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DIAGNOSTICS. LIFE SCIENCE. CONSULTING. RESEARCH.

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MEDICAL REPORT
e-mail: Date of Birth: Age: Sex: M F Saliva kit bar-code:

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Genetic testing was performed by application of polymerase chain reaction (PCR)-based methods. The detection of genetic variation is interpreted together with a medical and lifestyle assessment to identify a combination of risk factors that, if left untreated, could cause or contribute to disease development. This approach is based on the knowledge that a single genetic risk factor (e.g. heterozygous familial hypercholesterolaemia) is not sufficient to cause cardiovascular disease (CVD) (Kotze et al. 1993, Clinical Genetics 43: 295-299). The same applies for other complex disorders such as age-related cancer, obesity and Alzheimer’s disease which are also influenced by some of the genes included in the test. Treatment guided by genetic testing is aimed at reducing the risk of disease development or recurrence.

Genetic test results: Risk Area Gene Genetic variation Results

3937 T > C, allele E4

Heterozygous

Lipid and lipoprotein metabolism

Apo E

4075 C > T, allele E2 Homozygous

Haemostasis and thrombophilia

Factor V

1691 G > A, Leiden Homozygous

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Risk Area Gene Genetic variation Results
Not detected 677 C > T, A222V

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Homocysteine and folate metabolism

MTHFR
Not detected 1298 A > C, E429A

Haemostasis and thrombophilia

Factor II

20210 G > A

Heterozygous

Not detected 845 G > A, C282Y

Iron overload

HFE
187 C > G, H63D Heterozygous

Approved by:

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Family history
FAMILY MEDICAL CONDITIONS Alzheimer's Disease Coronary Heart Disease Myocardial Infarction Stress / Anxiety / Depression Myocardial Infarction Varicose Veins Varicose Veins 40 years 40 years 40 years AGE OF ONSET 87 years 85 years 85 years RELATIONSHIP Grandmother Mother Mother Mother Father Mother Sister

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Health status
PERSONAL MEDICAL CONDITIONS
Multiple Sclerosis Stress / Anxiety / Depression Varicose Veins CLINICAL ASSSESSMENT Cholesterol, total Homocysteine Serum ferritin Transferrin saturation Blood pressure - Systolic Blood pressure - Diastolic Weight Height Body mass index (BMI) Adult Contraceptive pill Hormone replacement therapy 110 mmHg 70 mmHg 60 kg 1.55 m 24.97 kg/m2 - High No Yes
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AGE OF ONSET 34 years 20 years 45 years VALUE 6 mmol/L - High 6.4 umol/L 98 ng/mL

MEDICATION

EVALUTATION 3.21-5.20 mmol/L 4.5-12.4 umol/L 15-300 ng/mL 34% 20-55 % <140 mmHg <90 mmHg

18.5-24.9 kg/m2

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Lifestyle assesment
LIFESTYLE ASSESSMENT Physical activity Smoker Alcohol consumption SCORE None / occasionally , Daily: Moderate - Low Current: No , Previous: No Abstain

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Nutrition assesment
Fat intake, saturated & trans fats
High

Fruit, vegetables, fibre intake
High

Folate intake
High

Score

Score

Score

Moderate

High

Low

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Interpretation
The information provided in this report is based on a) information reported by the patient, b) information supplied by the referring healthcare practitioner, and c) where applicable, results of tests performed by the reference laboratory on request of the healthcare practitioner who assisted with this analysis. Focus areas for risk reduction include any existing metabolic abnormalities, as well as environmental factors that may modify gene expression: The high cholesterol levels reported could not be explained by any of the genetic variations tested for and may be caused by other genetic and/or lifestyle risk factors. Weight gain should be avoided as obesity is associated with elevated cholesterol levels. Genetic variation in the MTHFR gene indicates an increased requirement of folate to prevent homocysteine accumulation and DNA damage. Individuals with both the 677 C>T and 1298 A>C mutations have less than 50% of normal MTHFR enzyme activity, which is associated with raised plasma homocysteine levels when folate status is low. The FV Leiden mutation is the most common inherited form of hypercoagulability and is associated with a 5-10 fold increased risk of venous thrombosis in heterozygotes. The use of hormone replacement therapy results in a more than 15-fold increased risk. Variation in the HFE gene is associated with over-absorption of iron from the diet, while in patients with multiple sclerosis (MS), iron deficiency has occasionally been described in the presence of the C282Y mutation. Adequate availability of iron, in addition to folate and other B-vitamins, amino acids and essential (unsaturated) fatty acids, are imperative for optimized myelin synthesis. The Detailed Interpretation and Health Guidelines are provided for counselling purposes. The diet scores are only an estimation of nutrient intake and may need to be further assessed by a registered dietician for implementation. Extended genetic analysis focusing on a specific health concern may be requested at no additional cost where appropriate, after providing full informed consent for research.

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Interpreted by:

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DETAILED INTERPRETATION AND HEALTH GUIDELINES
The genetic variations or mutations analysed determine different responses to medication and/or environmental exposures implicated in disease development or progression. Detailed information of relevance to both men and women is provided below for each of the genetic risk factors identified. Homozygous individuals inherited two copies of the mutation from their parents and heterozygous individuals only one copy. When a gene variation is not detected in a specific metabolic risk area, it does not necessarily imply the complete absence of genetic risk.

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HOMOCYSTEINE / FOLATE METABOLISM
METHYLENETETRAHYDROFOLATE REDUCTASE GENE: MTHFR677C>T & 1298A>C

IMPORTANCE: Methylenetetrahydrofolate reductase (MTHFR) is a main regulatory enzyme in folate and homocysteine metabolism. MTHFR catalyses the conversion of 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, the major circulating form of folate. Elevated homocysteine may be caused by nutritional deficiencies, particularly folate, or decreased activity of certain enzymes required to prevent high levels. Homocysteine is a potentially toxic amino acid produced from methionine found in normal dietary protein. The adverse effects of homocysteine include endothelial dysfunction, impairment of fibrinolysis and altered fibrin clot formation and stability. GENETICS: The C to T base change detected at nucleotide position 677 results in a thermolabile enzyme with decreased enzymatic activity, thereby contributing to increased homocysteine levels and decreased folate levels. Less MTHFR is available to produce 5-methyl-tetrahydrofolate, which is required to decrease homocysteine. This mutation is associated with high homocysteine levels in the presence of low folate status. The A to C base change detected at nucleotide position 1298 does not cause elevated homocysteine levels on its own, but acts in combination with mutation 677C>T. Although there is a 50% chance of passing on the faulty gene in a family, variation in the MTHFR gene does not cause disease in the absence of other genetic and environmental factors that may trigger gene/disease expression. DISEASE ASSOCIATION: Folate is necessary for DNA synthesis and low levels may result in DNA breakage and accelerated aging, especially when MTHFR activity is decreased. Variation in the MTHFR gene and elevated homocysteine levels are associated with neural tube defects in offspring, arterial and venous thrombosis and cardiovascular disease. High homocysteine levels are associated with diabetes, stroke, Alzheimer's disease, arthritis, multiple sclerosis, chronic fatigue, depression, headaches, infertility, obesity, osteoporosis, pregnancy complications, thyroid problems and gastric ulcers. Reduced MTHFR activity may reduce cancer risk if folate status is normal, but it increases the risk significantly when intake of folate and other B-vitamins is inadequate. Although most of the disease associations have been demonstrated in the presence of two copies of the MTHFR 677C>T mutation, compound heterozygotes with the 1298A>C mutation are also at increased risk due to gene-gene and gene-environment interaction.
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PREVALENCE: In the general population approximately 10% of individuals are homozygous for either the T-allele of the MTHFR 677 or C-allele of the 1298 variant, while more than 50% of individuals are heterozygous. The frequencies of the risk alleles are higher in patients with the associated medical conditions or correlate with disease onset, severity or response to treatment. COMBINED EFFECTS: Nutritional needs differ according to the MTHFR genotype. Reduced MTHFR activity leads to increased requirements for folate (above the RDA of 400 ug per day) to convert homocysteine into S-adenosyl methionine. Adequate levels of vitamins B2, B6, B12, zinc and trimethylglycine (TMG) are also required for this process. High alcohol intake interacts with the genetic variation in the MTHFR gene and may lead to abnormal folate metabolism due to malabsorption and increased excretion. Amongst carriers with the T allele, thrombotic risk increases 1.9-fold in patients with arterial thrombosis, 1.7-fold for venous thrombosis and 2.5 fold for both conditions. For recurrent venous thrombosis a relative risk of between 1.4 and 1.6 was found in the presence of the T-allele and a combined risk of 18.7 in the presence of the factor V Leiden mutation, the most common genetic risk factor for venous thrombosis. HEALTH GUIDELINES: • Confirmation that folate supplementation in individuals with high homocysteine levels reduces the risk in patients with existing cardiovascular disease or diabetes is still lacking, therefore it is important to identify individuals at risk of homocysteine accumulation before damage occurs to DNA, arteries and the brain. • Lowering of high homocysteine concentrations by 3 mmol/l by increasing folic acid intake was predicted to reduce the risk of ischaemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24%. • When folate intake is increased above the standard recommended daily dose of 400 ug per day (at least 800 ug per day recommended for homozygotes), it is important to also increase the intake of the vitamins B6, B12 and riboflavin proportionally. • Green leafy vegetables (spinach, broccoli, asparagus) are high in folate while whole wheat bread, orange juice and dried beans are also good sources. • Adequate intake of foods containing zinc such as egg yolk, nuts, oats and peas are of special concern in vegetarians, as phytates and fibre in vegetables inhibit zinc absorption. • Trimethylglycine is synthesised from choline found in eggs, fish, liver, nuts, citrus fruit and may be deficient if high homocysteine levels are not normalised by folate and B-vitamin supplementation. • Alcohol intake and certain medication (e.g. metformin, fibrates, diuretics) may also lead to an increase in homocysteine levels. • In patients with raised homocysteine levels and/or a family history of cognitive impairment or Alzheimer's disease, it is very important to keep glutathione levels high by regular intake of white meat, tuna, lentils, beans, nuts, seeds, onions and garlic to protect the brain and liver from damage. • Increased intake of folic acid is of particular importance in pregnant women or those planning a pregnancy, since low folate status can cause abnormalities (neural tube defects) in the foetus. • Folate supplementation should be avoided in cancer patients and may lead to seizures in patients taking anti-convulsant medication.
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THROMBOPHILIA
FACTOR V GENE: FV 1691G>A

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IMPORTANCE: Factor V is a component of the coagulation/anticoagulation cascade that promotes fibrinogenesis. Normally, there is a fine balance in the body which ensures that there is not too much bleeding or blood clotting. If this balance is disrupted, a blood clot may occur. Clinical conditions associated with the development of thrombosis include arterial thrombosis (myocardial infarction, ischaemic cerebrovascular disease, and peripheral vascular disease) and venous thrombotic disorders (deep vein thrombosis and pulmonary embolus). The factor V Leiden mutation (1691G>A) is the most common risk factor for the inherited form of hypercoagulability and predisposition for deep vein thrombosis (DVT). This gene defect was named after the city Leiden in The Netherlands, where it was first identified in 1994. GENETICS: The single G to A change at nucleotide position 1691 results in an arginine to glutamine amino substitution at a cleavage site for APC, thereby preventing efficient inactivation of factor V. Resistance of the factor V protein to inactivation by protein C is associated with overproduction of thrombin leading to excess fibrin generation and excess clotting. This effect increases the risk of thrombosis more in individuals with two copies of the defective gene (homozygotes) than those with only one copy (heterozygotes). Although there is a 50% chance of passing on the faulty gene in a family, the factor V Leiden mutation does not cause disease in the absence of other genetic and environmental factors that may trigger gene/disease expression. DISEASE ASSOCIATION: Factor V Leiden thrombophilia is characterized by poor anticoagulant response to activated protein C (APC) and an increased risk of venous thromboembolism. Excessive clotting that occurs in the presence of the Factor V Leiden mutation is usually restricted to the veins, where the clotting may cause a deep vein thrombosis (DVT). One copy of the Factor V Leiden mutation (heterozygous) is associated with a 5-10 fold increased risk of venous thrombosis while two copies of the defective gene (homozygous) are associated with an 80-fold increased risk of venous thrombosis in the general population. If the venous clots break off, these clots can travel through the heart to the lung, where they block a pulmonary blood vessel and cause a pulmonary embolism. This disorder does not seem to increase the formation of clots in arteries that can lead to stroke or heart attack, although a "ministroke" known as a transient ischaemic attack may occur. Women with the disorder have an increased risk of clotting in pregnancy that may be accompanied by preeclampsia, miscarriage and stillbirth. PREVALENCE: Approximately 5% of Caucasians have the factor V Leiden mutation. The mutation is less common in Hispanics and is rare in Africans and people of Asian descent. Up to 30% of patients who present with deep vein thrombosis (DVT) or pulmonary embolism test positive for the Factor V Leiden mutation. While only 1% of people with factor V Leiden have two copies of the defective gene, these homozygous individuals have a more severe clinical condition.

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COMBINED EFFECTS: The clinical expression of factor V Leiden thrombophilia is influenced by other genetic thrombophilic disorders that have an additive effect on overall thrombotic risk, hyperhomocysteinemia, high factor VIII levels, malignancy, and circumstantial risk factors such as long-distance travel, pregnancy, surgery, oral contraceptive use (OCP), hormone replacement therapy (HRT), selective oestrogen receptor modulators (SERMs), organ transplantation, and advancing age. The presence of one copy of the factor V Leiden mutation increases the risk of venous thrombosis by a factor of about 7 and use of oral contraceptives increases the risk by a factor of about 4, while their joint effect results in a more than 30-fold increased risk. The risk increases approximately 15 times in woman with the mutation using hormone replacement therapy. The risk of a myocardial infarction increases approximately 30 times in mutation carriers who smoke. HEALTH GUIDELINES: • Intervention strategies are targeted at reducing the risk of inappropriate blood clotting through anti-coagulant drug treatment, improvement of the diet and avoidance of lifestyle risk factors, as appropriate. • Regular dietary intake of foods rich in omega-3 fatty acids (e.g. oily fish without added cooking oils) is encouraged to reduce blood clotting. • Supplementation with omega-3 should be carefully considered when certain medications (e.g. warfarin) are already used. • Factor V Leiden heterozygotyes and homozygotes without clinical manifestation of venous thrombosis, should be aware of the signs and symptoms of this condition that require immediate medical attention, as well as the potential need for prophylactic anti-coagulation in high-risk circumstances. • Both active and passive smoking should be avoided and prophylactic measures may be necessary during periods of immobility (e.g. during long distance travel or surgery). • Regular exercise for at least 30-60 minutes 3-4 times per week is important to control body weight as obesity increases the risk of venous thrombosis. • In women hormone therapy should be carefully considered and anticoagulant prophylaxis may be required during pregnancy to reduce the risk of venous thrombosis.

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IRON OVERLOAD
HAEMOCHROMATOSIS GENE: HFE 187C>G, H63D

IMPORTANCE: Hereditary haemochromatosis (HH) is an autosomal recessive disease with variable clinical expression due to gene-gene and gene-environment interaction. The HFE protein is involved in the regulation of iron homeostasis and interacts with the transferrin receptor, thereby forming a link between HFE and iron transport.

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GENETICS: Serum ferritin and transferrin saturation levels will not be high in the presence of a single copy of the HFE gene mutation H63D (187C>G, rs1799945), unless another genetic alteration causing HH or secondary factors influencing iron regulation are also present. Although there is a 50% chance of passing on the faulty gene in a family, the HFE mutation does not cause disease in the absence of other genetic and environmental factors that may trigger gene/disease expression. Heterozygous carriers with one copy of the faulty gene are usually not affected but their children may be at risk of inheriting the mutation. When both parents are carriers, the risk of having a homozygous child is 25%. DISEASE ASSOCIATION: The features of iron overload or haemochromatosis include cirrhosis of the liver, diabetes, arthritis, skin pigmentation and heart failure due to organ damage. Individuals with one copy of the H63D mutation is unaffected (unless also a carrier of C282Y/other iron-related mutation), while those with two copies are likely affected with a mild form of HH. Excessive iron accumulation in the liver leads to increased production of reactive oxygen species (ROS). In a liver already compromised by another disease such as non-alcoholic liver disease (NAFLD), the increased production of ROS can cause further insult and therefore more severe disease. Additional tests are required when body iron stores are high or conditions characteristic of iron overload are present in the family (e.g. liver cancer, cirrhosis, diabetes, cardiomyopathy, sterility, impotence, porphyria, arthritis, chronic fatigue, or skin pigmentation). PREVALENCE: The carrier frequency of the HFE H63D mutation is between 20-30% in most populations. In Caucasian populations approximately 20% of patients with HH are compound heterozygotes with one copy each of the H63D and C282Y mutation. This gene combination occurs at a similar frequency in the general Caucasian population. COMBINED EFFECTS: Variation in the HFE gene is associated with over-absorption of iron from the diet. Due to geneenvironment interaction, most people with the defective gene never develop iron overload. Blood donors and vegetarians may be protected against iron overload despite the presence of a genetic predisposition for haemochromatosis. HEALTH GUIDELINES: • When serum iron parameters (especially ferritin and transferrin saturation levels) are within the normal range dietary iron intake should not be restricted in mutation carriers since it can lead to iron deficiency, especially in menstruating women and vegans. • If current iron status is unknown, determination of serum ferritin and transferrin saturation levels are recommended, especially when clinical symptoms characteristic of iron overload are present (e.g. chronic fatigue). • Blood donation or regular phlebotomy may be advisable to normalise serum ferritin and transferrin saturation levels if these levels are elevated above the reference range.

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• Reduced intake of red meat (1-2 times per week), replaced by increased intake of vegetables, grains and legumes containing non-haem iron that has a poorer absorption of iron, may also be advisable if serum iron status is high. • Ferritin levels may rise significantly with increasing alcohol consumption above a baseline of 1–10 g/day and this should be avoided. • High ferritin levels may be related to inflammation, therefore possible secondary causes of abnormal iron levels also need to be addressed if appropriate. • High ferritin levels in the presence of normal transferrin saturation and low/abstain alcohol intake raise the possibility of non-alcoholic fatty liver disease and the dysmetabolic iron overload syndrome.
Disclaimer: Depending on the patient’s particular circumstances, it may be necessary to modify this advice for optimal clinical management. The interpretation and health guidelines were compiled based on the test results provided by the laboratory and current knowledge from extensive research published in peer-reviewed journals and books. Responsibility is disclaimed for any liability, loss, or risk that may be or is incurred as a consequence, directly or indirectly, of use and application of this confidential report without consultation by a registered health professional.

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