanine and subsequent vascular reactivity.
" Diabetes- polymorphisms in the sulfonyurea receptor gene imparts differential responsiveness to sulfonyurea hypoglycemic agents
" Coronary atherosclerosis - polymorphisms in the gene which controls the enzyme cholesteryl ester transfer protein impart differential efficacy of the drug pravastatin in patients with coronary disease.
" Dysrthythmias- Potassium channel mutations predict drug -induced dysrthmias as an adverse effect.
" Drug Metabolism- Polymorphisms in the P-450 enzymes responsible for metabolizing drugs such as caffeine and codeine impart differential clearance of these and other substances. One such an enzyme is the CYP2D6 .
" Breast Cancer- Trasruzumab is a drug known to target a certain genetic mutation in a protein product of the HER2/neu oncogene ( which is overexpressed in breast cancers) and has been found compared to standard therapy to be superior un preventing metastatic breast cancer.
" Diuretic therapy- There is a gene known as C825T involved with a second messenger G-protein {beta}3 whereas polymorphisms in this gene predict responsiveness to the anti-diuretic drug ( used to treat hypertension ), hydrochlorothiazide.
" Lipid reponse- Genetic variation of the apolipoprotein constituents of the lipoprotein molecules (APOE gene locus) predicts plasma low -density lipoprotein cholesterol (LDL-C) concentrations. Interesting carrying one form of the APOE ( E4) seems to be more responsive to dietary modification than carriers of E3 and or E2 forms of the same gene.
PHARMACOGENOMICS OF BRAIN DYSFUNCTION
Mood and brain disorders represent one of the major sources of health -related disability worldwide. There is growing evidence that certain gene polymorphisms predict treatment response ( Busto, 2000,Gohil, 2002, Harada et al. 2003, Davis et al. 2003, Kondo et al 2003).
Such examples include the following:
" Major depressive disorder- polymorphisms in a gene responsible for the production of the serotonin transporter protein predicts response to SSRI's .
" Sleep deprivation- polymorphisms in a gene responsible for the production of the serotonin transporter protein predicts response to SSRI's .
" Anti-depressant response- polymorphisms of a gene responsible for serotonin synthesis ( tryptophan hydroxylase gene -THP) predicts slow response to SSRIs.
" Mania- Positive Lithium response was dependent on not only the TPH gene polymorphisms but on variants found on chromosome 15q14 and on chromosome 7q11.2. Interestingly both of these chromosome regions have not been associated with manic/depressive illness.
" Neuroleptic Response- polymorphisms in the gene which regulates the 5-hydroxytrytamine receptor imparts differential responsiveness to the neuroleptic drug clozapine.
" Alzheimer's disease- mutations in the apolipoprotein E gene predicts responses of patients with Alzheimers disease to tacrine therapy.
" Tardive dyskinesia(TD)- Dopamine D3 receptor polymorphisms are linked to drug -induced TD.
" Alcoholism treatment- polymorphisms in the dopamine D2 receptors predicts responsiveness to bromocriptine ( a D2 agonist) to prevent relapse in alcoholics.
" Attention Deficit Disorder (ADHD)- polymorphisms in the dopamine transporter gene predicts responsiveness to methyphenidate (Ritalin) to treat ADHD.
" Posttraumatric Stress Disorder (PTSD) - polymorphisms in the dopamine D2 receptors predicts responsiveness to the SSRI paraxetine to treat PTSD.
" Schizophrenia- Dopamine D2 receptor gene polymophisms is a predictor of treatment -resistance to dopamine antagonists in schizophrenic patients.
" Nicotine Withdrawal The DRD2 TaqA1 allele modifies the treatment outcome of bupropion activity to attenuate nicotine withdrawal.
GENOME -BASED NUTRIENT RESPONSE
Certainly we have come full circle from the "Naturalistic Era" (400B.C. -1750 AD), to the "Chemical Analytical Era" (1750-1900) to the "Biological Era" ( 1900-present), to the "Cellular Era"( post 1955) and the current era of the 21st century where "genomics" is the new buzz word ( Fogg-Johnson & Merolli). Utilizing tools derived from this new science will allow us to identify and understand molecular -level interaction between nutrients and other dietary bioactives with the human genome during transcrption , translation and expression, the process during which proteins encoded by the genome are synthesized and expressed. There is growing evidence that certain gene polymorphisms predict response to nutrients ( Chavez , Munoz de Chavez, 2003, Paoloni-Giacobino, Grimble & Pichard 2003)
In the broadest terms the interface between the nutritional environment and cellular/genetic processes is being referred to as "nutrigenomics". While nutrigenomics in this sense seeks to provide a molecular genetic understanding for how common dietary chemicals ( i.e. nutrition) influences health by altering the expression and/or structure of an individual's genetic makeup, the more restricted view is governed by the same principles as seen with advent of pharmacogenomics in clinical medicine which involves DNA based - targeted response to biologically active compounds ( Mammes et al 2001, Junien, 2001, Uyeda,Yamashita & Kawaguchi, 2002, Loktionov 2003, Paoloni-Giacobino, Grimble & Pichard 2003), Ernest et al 2003, Lucock, 2000).
The tenants for nutritional genomics include in the broadest sense the following:
" Common dietary substances act on the human genome
" Diet can be a risk factor for a number of genetic diseases or behavioral disorders.
" Diet-regulated genes are likely to play a role in the onset, incidence, progression and/or severity of chronic diseases.
" Diet affects the balance between healthy and disease states and this interaction depends on an individuals genetic makeup
" Dietary intervention based on knowledge of nutritional requirement, nutritional status, and genotype ( i.e. "individualized nutrition") can be used to prevent, mitigate, or cure chronic disease or behavioral disorders.
While there is plethora of scientific information concerned with four of the five tenets, there is a paucity with regard to "individualized nutrition".
In terms of dietary intervention based in individualized nutrition such examples of a number of gene-disease association studies have shown promise of this approach as follows:
" Hypertension- The amount of circulating angiotensinogen (ANG) is associated with increased blood pressure. A SNP ( polymorphism) , designated AA, at nucleotide position -6 of the ANG gene is linked with the level of blood ANG protein. Individuals with the AA genotype who eat the Dietary Approaches To Stop Hypertension( DASH) diet show reduced blood pressure., but this diet was less effective of carriers of the GG genotype.
" Cardiovascular Apo-A1 gene plays a role in lipid metabolism and coronary heart disease. The A allele ( variant) was associated with decreased serum HDL levels. The variant was coupled with consumption of type of fat and subsequent effect on HDL levels in both males and females carrying different genotypes.
" Cancer- Methylenetetrahydrofolate reductase (MTHFR) is a key gene in one-carbon metabolism and, indirectly, in all methylation reactions. The C667T polymorphism of this gene, which reduces enzymatic activity, is inversely associated with occurrence of colorectal cancer and acute lymphocyte leukemia. Low intake of folate, B12 , B6 and methionine was associated with increased for cancer among those with the MTHFR TT genotype.
" Rheumatoid arthritis - Polymorphisms in the proinflammatory cytokine tumor necrosis factor (TNF) impart a differential response to fish oil supplementation to treat rheumatoid arthritis.
" Oxidant stress and inflammation- Polymorphisms in the TNF gene impart a differential response to vitamin E to promote anti-oxidant activity and reduce inflammatory processes.
" Carbohydrate metabolism-Based on polymorphisms in the gene called carbohydrate responsive element-binding protein (ChREBP) , a key regulator of glucose metabolism and fat storage , Cyclic AMP and a high fat diet inhibit ChREBP and slow down glucose utilization.
" Obesity- In overweight women carriers of the C polymorphisms of the Leptin receptor gene lost more weight in response to low calorie diet than the non carriers.
" Central Nervous System - Extracts of Ginkgo biloba induce differential expressions of 43 cortex genes, 13 hippocampus genes, and four other genes common to both brain regions.
A Case Study: Chromium and Dopamine Genes
While there is still controversy regarding the effects of chromium salts (picolinate and nicotinate) on body composition and weight loss in general, recent work seems to support the positive change in body composition in humans. My lab embarked on the present study with chromium picolinate to test out the principles of nutrigenomics ( Blum & Braverman , 2000)
In this study we genotyped obese subjects for the dopamine D2 receptors gene (DRD2).The subjects were assessed for scale weight and for percent body fat. The subjects were divided into matched placebo and chromium picolinate (CrP) groups. The sample was separated into two independent groups; those with either an A1/A1 or A1/A2 allele and those with only the A2/A2 allelic pattern
The measures of the change in fat weight ,change in body weight, the percent change in weight , and the body weight change in kilograms were all significant, whereas no significance was found for any parameter for those subjects possessing a DRD2 A1 allele.
These results suggest that the dopaminergic system, specifically the density of the D2 receptors, confers a significant differential therapeutic effect of CrP in terms of weight loss and change in body fat. Moreover, we propose for the first time that mixed effects now observed with CrP administration in terms of body composition, may be resolved by typing the patient via DRD2 genotyping prior to treatment with chromium salts.
TOXINS, DIET & GENES
There is a current interest in the relationship between toxins, diet and the role of our genes and biological response. There is emerging data showing differential response to heart disease and other medical conditions based on levels of specific toxins as well as genetics. There is some interesting data on excitotoxins and their widespread use in foods ( especially un artificial sweeteners). Blaylock has reviewed the effects of such toxins like lead, aluminum, cadmium, mercury, manganese etc and biological response and the role of genes. (NEED REF). To give just one example of an interaction between race, diet and a toxin, American Blacks tend to have a genetic vulnerability to lead due to lactose intolerance, which results in low levels of calcium in their diet. Since lead is, like calcium, a divalent cation, exposure to lead by individuals with very low calcium in their circulating blood or body stores are more likely to absorb lead. And insofar as both genetics and poverty have reinforcing effects in this vulnerability , this may have important ramifications. Aster all, the prevailing cultural stereotypes of black inferiority just hace to coincide with the effect of lead neurotoxcity.
DNA-BASED INDIVIDUALIZED NUTRITION: A NUTRIGENOMICS WONDERLAND
certainly if we could get the cost of identifying a person's SNPs down to pennies rather than hundreds of dollars, we will be on the correct path to induce the concepts of nutrigenomics. Current costs of genetic tests range from $250 for prenatal assessing 76 diseases to $1,595 for Alzheimers ( MacKeen, 2005) While there are a number of companies involved in genotyping an individuals DNA, there are few that couple DNA with individualized nutrition. On the other hand, tools are now available and new ones are in progress which will have relevance to the arising field of nutrigenomics. One company already involved in "individualized nutrition", Signature Health Partners, Inc (SHP) in Ventura California, developed a computerized program called Nutrascan which catalogues health priorities and screens out drug - nutrient interactions using approximately 5000 evidence -based rules which will identify individualized nutritional needs. In one scenario a person can swab their mouth for cheek cells and submit the swab to a central DNA laboratory and determine brain related neurotransmitter gene ( serotonin, endorphins, GABA, dopamine, acetylcholine etc) polymorphisms. If a person carries a gene variant in the serotonin receptor (deficient) then it quite plausible to induce receptor proliferation by providing that individual a tryptophan enhancing substance like chromium and or 5-hyroxytryptophan. This may be important for adjunctive supplementation to offset some of the symptoms related to a "sweet tooth" which could ultimately result in a reduction of weight. This can then be incorporated into a program on an genome based individualized basis using the Baxter customized packeting system already utilized commercially by our company. We believe that nutrigenomics is closer than ever before and will indeed be the wave of the future"
SUMMARY
As scientists engaged in understanding the potential of drug/nutrient responses, as a function of our genome, and all of its ramifications, including academic and commercial aspects, our future looks bright. While, however, being cautious about our future especially in terms regulatory issues, gene -nutrition interactions especially related to genome based response will indeed be the next cornerstone of solid scientific approaches to assist individuals in choosing dietary supplements, functional foods, and even nutritional beverages on an individualized basis. Nutrigenomics is the key to what I have termed "nutritional gene therapy" and from its origin will spring gene mapping as the wave of the future in nutrition. The information provided in this treatise will serve as evidence of our conviction of this scientific wonderland of opportunity ( Daniel, 2002).
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Dr. Blum and Dr. Waite advocated a non-specific "healthy diet" and non-specific regular exercise to accompany a regimen of taking Synaptose
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TM
changes the plasticity of the brain synapses while balancing the endogenous neurotransmitters, positively affecting the Brain Reward Cascade.
