Client Report. Anastasis Tzanis. Welcome to Opus 23 Pro. Anastasis Tzanis Light Centre Moorgate 114 London Wall London EC2M 5QA

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1 Client Report Anastasis Tzanis Anastasis Tzanis Light Centre Moorgate 114 London Wall London EC2M 5QA Current Build: / 04 /07 [10:03:18] Welcome to Opus 23 Pro. Opus 23 Pro interprets the 'raw data' provided by reporting services (such as 23andMe) into its medical significance. To do this Opus 23 Pro scans over 20 peerreviewed, evidence based scientific databases and cross references their information with the results of your raw data. This report summarizes the findings from your genomic data that have been curated by your clinical team into a human understandable format. However, before we begin, let's introduce a few genetic concepts to set the stage and advance your understanding a bit. OPUS 23 IS A REGISTERED TRADEMARK OF DATAPUNK INFORMATICS, LLC. COPYRIGHT 2015, ALL RIGHTS RESERVED.

2 GENOMIC PROFILES Although SNPs are the 'letters' of individuality, genes are in fact the words and vocabulary. After all, it is the genes that have to do the work, coding for the construction for a myriad of enzymes and proteins. Because gene function is central to any sort of biochemical prediction, Opus 23 Pro groups all the SNP outcomes under their parent gene, and presents its results as a reflection of their combined influence on the effectiveness of that gene. Although SNPs are pretty much unchangeable, our genes can be influenced (for better or worse) by lifestyle, diet, emotions and nutritional supplementation. Each gene is depicted as a grid showing the result of its SNPs: The sum of the significant SNPs in the gene that indicate a higher (homozygous) risk are the orange squares The sum of the significant SNPs in the gene that indicate a lower (heterozygous) risk are the yellow squares The sum of the significant SNPs that are working just fine (no problem polymorphisms) risk are the gray squares You might even find that for some genes you may have a polymorphism that conveys some benefit. These are the green squares NOTE: The genes that appear in this report have been selected for inclusion by your clinical team. Generally these are genes that the team feel are worthy of attention. Rest assured that this is but a small percentage of all the gene data the team has examined. In a way similar to conventional lab tests, all those normal results are great, but what we're really interested in is the problem areas! Genetics can be complicated to the layperson. Sometimes a word is used to descibe a gene function that you might not recognize. If Opus 23 Pro thinks that you might need some help with a technical term, 'Mr. Smart Owl' will try to explain it to you. These terms are also included in a Glossary at the end of this report.

3 IMMUNITY/ ALLERGY GENOMICS Immunity is the balanced state of having adequate biological defenses to fight infection, disease, or other unwanted biological invasion, while having adequate tolerance to avoid allergy, and autoimmune diseases. NAT2 Full Name: 'N acetyltransferase 2 (arylamine N acetyltransferase)' NAT2 NAT2 encodes a critical Phase II detoxification enzyme that functions to both activate and deactivate arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N acetylation polymorphism in which human populations segregate into rapid, intermediate, and slow acetylator phenotypes. Polymorphisms in this gene are also associated with higher incidences drug toxicity. Carcinogens resulting from grilled and barbequed foods are processed by NAT2 and compromised NAT2 function affords a higher risk for colorectal cancer in those eating well cooked meats. Found in: Colon Intestine Liver Lung Mammary gland Oesophagus Stomach Uterus Your clinical team considers this gene result significant and actionable. The gene is the fundamental physical and functional unit of heredity. A gene is an ordered sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific product (i.e., a protein). A polymorphism is a difference in DNA sequence among individuals. Phenotype is the observable or detectable characteristics of an individual organism the detectable expression of a genotype. You have a few especially noteworthy SNP polymorphisms on NAT2: rs T341(I114T) (+ ) OPUS: Associated with slow acetylator phenotype (risk) rs1208 A803G(K268R) (++) OPUS: Associated with fast acetylator (risk) rs C481T (++) OPUS: Associated with slow acetylator phenotype (risk) HNMT Full Name: 'histamine N methyltransferase' HNMT HNMT provides instructions for making the histamine N methyltransferase protein, and is also used as a neurotransmitter in the brain. Histamine is a compound released by histamine containing cells in response to injury and in inflammatory and allergic reactions. Histamine is broken down by two major pathways: N methylation via histamine N methyltransferase, and oxidative deamination via diamine oxidase. The HNMT enzyme uses S adenosyl L methionine (SAMe) as a cofactor. In the brain, the neurotransmitter activity of histamine is controlled only by N methylation from the HNMT enzyme, as diamine oxidase is not found in the brain. Variations in the HNMT gene can affect the activity levels of this enzyme. Found in: Brain Colon Heart Kidney Liver Lung Lymph node Ovary Pancreas Placenta Prostate Saliva Small Intestine Spinal cord Spleen Stomach Thyroid gland Urine Your clinical team considers this gene result only for informational purposes Methylation is the addition of a single carbon and three hydrogen atoms (called a methyl group) to another molecule. The removal of a methyl group is called demethylation. Methylation is a key mechanism behind the regulation of gene expression. Proteins are large molecules composed of one or more chains of amino acids. Proteins are required for the structure, function, and regulation of the bodys cells, tissues, and organs, and each protein has unique functions. Examples are hormones, enzymes, and antibodies.

4 MAOB Full Name: 'monoamine oxidase B' MAOB MAOB is an enzyme located in the outer mitochondrial membrane. It and plays an important role in the breakdown of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. Like MAOA, it degrades dopamine. Alzheimer's disease and Parkinson's disease are both associated with elevated levels of MAO B in the brain. The normal activity of MAOB creates reactive oxygen species, which directly damage cells. MAOB levels have been found to increase with age, suggesting a role in natural age related cognitive decline and the increased likelihood of developing neurological diseases later in life. More active polymorphisms of the MAOB gene have been linked to negative emotionality, and suspected as an underlying factor in depression. Activity of MAO B has also been shown to play a role in stress induced cardiac damage. The use of MAOB inhibitors to slow natural human aging in otherwise healthy individuals has been proposed, but remains a highly controversial topic. Supplements such as catechin and epicatechin and garlic show some ability to inhibit excess MAOB production. MAOB activity was increased for 60 minutes after exercise. Found in: Adrenal gland Alpha cell Cardiomyocyte Cholangiocyte Clara cell Duodenum Enterocyte Ependymal cell Frontal cortex Hepatocyte Loop of Henle Lung Pancreas Pituitary gland Platelet Proximal convoluted tubule Smooth Muscle Spleen Your clinical team considers this gene result only for informational purposes Amines are organic compounds contain a basic nitrogen atom. Important amines include amino acids, histamine, dopamine and serotonin. Mitochondria are a cell constitutent (organelle) found in large numbers in most cells, in which the biochemical processes of respiration and energy production occur. AOC1 Full Name: 'amine oxidase, copper containing 1' AOC1 The AOC1 gene provides instructions for making the amine oxidase, copper containing 1 enzyme known as diamine oxidase, histaminase, misnamed 'DAO'. This is different to the DAO gene (D amino acid oxidase). It is found largely in the intestines and kidney, and breaks down histamine and other related compounds such as putrescine and spermine, substances involved in allergic response and the immune system. Lower AOC1 enzyme activity may be associated with inflammatory bowel disease such as Crohn's disease and ulcerative colitis, as well as a form of asthma that is more easily triggered with normal levels of allergy stimulating IgE antibodies. Your clinical team considers this gene result significant and actionable. You have a few especially noteworthy SNP polymorphisms on AOC1: rs C>T Thr16Met (+ ) OPUS: Associated with histamine intolerance (risk) rs *102G>A (++) OPUS: Associated with histamine intolerance (benefit) DDC Full Name: 'dopa decarboxylase (aromatic L amino acid decarboxylase)' DDC The DDC gene provides instructions for making the aromatic l amino acid decarboxylase (AADC) enzyme, which is important in the brain and nervous system. This enzyme takes part in the pathway that produces dopamine and serotonin, which are chemical messengers that transmit signals between nerve cells (neurotransmitters). DDC is responsible for the synthesis of dopamine and serotonin from L DOPA and L 5 hydroxytryptophan, respectively. Found in: Ubiquitous Your clinical team considers this gene result noteworthy but not actionable Amino acid are small molecules that are the components of proteins. There are 20 different kinds of amino acids in living things. Proteins are composed of different combinations of amino acids assembled in chain like molecules.

5 Full Name: 'aldehyde dehydrogenase 2 family (mitochondrial)' Aldehyde dehydrogenase is the second enzyme of the major metabolic pathway of alcohol metabolism. There are two major forms of aldehyde dehydrogenase. Most Caucasians have both major major forms while approximately 50% of Orientals have one. A remarkably higher frequency of acute alcohol intoxication among Asians than among Caucasians could be related to the absence of a the missing form in Asian populations. Found in: Brain Heart Kidney Liver Lung Muscle Ovary Spleen Stomach Your clinical team considers this gene result noteworthy but not actionable A dehydrogenase is an enzyme that accelerates the removal of hydrogen from metabolites and its transfer to other substances.

6 MULTI SNP ALGORITHMS Algorithms are perhaps the most significant and flexible aspect of your Opus 23 data. They are usually the easiest result for the non medical person to understand, because their conclusions are usually simplified statements in everyday language. Many correlations between SNPs and various traits exist as 'haplotypes,' clusters of SNPs, often on different genes, that must be evaluated as 'true' or 'false' based on their total outcome values. Some algorithms may identify risks for certain problems, while others identify special strengths or benefits you might possess. It's helpful to think of an Opus 23 algorithm as a tiny flowchart, that depending on which way the result branches, generates a 'true or false' result. For example, a simple algorithm to determine if you should get out of bed might be: If you hear the alarm clock, open your eyes. If it's dark outside, go back to bed. If it's light outside, check the time. If it's earlier than 7AM, go back to bed. If it's later than 7AM, get up, check calendar If it's Saturday, go back to bed. As can be seen, there are a lot of ways you can go back to bed with this algorithm! And this is also true as well for the Opus 23 Pro algorithms: In order for an algorithm to be true, it must fufill all of several conditions. If even one condition fails, the whole algorithm will be false. Each algorithm is displayed in its own box, and contain information about the genes and SNPs used in its creation. The title of the algorithm is generally its conclusion. Typically, your report contains only true algoriths, although your clinical team may choose to include false algorithms as well, especially if it would be helpful to make you aware of something you're likely to not be prone to. Thus: An algorithm that returns a true will have a 'check' icon in the bottom left hand box. The conclusions of these algorithms pertain to you based on your genomic data results. An algorithm that returns a false will have a 'cross' icon in the bottom left hand box. The conclusions of these algorithms do not pertain to you based on your genomic data, other than perhaps the added knowledge that this is one less thing in life to worry about.

7 METHYLATION Risk of asthma, ADHD and Parkinson's disease from high histamine. FALSE Genes: HNMT Repute: RISK Magnitude: 3 Frequency: N/A INTERPRETATION: Histamine is a chemical found in foods and produced in the body. It is involved in allergic responses as well as being a neurotransmitter in the brain and central nervous system, and affects stomach acid secretion. Histamine can only be removed from the brain by methylation with the HNMT enzyme. Differences among individuals in the methylation of histamine could potentially be related to asthma, stomach ulcers, diseases of the brain including autism and ADHD, and movement disorders such as Parkinson's disease. Variation in either of the two SNPs in HNMT, rs and rs (listed as i in 23andMe) result in reduced activity of this histamine degrading enzyme in the brain and central nervous system. This Methylation algorithm is not true (false) for you Your results: rs (AA) i (CC) NETWORK MAPS These network maps allows you to visualize your genomic data directly in a number of hand curated pathway maps. Boxes in the map generally depict genes, and the box color(s) are determined by the percentage of SNP values that are homozygous recessive for risk (orange), heterozygous for risk (yellow) and negative for risk (gray).

8 Histamine Metabolism The following genes in this map have been described in the previous section on genomics: MAOB, AOC1, DDC,, HNMT, NAT2 Intracellular activity GLUTATHIONE CONJUGATION DDC IGE AND COMPLEMENT Histidine P 5 P HDC NAT2 NAT1 N Acetylhistamine Extracellular secretory activity NO METABOLISM B5 Histamine H1, H2, H3, H4 receptor antagonists Cu2 FAD HNMT Mast cell / basophil / platelet / neuronal vesicle Imadazole acetaldehyde Mg B6 Cu2 Vit C AOC1 SAMe B12 5 MTHF SAH N methyl histamine ONE CARBON METABOLISM SAMe B12 SAH 5 MTHF B1 Mg B6 Cu MAOB B2 Mg B6 Vit C MAO Inhibitors B1 Mitochondria Histamine aldehyde N methyl imadazole acetaldehyde B1 ALDH1B1 N methyl imidazole acetic acid CATECHOLAMINE METABOLISM OPUS 23 IS A REGISTERED TRADEMARK OF DATAPUNK BIOINFORMATICS, LLC. COPYRIGHT 2015, 2016, 2017 ALL RIGHTS RESERVED. DEVELOPER BLOG