CYP2D6 is one of the most important enzymes associated with detoxification. 25% of clinical drug clearance is carried out by this enzyme, which includes antitumor drugs and antipsychotic drugs. This enzyme is also responsible for the metabolism of serotonin and dopamine and it also constitutes 40% of hepatic human phase I metabolism.

As humans, we are exposed to a lot of toxins, from the natural plant-based toxins to man-made toxins, to the pollutants discharged by chemical factories to chemicals present in skin creams among others. Our body, however, has the ability to remove certain toxic waste from it. The CYP2D6 enzymes coded by the CYP2D6 genes play an important role in liver detox.

Evolutionary and molecular aspects of CYP2D6

CYP2D6 belongs to the cytochrome P450 family of genes which originated from a prokaryotic ancestral gene. The CYP family of genes were instrumental in protecting the prokaryotes form oxygen toxicity. These genes constantly expanded and about 1.5 billion years ago, they expanded to include genes that were endogenous compound metabolising. The last expansion of the CYP genes occurred about 400 million years ago.

The CYP family of genes are found to be one of the most  rapidly evolving genes, an imperative characteristic required to protect cells and to avoid injuries when the cells are exposed to toxins.

The CYP2D6 gene is present in chromosome 22q13.1 and contains more than 100 allelic variants. With the advent of farming and modern day practices, humans have restricted the type of food consumed. This has lead to a loss of selection pressure which is required to keep genes active. Therefore, humans have only one functional gene, while other organisms like rat or mouse have multiple.

CYP2D6 metabolizer status:

Evolution of human CYP2D locus has resulted in the following types of alleles

The metabolic activity of CYP2D6 depends on the highest functioning allele

[table id=55 /]


Genetic Variants of CYP2D6 - How is it important?


"Identifying the CYP2D6 variant carried can help in finding out which medications will work for you or which toxins you are hypersensitive to."

The detox genes we carry work at different efficiencies and finding out about those helps us in understanding the metabolism and dosage of various drugs. A lack of CYP2D6 enzyme is associated with lowered drug effectiveness among drugs that require activation by CYP2D6

Use your 23andme raw data or your Ancestry DNA raw data to check for rs1135840 (CYP2D6 s486t )

This is one of the important and well known SNP of CYP2D6- CYP2D6 s486t

[table id=56 /]

Use your 23andme raw data or your Ancestry DNA raw data to check for rs1065852

[table id=57 /]

Use your 23andme raw data or your Ancestry DNA raw data to check for rs5080367

[table id=58 /]

Apart from these SNPs that are reported in the 23andme reports, there are other important CYP2D6 polymorphisms which contribute to determining CYP2D6 activity. Authority sites like Pharm GKB list out the significant polymorphisms, all of which are included in the Xcode Life science’s PGX report. Upload your 23andme raw data or your ancestry DNA raw data into Xcode Life science’s dashboard to get your comprehensive report.

For the entire list of CYP2D6 inducers and CYP2D6 inhibitors, check out CYP2D6 in wikipedia.

As the liver is the major source of the CYP2D6 enzymes, ensuring a healthy liver is important.

What is the need for a liver detox?

Every individual should focus on liver detox, especially with the amount of processed foods that are consumed and the amount of synthetic chemicals that enter our water and food supply through industrial, agricultural and other activities. While people may look good on the outside, their internal organs may be stressed due to non clearance of toxins.


The liver is responsible for many essential functions like

  1. It plays a role in protein, fat and carbohydrate metabolism
  2. Produces bile which is essential for breaking down fats
  3. Associated with storage of fat soluble vitamins
  4. Production of cholesterol: According to Harvard health reports, the liver produces 1000 mg of cholesterol which is required for the production of vitamin D, bile and hormones
  5. Protein synthesis: According to a study by Brown University, the liver is responsible for the synthesis of certain proteins that are required for the clotting of blood and for transporting nutrients.
  6. The liver plays a role in maintaining blood sugar
  7. Detoxification: The liver contains numerous enzymes that play a role in detoxification. A healthy liver can transform a potentially harmful substance into harmless products to be excreted.

The detoxification potential of a liver is very important and makes it important to focus on liver detox to keep it healthy.

How to detox liver naturally- 6 tips for detoxification

  1. Vegetable juice: Vegetables are a good source of nutrients and fibre which help in detoxifying the liver. Since it is difficult to consume a lot of salad, juicing vegetables like cabbage, brussels sprouts, beetroot, beans, carrots and cucumber may be the next best thing to do. Adding a dash of lime or mint could improve flavour.
  2. Bust the visceral fat: A study published in nature showed that the presence of excess of visceral fat leads to a protein called TRIP-Br2 initiating an inflammatory response. Regular exercise will help in reducing visceral fat.
  3. Intermittent fasting: Intermittent fasting will help in lowering fat content and is also found to increase stem cells which are needed to regenerate organ tissue.
  4. Avoid processed foods: Processed foods are high in saturated fat, sugar and salt, all of which get the liver to work harder. This can affect liver health over time. Therefore, the first step would be to avoid such foods.
  5. Increase intake of Vitamin C : Vitamin C plays an important role in reducing inflammatory markers. Detox water, which is nothing but lime water, consumed regularly could up your levels.
  6. Broccoli sprout extract: A study by researchers from The University of Tokyo showed that consumption of broccoli sprout extract protected the liver from xenobiotic substances by upregulating certain detox genes and by glutathione synthesis.

Genetic testing for medication effectiveness- CYP2D6

There is an intricate drug-gene interaction which makes genetic testing for medication effectiveness imperative.

DNA testing for drug effectiveness can be used for the following

Pharmacogenomics is a growing industry with many physicians utilising DNA testing for drug effectiveness. The significance of this method of testing was understood by the former President of the United States, Mr. Barack Obama, who felt that pharmacogenomics could make US healthier. He had wanted to dedicate $215 million towards precision medicine in his budget, signalling the growing interest in the field.

CYP2D6 gene polymorphisms are included in the Xcode PGX reports and should be interpreted only by a medical practitioner to identify the right drug and the right dose for each individual.  

References:

  1. https://www.nature.com/articles/ncomms11378
  2. https://www.ncbi.nlm.nih.gov/pubmed/29727683

Xcode Life Reports

  1. Nutrition
  2. Fitness
  3. Health
  4. Allergy
  5. Skin
  6. Precision Medicine
  7. Methylation and MTHFR
  8. Carrier Status
  9. Personality
  10. Breast Cancer and BRCA
  11. ACMG
  12. COVID-19 Genetic Report
How To Analyze DNA Raw Data

The vast majority of the people are trying to analyze DNA raw data results from ancestry genetic testing companies like 23andMe, Ancestry DNA, Family Tree DNA (FTDNA), Living DNA etc., and other raw DNA data providers. However, they are completely unaware that their raw DNA data also contains vast amounts of other information.

These companies do not perform genome sequencing. They instead use microarray genotyping to get ancestry and health information. This may be about their health aspects such as diet, nutrition, obesity, diabetes, fitness, allergies, weight loss, detox analysis, skincare etc.

Those who are aware are mostly familiar with Promethease, an SNPedia-based literature retrieval system. Promethease reports gained popularity after the FDA ban on 23andme providing health reports to customers. With the FDA ban, there was a huge demand for alternative 23andme health report providers. Promethease report was positioned well to benefit well from this development.

Fast forward to 2018, the landscape of alternative health report providers and third-party tools has matured significantly. A number of options are available to people with 23andme raw data and data from other ancestry DNA test providers. These options are well covered in our recent blog titled 10 Amazing Tools For 23andme Raw Data Analysis.

In this blog, we address, what more and what else you can do with your ancestry DNA test raw data? This blog will open up a number of possibilities to those who wish to explore their raw DNA to the fullest.

Hand-Picked article for you: Worrier Or Warrior? Analyze Your DNA Raw Data For COMT – The Warrior Gene

I. Health Reports

DNA Raw Data analysis

This is a concept most users of 23andme are familiar with.

Arguably, this is one of the motivations for people to opt for DNA testing services from 23andme in lieu of AncestryDNA.com, FTDNA and other ancestry companies.

23andme used to provide a health report before the FDA ban on their health results.

23andMe now provides a significantly scaled down version of the DNA health reports which are approved by the FDA for $99. However, a lot more health info can be gained from the ancestry DNA test raw data that you obtain from 23andme. Health conditions like hypertension, type 2 diabetes, heart diseases and obesity are all manageable and very much preventable when detected early.

A number of genetic markers have been discovered for a variety of other health conditions, ranging from cancer to autoimmune conditions. Learning about your genetic predisposition helps you keep a tab on early symptoms and take preemptive action.

A comparison between Xcode Life and Promethease as third-party tools for raw data analysis have been done previously.

II. Nutrition Insights

Nutrition has a profound impact on human health. Several aspects of nutrition are genetically influenced. Macronutrient metabolism, micronutrient requirements, food intolerances like lactose intolerance and gluten intolerance are familiar to many people.

However, there are several more aspects that are genetically influenced. Third party raw data analysis tools will help you interpret your raw DNA data to get these results.

Once you understand your genetic nutritional tendencies, you can align your dietary habits accordingly. Your genetic data will help you eliminate many of the genetic food intolerance and sensitivity related symptoms. These are a useful set of insights to get from your ancestry DNA test genetic data.

Get your nutrition genetic report from your DNA raw data here

III. Fitness Reports

Human physical attributes are clearly genetically influenced, for example, height is largely genetic, so is wingspan and flexibility, etc.

Several other attributes such as red blood cell count, heart capacity, lung capacity, muscle strength,  all are significantly genetically influenced.

Additionally, whether you are largely built for endurance type of activities or sprint or powertype activities is also genetically influenced. So, whether you are an amateur or professional sportsperson, all you need is your DNA raw data.

Fitness reports generated by analyzing your raw DNA data will help you align your activities with your genes.

Get your fitness genetic report from your DNA raw data here

IV. Allergy Reports

Those of us who are allergic to anything can relate to the nightmarish experience that seemingly harmless entities can cause. Allergy information can also be extracted by a raw DNA data analysis.

Close to 20-25% of the adrenaline administrations in schools happen because the allergies were unknown at the time of the reaction. More than 170 foods have been found to instigate allergic reactions in the body. Some of the common food allergies come from milk, egg, peanuts, tree nuts, wheat, soy, fish and crustacean shellfish. You can learn about your susceptibility to these allergens by analyzing your ancestry DNA raw data. These are only food allergies. An estimated 10% of the population is allergic to objects like pollen, animal dander, droppings of cockroaches and contact with dust mites.

Learning about your allergy susceptibilities can be life-saving. And it is as simple as a raw DNA data analysis. You can now extract this information about your allergy predisposition from your ancestry DNA test raw data.

Using hundreds of peer-reviewed scientific literature third-party tools examine genetic markers corresponding to each type of allergy. Based your variant gene, your body is at a higher or lower risk of invoking an exaggerated response to an allergen.

This keeps you alert. Also helps you take proactive measures like avoiding certain foods, saying no to tattoos.

Other forms of allergies covered in a genetic report are misophonia and histamine intolerance.

Get your allergy genetic report from your DNA raw data here

V. Skin Reports

Skin is one of the most dynamic organs in the body. It interacts with environmental agents like sunlight (ultraviolet radiation), pollutants, chemicals and internal factors like hormonal regulation. Maintaining skin health would require knowledge of your underlying genetics.

For example, each of us will display a different kind of reaction on exposure to light. This information can be extracted from your ancestry DNA raw data. Some skin types are immune to strong light but others develop rosacea characterized by red skin eruptions. This is often misdiagnosed as acne and hence becomes worse over time because it is not given specific treatment.

Another example is the development of cellulite or orange peel syndrome that manifests as skin dimpling and nodularity. This is common in the abdomen and pelvic regions. Cellulite affects about 85-98% women. Your susceptibility to cellulite is influenced by the type of gene variants you have in your raw DNA data results.

Even how much you tan is genetically influenced!

Now you can see why generic face creams and medications fail no matter how many times you change brands.

Analyzing DNA raw data will give you skin insights which will help you treat and manage skin conditions. Or just maintain a healthy and glowing skin.

Get your skin genetic report from your DNA raw data here

VI.Precision Medicine Reports

According to industry statistics, on average more than 50% of medications prescribed today do not benefit those who take them.

Precision medicine through genetics promises to deliver right drug at the right dose to the right patient using your personal DNA data.

Doing a DNA raw data analysis will help you learn about your genetic polymorphisms. Specifically those that impact the majority of the drugs you consume on a regular basis.

And what do you need for getting this precious information from your DNA  data? Once you analyze your DNA raw data you can download the raw data DNA file. This has most of the information necessary to create your precision medicine drug sensitivity report.

Download your DNA files from the following genetic testing companies now:

23andMe

Ancestry DNA

Family Tree

Analyze your DNA raw data with caution

Please bear in mind that the vast majority of human traits are not influenced by a single gene. Rather, they are a combination of smaller effects produced by a number of genes. When you order a report from any DNA testing service, you must bear in mind that these are based on likelihood. This means that the effect was observed on a group of individuals, who also happen to carry the same genetic variants.

Whether or not you will see the same effect is dependent on a number of factors, the science of  which has not been fully mapped out yet. So, use this information in that context and do not be alarmed when you see concerning information.

Genetics should be considered as additional information to be added to your analysis, not a diagnosis.

Here is another interesting article on What Else You Can Do With Your DNA Raw Data

Did I miss out any other application? Drop them in comments below.

Tracy is  a 40-year-old African American who is an aerobics instructor, a mother of two and a college student pursuing a degree in business. She looks like any other normal person, except that she is not normal. Not normal in the sense of her LDL cholesterol levels. Her LDL cholesterol is 14, where as the normal range for the population is somewhere around 100.

Scientist have been studying the anomaly in cholesterol levels in people like her and investigating what makes them have such low levels. And whether, there is a negative health effect of having such low LDL levels. They found their answer. Tracy and people like her are carriers of a mutation in a gene called PCSK9. People who carry this mutation have very low cholesterol levels and have a 90% reduced risk of heart disease.

Tracy has a genetic gift. But there are millions of people who suffer from high cholesterol and have to endure the side effects of cholesterol lowering drugs called statins.

It’s estimated that up to 20% of patients cannot tolerate statins' side effects, which include muscle pain and even forgetfulness. And in many others, the drugs simply don't control cholesterol levels well enough.

Now Tracy’s gift has been put to good use, leading to the development of a new class of cholesterol lowering drugs, called, well, PCSK9 drugs. Unlike statins, this drug works naturally and is not likely to produce side effects. These drugs worked so well that FDA had to halt the clinical trial early.

So how does the PCSK9 drug work?

The human body has many sensors that allows it to sense and control the levels of various biochemicals, hormones, enzymes and proteins. If the sensors are not working properly, things can go haywire. For example, the smoke sensor in your room is supposed to sense smoke to trigger the sprinkler in the event of fire. However, if there is dust accumulated on the surface of the sensor, then the smoke is not detected and sprinkler not triggered.

Another example is that of a temperature sensor which shuts off the air conditioner once the set temperature is reached. If the sensor is not functional, the AC will continue to operate without shutting off and cool the room to much lower temperature than desirable. Similarly, the liver has a cholesterol sensor. If the cholesterol sensor does not detect enough cholesterol, because there is biological “dust” accumulated on the sensors, then the liver thinks there is not enough cholesterol in the system, and starts producing more and more of it. This dust is PCSK9. For people like Tracy, their body does not produce PCSK9, hence no “dust” to block the sensor.

Though Tracy is an extreme case, a lot of us have various mutations in the PCSK9 genes and other genes such as APOA, LDL, LPL, APOB and other genes that modulate our cholesterol levels and predisposition to heart disease. Being informed about the various mutations we carry can help develop a personalized diet, exercise and preventive program that is uniquely tailored for us.

Genes are the storehouse of all biological information

Even as we inherit our genes from our parents, we also inherit some of the gene mutations that can cause significant changes in our body. Mutations are variations in the genetic code of a gene that can alter or affect its functions. These inherited mutations, however small they are, can increase our risk to certain diseases.

Research studies have established that BRCA1 (Breast Cancer Susceptibility Gene 1) and BRCA2 (Breast Cancer Susceptibility Gene 2) genes are linked to breast cancer. Mutations of these genes that belong to a class of genes known as tumour suppressors are linked to hereditary breast and ovarian cancers. While it is true that not all genetic changes or mutations are harmful, a woman who inherits this faulty or harmful genetic mutation in BRCA1 or BRCA2 is prone to the risk of developing breast or ovarian cancer before menopause. It is also very likely that breast and ovarian cancers run in the family with some of her close family members being diagnosed with the diseases. Apart from breast and ovarian cancers, harmful BRCA1 mutations are also likely to increase a woman’s risk of developing cervical, uterine, pancreatic and colon cancer and harmful BRCA2 mutations may increase risk of pancreatic, stomach, gall bladder, bile duct cancers and melanoma. However researchers add that not all women who hail from families with a history of breast or ovarian cancer are carriers of harmful mutation and further not every woman who has inherited this deleterious mutation will develop breast or ovarian cancer.

How does a woman learn whether she is or not a carrier of the faulty gene?

Genetic testing plays a key role in detecting BRCA1 and BRCA2 mutations. Genetic testing gives the woman the chance to learn if her family history of breast cancer is due to an inherited gene mutation.

BRCA gene test is conducted to identify the harmful changes in the DNA of the two breast cancer susceptibility genes. Genetic counselling by qualified professionals in the field of cancer genetics is usually recommended before and after the test to discuss with the candidate about the importance of the test, its benefits, and implications of its outcome, psychological impact and the inherent risk of passing on the mutations to one’s kids.

A woman becomes a candidate for BRCA gene testing under the following conditions:

What should a woman who tests positive for BRCA mutation do?

A woman who tests positive now understands that she has a high lifetime risk of developing breast or ovarian cancer. However she should also understand that just because she is a carrier of the faulty gene, it does not mean that she would certainly develop the disease.

The woman who has the harmful BRCA1 or BRCA2 mutation will be placed under the radar of surveillance that includes periodical mammography and clinical breast examinations in the case of breast cancer and for ovarian cancer, surveillance methods include transvaginal ultrasound, blood tests and clinical exams. Screening will go a long way in detecting breast cancers early enough to be successfully treated with minimal damage to the quality of life of the individual.

The option of resorting to surgery as a pre-emptive step to reduce the risk of developing cancer is also explored by some women. Prophylactic surgery involving removal of tissues that are more exposed to risk i.e., prophylactic mastectomy (removal of healthy breasts) and prophylactic salpingo-oophorectomy (removal of healthy fallopian tubes and ovaries) might offer some degree of protection against the development of breast and ovarian cancers. However, this does not offer any guarantee against development of the diseases.

Prescription of drugs like tamoxifen has shown to reduce the risk of developing breast cancer in women, who are at premenopausal stage and who are at increased risk of developing the disease. Clinical studies have also proved that the drug also serves to reduce the risk of recurrence of breast cancer in women who are already undergoing treatment for a breast tumour diagnosed earlier. Similarly, raloxifene is another drug that has shown to reduce the risk of developing invasive breast cancer in postmenopausal women.

It is imperative that women who seek risk avoidance measures like surgery or intake of drugs should discuss their options in detail with their physicians before implementing them.

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Advantages of genetic testing

Genetic testing for breast cancer will help in taking the fight against cancer to the next level. For those women who have known reasons like strong family history of the disease, it is essential to consider being tested for a genetic mutation. However, the risk for developing the disease in women with the faulty genes varies from individual to individual.

Though genetic testing for cancer can cause a lot anxiety, stress, anger, guilt and even chronic depression in some individuals, it can have its own benefits irrespective of the outcome of the test. While it gives a sense of direction by way of adoption of preventive measures to those who test positive for a faulty gene, those who test negative experience a great sense of relief which helps in motivating them to increase their awareness.

Risk factors for breast cancer other than genetic mutations

Apart from inheritance of harmful genetic mutations it is common wisdom that women empower themselves with the knowledge of the factors that increase or decrease their chances of developing breast or ovarian cancer. The following factors have a significant impact on the onset of the diseases:

Hereditary risk:

Women who have a first degree or second degree relative with breast or ovarian cancer is at increased risk for developing the diseases. Besides, women who have already had breast cancer are at an increased risk of recurrence or developing ovarian cancer.

Age:

Age is a crucial factor. The risk of developing breast or ovarian cancer increases with age. Genetic mutations can lead to early onset of the disease.

Hormonal influences:

The greater the exposure of a woman’s body to oestrogen, a hormone that stimulates breast tissue, the greater is her risk for developing the disease. Women whose menstrual periods commenced early or whose menopause set in late (after 55) and women who delivered their first child at 30 or beyond are said to be prone to breast cancer as these events in their lives indicate increased exposure of their bodies to oestrogen.

Hormone replacement therapy:

Women who undergo hormone replacement therapy for symptoms of menopause are at an increased risk of breast cancer, besides heart attack, stroke and blood clots.

Medical and hereditary risks apart, there are certain lifestyle factors like obesity, lack of physical activity, alcohol consumption and increased intake high-fat diet that contribute to the risk of developing breast cancer.

The fight against breast cancer calls for a proactive approach by empowering oneself with the knowledge about the disease and through intelligent use of the support system that has been put in place by scientists in the field of genetic research. As a woman if you have valid reasons to worry about your chances of developing the disease, it is time you explored the option of genetic testing as a preventive strategy that could embolden your spirit, imbibe confidence and direct you on the path of preventive self- care.

 

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