Molecular Genetics in Clinical Psychiatry

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Molecular genetics in clinical psychiatry Dr Kobus Roux Psychiatrist Chairperson for GMPP CPD Committee Benoni, Johannesburg

Dr Eugene Allers Psychiatrist Benoni, Johannesburg

Report on a workshop of the South African Psychiatry Society’s Molecular and Cellular Special Interest Group.

Introduction “Molecular medicine has the capacity to deliver a precise diagnosis of an individual’s complaint/disease so that therapy can be more effectively tailored. While oncologists are leading the way in this field, psychiatry needs to catch up,” Dr Kobus Roux, psychiatrist in private practice, Benoni, stated at the outset of his well-attended meeting held in February 2016, with support from the Cipla Neuroscience Academy, at the Arabella resort near Hermanus. Advances in bioinformatics will soon allow storage of an individual’s total genomic data on a single gigabyte memory stick. Costs of DNA determination are also dropping rapidly and analysis of the whole genome can be done for less than US$1000. 23andMe and Illumina market directly to the public and advertise analysis and reporting of raw data from as little as US$390.

KEY MESSAGES

Dr Elizabeth Peter-Ross Intellectual Disability Psychiatrist Life Vincent Pallotti Hospital Cape Town

• Understanding of coding genes (exons) and their control by non-coding mechanisms, which are situated in the chromosome (introns) and around the chromosome in the epigenetic environment, is set to re-classify medical illnesses because the ICD10 codes and the DSM-V are not appropriate to the delivery of precision medicine • All branches of medicine are behind oncology in the use of genetic information to tailor therapeutic options and individualise treatment • Neuropsychiatry will, over time, move away from defining drugs as affecting particular neurotransmitters to defining them in terms of their capacity to ‘switch on/off’ or modify gene expression

Dr Leigh Janet Psychiatrist Sandton, Johannesburg

• Pharmacogenomic insights can already be added to current pharmacokinetic and pharmacodynamic knowledge to avoid under-reaction and hypersensitivity reaction to psychiatric drugs • The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with increased risk of coronary artery disease (CAD) in young South African Indians1

This article was made possible by an unrestricted educational grant from Cipla, which had no control over content.

• A number of treatable genomic MTHFR polymorphisms are important in mood disorders, particularly depression, suggesting that there is a need to augment medication with nutrients such as L-methylfolate or folate • Lithium should be considered not only as first line for bipolar disorders, but also for other neuropsychiatric disease such as Parkinson’s and mild cognitive impairment (namely the early stages of Alzheimer’s). (Dosage not yet determined)

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Molecular Genetics in Clinical Psychiatry

Relation between genotype and phenotype There is a complex relationship between genotype and phenotype (Figure 1). “All our phenotypical differences are encoded by 0.1% of an individual’s DNA; the larger variations in phenotype are determined by the epigenetic environment and its capacity to modify gene function,” Dr Roux pointed out. On average, 60 new

mutations occur in the coding genes de novo (referring to new mutations that were not present in the maternal or paternal genomes), while point mutations (SNPs) occur on average once per 1 000 base pairs (Figure 2). SNPs can be either active or silent, and can also cluster and be inherited together (haplotypes).

Environment

Mental illness

Organism

Organisational phenotype

Anatomy

Physiology

Behaviour

Proteome

Epigenetics Gene interaction Cell Function

Transcriptome

Metablomics

Metabolism

Signaling

Motify

Mitosis

Adhesion

Stress response

MtDNA Gene network

Proteome

Genome Figure 1. The relation between Genotype and Phenotype 2

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Molecular Genetics in Clinical Psychiatry

For example, in breast cancer, the Human Hapmap project has determined 2600 different alleles of the BRCA1 gene. Of these, some 1100 alleles are associated with a high risk of breast cancer, colon cancer and other specific cancers, and encode for a protein that aggressively stimulates cancer cell replication. Figure 2. Single nucleotide polymorphisms (SNPs) are the most common genetic variation between people

Control of human gene expression – switching genes on and off Complex mechanisms control the switching on and off of genes. The epigenetic environment is a relatively stable area of gene control; once set, it reacts mostly to severe challenge or in specific pathologies. The dangerous time for modification of the epigenetic area is during the period of conception to birth and during the perinatal period. This highlights the importance of being exceedingly cautious in prescribing drugs during pregnancy and breastfeeding. Figure 3 describes the process of control of gene expression and notes also the importance of small noncoding RNA in the control of microRNA. Errors in these microRNAs have been linked causatively with conditions such as muscular dystrophy and offer a potential target for therapy. The promoter area (illustrated in Figure 3) acts as a switch to silence or express genes. About 32% of all human genomic promoters have a TATA box (consisting of TATA sequences). “To read the TATA box you need a PHD, which in this case stands

for ‘planthomodomain’.” Examples of these PHDs are zinc fingers and leucin zippers. This explains the high association across the entire genome between zinc finger genes and many disorders, including mental disorders. Further regulatory functions are now being ascribed to RNA, beyond its being merely a messenger between RNA and DNA.2 Small non coding RNA: mi RNA si RNA “gene silencer”

Proteins

mRNA

promoter TATA Box

Exon

Intron

Exon

To read the TATA Box you need a PHD • Leucin Zipper • Zinc finger (DNA Polymerase) Figure 3. Control of gene expression

A ‘Google map’ of an individual’s molecular profile

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The ENCODE project, undertaken as part of the 1000 Genomes Project, focuses on the control of gene expression and identified four million switches involved in gene expression, thereby placing ’junk DNA’ in a premier regulating role. While the data sets are large, a matrix data set built in layers could provide a functional ‘Google map’ of an individual’s total genome against the background of the big data collected from numerous projects. This would allow a prediction to be made of an individual’s health and disease over time (Figure 4). This idea was proposed in a workshop hosted in 2011 by a special task team of the national

academies, namely the Committee on a Framework for Developing a New Taxonomy of Disease. Google maps: GIS layers Organised by Geographical Positioning

Information Commons Organised around individual patients

Transportations Land use Census Tracts Structures Postal Codes Raster Imagery Figure 4. Building a knowledge network for biomedical research and a new taxonomy of disease APRIL 2016

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Molecular Genetics in Clinical Psychiatry

Pharmacogenomics of major depression – Dr Eugene Allers The over-arching aim of pharmacogenomics is individualisation of drug choice for the best treatment outcome with minimum side effects. Using the science of genomics and the understanding of genes and their functioning, optimal drug choice for the individual is possible. In psychiatry, this will help to avoid the situation where patients with the same diagnosis are non-responders to a classic treatment while others experience more toxic events than the norm. The most significant advance has been in the understanding of the role of telomeres and telomerase, which functions as a reverse transcriptase and protects the telomeres, thereby protecting an individual from the chronic diseases of ageing, including psychiatric illness. (Lectures

by the Nobel Prize winner, Elizabeth Blackburn, at www.ibiology.org are insightful.) “The environment/gene interaction is critical to our health and the development of disease,” Dr Eugene Allers said. “Overall, our resistance to disease is built on genetic modification.” In psychiatry, it is evident that major depression is polygenetic, involving more than one gene with their associated SNPs. This makes drug targeting much more difficult and complex. “Currently, pharmacogenetics is being used to anticipate adverse drug reactions; either hypersensitivity or resistance to medication beyond the well-recognised pharmacokinetic properties and drugdrug interactions,” Dr Allers pointed out.

Pharmacokinetics and pharmacogenomics overlap The metabolism of most antidepressant drugs involves oxidation by the cytochrome P450 system. There are more than 50 forms of the CYP450 enzyme, but only six (CYP1A2, CYP2C9, CYP2C19, CYP2DG, CYP3A4 and CYP3A5) metabolise 90% of drugs. Genetic information on these enzymes can be clinically +

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useful. For example, when patients are extremely sensitive or resistant to a drug at a normal dose, the clinician should first exclude drug-drug interactions and then maybe search for genetic variations in the CYP450 enzyme as an underlying cause3 (Figure 5).

–

Substrate*

Omeprazole, insulin, tobacco, grilled meat, broccoli, cabbage, brussel sprouts

Amiodarone, cimetidine, fluoroquinolones, fluvoxamine, caffeine

CYP1A2

Naproxen

Phenobarbital, phenytoin, rifampicin

Smooth liquorice

CYP2B6

None in drug top 100

Rifampicin

Glitazones, trimethoprim

CYP2C8

None in drug top 100

Rifampicin

Amiodarone, fluconazole, isoniazide, sulfamethoxazole, smooth liquorice

CYP2C9

Dicolfenac, ibuprofen, irbesartan, losartan, naproxen, sulfamethoxazole

Prednisone, rifampicin

Fluoxetine, fluvoxamine, ketoconazole, omeprazole, pantoprazole, grape seeds

CYP2C19

Amitriptyline, omeprazole, pantoprazole

Rifampicin

Amiodarone, citalopram, cimetidine, fluoxetin, paroxetine, ranitidine, methadone, metoclopramide, cocaine, grape seeds

CYP2D6

Amitriptyline, codeine, paroxetine, tramadol

Isoniazide, alcohol (ethanol)

None in drug top 100

CYP2E1

NAPQ1 (metabolite of paracetamol), alcohol (ethanol)

Phenobarbital, phenytoin, glucocorticoids, St. John’s wort, garlic

Amiodarone, cimetidine, clarithromycin, fluvoxamine, ketoconazole, grapefruit, starfruit, smooth liquorice

CYP3A*

Amlodipine, atorvastatin, clarithromycin, nifedipine, simvastatin

*P450 3A4, 3A5, and 3A7 have overlapping catalytic specificities, although some selectivity exists

Figure 5. CYP450 inhibitor, inducer and substrate data for drugs present in the Dutch drug top 500 and frequently used food components. (Amended from reference 3)

Molecular Genetics in Clinical Psychiatry

Similarly, hypersensitivity reactions to drugs can be caused by human leukocyte antigen class 1 (HLA-class 1) alleles and the HLA-allele test for HLA-B*

1502 (not yet available in South Africa) can be used to assess the likelihood of a severe hypersensitivity/allergic reaction to carbamazepine.

The future of pharmacogenomics in psychiatry Currently, GENESIGHTRx is available to test for psychiatric medication responses by analysing a number of relevant genes; the serotonin transporter and receptor genes (SLC6A4 and HTR2A), the P450 and the HLA system. “While

this is currently beyond the average South African’s health budget, these reports provide a view of the future of choosing psychiatric therapy for a particular individual,” Dr Allers concluded (Figure 6).

GeneSight Psychotropic Results Patient, Sample DOB: 7/22/1984 Reference: Clinician:

1456CIP Sample Clinician

Order Number: 9299 Report Date: 4/03/2014

Antidepressants USE AS DIRECTED

USE WITH INCREASED CAUTION AND WITH MORE FREQUENT MONITORING

USE WITH CAUTION

desvenlafaxine (Pristiq®) levomilnaciprain (Fetzima®)

bupropion (Wellbutrin®) [1,6] selegiline (Emsam®) [1] sertraline (Zoloft®) [1,4] trazodone (Desyrel®) [1] vilazodone (Viibryd®) [1]

amitriptyline (Elavil®) [1,6,8] citalopram (Celexa®) [1,4,6] clomipramine (Anafranil®) [1,6,8] desipramine (Norpramin®) [1,6,8] doxepin (Sinequan®) [1,6,8] duloxetine (Sinequan®) [1,6,8] escitalopram (Sinequan®) [1,6,8] fluoxetine (Sinequan®) [1,6,8] fluvoxamine (Sinequan®) [1,6,8] imipramine (Sinequan®) [1,6,8] mirtazapine (Sinequan®) [1,6,8] nortriptyline (Sinequan®) [1,6,8] paroxetine (Sinequan®) [1,6,8] venlafaxine (Sinequan®) [1,6,8] vortioxetine (Sinequan®) [1,6,8]

Antipsychotics USE AS DIRECTED

USE WITH INCREASED CAUTION AND WITH MORE FREQUENT MONITORING

USE WITH CAUTION

asenapine (Saphris®) lurasidone (Latuda®) paliperidone (Invega®) thiothixene (Navane®) ziprasidone (Geodon®)

clozapine (Clozaril®) [1,8] fluphenazine (Prolixin®) [1] haloperidol (Haldol®) [1,8] olanzapine (Zyprexa®) [1] quetiapine (Seroquel®) [1]

aripiprazole (Abilify®) [1,6,8] chlorpromazine (Thorazine®) [1,6] iloperidone (Fanapt®) [1,6,8] perphenazine (Trilafon®) [1,6,8] risperidone (Risperdal®) [1,6,8] thioridazine (Mellaril®) [1,6,9]

[1]: Serum level may be too high, lower doses may be required.

[8]: FDA label identifies a potential gene-drug interaction for this medication.

[4]: Genotype may impact drug mechanism of action and result in reduced efficacy.

[9]: Per FDA label, this medication is contraindicated for this genotype.

[6]: Use of this drug may increase risk of side effects. All psychotropic medications require clinical monitoring. Drugs are reported in alphabetical order. This report is not intended to imply that the drugs listed are approved for the same indications or that they are comparable in safety or efficacy. The brand name is shown for illustrative purposes only; other brand names may be available. The prescribing physician should review the prescribing information for the drug(s) being considered and make treatment decisions based on the patient’s individual needs and the characteristics of the drug prescribed.

Order:

9299

Report Date:

4/03/2014

CONFIDENTIAL HEALTHCARE INFORMATION © 2014 AssureRx Health, Inc.

Patient, Sample

All Rights Reserved

Figure 6. An example of genesight psychotropic results. APRIL 2016

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Molecular Genetics in Clinical Psychiatry

Treatable genomic polymorphisms of 5,10-ethylene methylenetetrahydrofolate reductase (MTHFR) – Dr Elizabeth Peter-Ross, Groote Schuur Hospital, Neurogenetic Psychiatric Clinic Introduction “Psychiatrists are going to have to stretch their understanding – moving from clinical evaluation to a molecular and cellular understanding of the conditions they treat. The clinical construct referred to as schizophrenia, for example, is an ‘umbrella term’ and in the future there will be many different causative environmental factors and genetic abnormalities identified, each giving rise to a specific subtype,” Dr Elizabeth Peter-Ross noted at

Patients with resistant depression should be tested for MTHFR polymorphisms. These polymorphisms are the only known treatable genomic polymorphisms.” “A resulting additional benefit of this approach is that the patient begins to focus on better nutrition and making lifestyle changes.” Dr Elizabeth Peter-Ross

Genomic polymorphisms of MTHFR include MTHFR C677T and MTHFR A1298C “Patients with resistant depression should be tested for MTHFR polymorphisms. These polymorphisms are the only known treatable genomic polymorphisms. A resulting additional benefit of this approach is that the patient begins to focus on better nutrition and making lifestyle changes,” noted Dr Peter-Ross. MTHFR is a key enzyme in the folate metabolism pathway because it directs folate from the diet either to DNA synthesis or homocysteine remethylation. MTHFR is on chromosome 1p36.22. There are a number of SNPs of the MTHFR gene. MTHFR C677T and MTHFR A1298C are considered the most relevant ones for neuropsychiatric disorders as they can reduce methylation. Homozygous MTHFR A1298C is common but does not seem to pose as much of a problem as MTHFR C677T. However, if homozygous for both MTHFR polymorphisms, the residual enzymatic activity may be further FOLIC ACID SYNTHETIC Supplements Fortified Foods

DIETARY FOLATE dark green vegetables, dried legumes, avocados, papayas

DHFR slow DHFR fast

the outset of her presentation. Psychiatrists should keep up to date on the latest clinical and molecular psychiatric findings by reading Molecular Psychiatry and the free online publication, Translational Psychiatry. These informative journals are part of Nature publications and are available to better understand developments in this rapidly expanding field. www.nature.com/mp/index.html and www. nature.com/tp/index.html

Unmetabolised Folic Acid UMFA Increased levels are unhealthy

diminished. These two treatable genomic polymorphisms need to be DNA tested. Genomic polymorphisms are treatable with L-methylfolate, a prescribed medical food (as yet not available in South Africa in tablets containing a large enough amount of L-methylfolate). The therapeutic dose range for depression is thought to be 7.5-15mg. Only low-dose preparations are available in South Africa at present: Metafolin 1000ug, Folapro 800ug and 5-MTHF ES as nutrient supplements to be taken along with vitamin B complex (vitamin B2, 6 and 12) supplements and dietary and lifestyle changes. Dietary folate (vitamin B9) requires the two enzymes dihydrofolate reductase (DHFR) and MTHFR to transform folate into L-methylfolate within the brain. Folic acid is a synthetic substance taken as a nutrient or as a supplement in fortifying food. The healthiest way to obtain folate and L-methylfolate is by eating the correct foods (Figure 7).

Blood Brain Barrier

Dihydrofolate DHF

Sepiapterin

Phenylalanine

BH2 DHFR L-Methylfolate

Tetrahydrofolate THF MTHFR

5, 10-methylene - THF

L-methylfolate

Blood Figure 7. L-methylfolate’s mechanism of action APRIL 2016

+

PAH

Tyrosine

Brain

TH

Dopamine Noradrenaline

BH4

TPH

DIETARY L-METHYLFOLATE raspberries, strawberries, blueberries

6

Synthesis of BH4

Epinephrine Tryptophan

Serotonin

Molecular Genetics in Clinical Psychiatry

L-methylfolate, along with the co-factor of tetrahydrobiopterin (BH4), produces the monoamine neurotransmitters (serotonin, dopamine and noradrenaline). L-methylfolate is essential for single carbon methylation and functions to turn genes on and off. Other functions of

methylation include synthesis of nucleic acids, producing and repairing DNA and tRNA, maintenance of methyl pool, genomic stability, energy production and myelination, processing estrogen hormones and building immune T cells and natural killer (NK) cells.

Medications and factors that lower folate levels It is hoped that the alphabetical list below of medications and lifestyle factors that lower folate levels will be helpful for all

healthcare practitioners and their patients (Table 1).

Table 1. Medications and lifestyle factors that lower folate levels Folate plasma level with adjuvant drugs

Drug plasma level with adjuvant high dose folate*

Medication Anticonvulsants (1st generation): carbamazepine, fosphenytoin, phenytoin, phenobarbital, primidone, valproic acid, valproate

↓

↓

Anticonvulsants/mood stabilisers, lamotrigine

↓

–

Cholestyramine

↓

–

Colchicine

↓

–

Colestipol

↓

–

Isotretinoin (Roaccutane)

↓

–

Methotrexate

↓

–

Methylprednisone

↓

–

NSAIDs (high dose): ibuprofen, naproxen, indomethacin, sulindac

↓

–

Oral contraceptives

↓

–

Pancreatic enzymes: pancrelipsase, pancratin

↓

–

Pentamidine

↓

–

Pyrimethamine

↓

↓

Sulfasalazine

↓

–

Triameterene

↓

–

Trimethoprim

↓

–

Smoking

↓

–

Alcoholism

↓

–

Poor nutrition

↓

–

Coffee (more than four cups/day)

↓

–

Gastrointestinal and absorption disorders

↓

–

Pregnancy

↓

–

Lifestyle

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Molecular Genetics in Clinical Psychiatry

Lithium increases MTHFR and thus increases L-methylfolate in the brain Lithium is still the most important and first-line treatment for bipolar disorder. “In this presentation, I want to focus on the cellular and molecular pathways involved in lithium’s mechanism of action,” Dr Peter-Ross pointed out (Figure 8). Current research is exploring the pharmacogenetics of lithium responders – but this is still in its infancy.

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Figure 8. First-line treatment for bipolar disorder

Lithium is known to increase the essential cellular process of autophagy and as part of the underlying etiopathology of Parkinson’s disease and neurodegenerative disorders includes impaired and/or altered autophagy, lithium is now being considered as a possible preventive and way to reduce the progression of the neurocognitive aspects of these diseases.

Molecular Genetics in Clinical Psychiatry

Immunology, stress and brain circuits – Dr Leigh Janet There is extensive evidence supporting the role of activation of the immune system in the serious mental illnesses, such as schizophrenia, bipolar disorder and major depressive disorder. The models described are derived largely from rodent models and caution should be exercised when extrapolating the findings to humans. Immune

activation may arise from many causes, including, but not limited to, intrauterine challenges such as maternal infections and maternal stressors. There is also growing appreciation that the gut microbiome plays a significant role in the modulation of the state of inflammatory preparedness of the body4 (Figure 9).

Figure 9. Microbiota-gut-brain axis in health and disease4

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Early postnatal psychosocial stressors also give rise to immune activation. One of the key messages is that psychosocial stressors impact the brain, and the stress may be transferred to the brain via the immune system, among others. Other mediators of stress that impact the brain are the HPA axis, predominantly through the activity of cortisone/corticosterone (in rodents). The role of cortisone was discussed. Dr Janet focused particularly on the hippocampus, the amygdala and the prefrontal cortex, which are the best studied sites, but there are probably many other brain areas affected by these processes. The impact of the stressors on the brain affects the genetics and epigenetics of the neurons in the regions mentioned. However, there are also effects on the structure and function of the neurons, including the length and branching of dendrites - which implicitly affect

local synaptic connections and networks. Different areas of the brain react differently to the stress. In some areas the dendrites shorten and lose their spines (e.g. area CA3 of the hippocampus) whereas in parts of the amygdala, the spines may lengthen in response to stress. Other changes that occur under stress are changes in neurogenesis and receptor and mitochondrial trafficking. The impact of excitatory amino acid activity, the kynurenic acid system and possible mechanisms for monoaminergic amino acid depletion in the immunestress model were reviewed. Apart from the structural changes in the neurons which follow exposure to stressors, signalling molecules, such as BDNF, tissue plasminogen activator, CRF, lipocalin-2 and endocannabinoids, are secreted in response to stressors. In resilient rodents these changes reverse when the stress passes, but in other vulnerable rodents APRIL 2016

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Molecular Genetics in Clinical Psychiatry

the changes, especially the epigenetic markers, do not reverse when the stress passes. This has the effect of ‘biologically embedding’ the vulnerable state, so that when exposed to subsequent stressors, the rodent’s response, in the form of the abovementioned changes, is exaggerated and further changes are inflicted on the stress response mechanisms of the brain.

Dr Janet discussed the epigenetic mediation of stress in the brain via, among other mechanisms, histone modifications. There is a possible ‘window of opportunity’ in respect of the time to intervene if these processes are to be modified in order to mitigate the prior negative impact of stressors on the brain.

References 1. Ramkaran P, Phulukdaree A, Khan S, et al. Methylenetetrahydrofolate reductase C677T polymorphism is associated with increased risk of coronary artery disease in young South African Indians. Gene 2015; 571(1): 28-32. 2. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet 2014; 15(6): 423-437.

3. De Graaf LCG, van Schaik RHN, van Gelder T. A clinical approach to pharmacogenetics. Neth J Med 2013; 71(3): 145-152. 4. Borre YE, O’Keeffe GW, Clarke G, et al. Microbiota and neurodevelopmental windows: Implications for brain disorders. Trends in Molecular Medicine 2014; 20(9): 509-518.

Glossary: Molecular clinical psychiatry Precision medicine: An emerging approach to medicine, based on an individual’s genes, environment and lifestyle Genome: The complete set of DNA consisting of three billion base pairs: adenine (A) paired with thymine (T) and guanine (G) with cytosine (C) Epigenome: Not part of the DNA sequence, but chemical compounds that surround the DNA. Epigenetic changes can switch genes on/off with the main mechanism being DNA methylation and histone acetylation. Environment, exposure to disease, diet and hereditary factors alter the epigenome Methylation of DNA segments: An epigenomicdriven process that switches off/silences a gene Mitochondrial DNA: DNA content that is not packaged in the chromosome within the nucleus, but is part of the mitochondria (37 genes)

Molecular medicine: Working from the genetic level upwards to assess changes that determine health/disease SNPs: A single variation in a single base pair of a DNA sequence (both coding and non-coding material) Allele: The descriptor of the SNP Haplotype: A set of associated SNP alleles that tend to be inherited together Proteome: All the proteins active in the body Metabiome: All the metabolites present in the body Telomeres: Repeated protein sequences at the end of each gene that constitute the biological clock Telomerase: Enzyme which activates and protects the telomeres, thereby extending the life of the cell, i.e. it is capable of more cell division cycles HLA: HLA systems encode the proteins of the major histocompatibility complex (MHC).

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Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

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