Should I Take Aspirin to Prevent Heart Disease?

Everyone knows that aspirin protects against heart disease, right?

Well, it turns out that aspirin may only protect some people from heart disease, and for others, it can actually slightly increase the risk of heart disease.  It all seems to depend on a variant of the COMT gene.

Catechol-O-methyltransferase (COMT) is the gene that codes for an enzyme that breaks down dopamine, epinephrine, and norepinephrine, as well as other substances.  There are many studies on the common genetic polymorphisms of the COMT gene, and most of the studies focus on the neurological aspects of the enzyme.

study published in the Journal of the American Heart Association looked at the effect of a common COMT polymorphism on cardiovascular disease.  The study also looked at the combined effect of the variant along with either aspirin or vitamin E and cardiovascular disease. Continue reading “Should I Take Aspirin to Prevent Heart Disease?”

Decrease Your Risk of Diabetes – Using Genetics

What comes to mind as far as the risk of type 2 diabetes? Usually first up is the mental picture of someone eating donuts and slurping down soft drinks.  While diet definitely contributes to diabetes risk, not everyone who eats donuts and slurps soft drinks will get diabetes. Alternatively, not everyone with type 2 diabetes got it through poor dietary choices.

Obviously, the must be more to diabetes than just poor dietary choices. (Don’t get me wrong – you should still make good dietary choices…)

Genetics plays a role in diabetes, as anyone who has several diabetics in their family well knows.  This is a big, broad topic, though, since there isn’t just one gene that causes diabetes or even one way that people can have problems with regulating their blood sugar. Continue reading “Decrease Your Risk of Diabetes – Using Genetics”

Changing Your Circadian Gene Expression with Polyphenols

This is a bit of a departure from my usual article. It is a paper that I recently wrote for a class that I’m taking for my Master’s in biology.  Thought I would share it in case anyone is interested…

Overview:
Resveratrol, EGCG, grape seed extract, passion flower, and other polyphenol supplements can increase the amplitude of core circadian genes — depending on the time of day that you take them.  Timing may be everything when it comes to the benefits from polyphenols.

 

 Introduction
All living things have core biological rhythms, which are set around the 24-hour period of dark and light. Life on Earth has evolved over the last 3.5 billion year with one constant: a 24-hour cycle of day and night.

Rhythms based on the 24-hour day are called circadian from the Latin word circa (about) and diem (day). (McClung 2006) Circadian rhythms are found in both plants and animals. Plant circadian examples include photosynthesis during the daylight hours, the opening and closing of flowers such as morning glories, and seasonal variations that respond to light and temperature. (Song, Ito, and Imaizumi 2010) Examples of animal circadian rhythms include sleep/wake cycles, body temperature fluctuations over the day, and blood pressure naturally rising in the early morning hours. (Thosar et al. 2018)

Plant Compounds Impact Our Human Circadian Rhythms
Recently, research has shown that many plant compounds interact with human circadian clock genes and can impact the amplitude or period of the transcription of the genes. Compiling the data from recent studies on polyphenols and circadian gene expression will show that the benefits of polyphenol consumption are derived, in part, from their impact on our circadian clock.

Plant Circadian Rhythms
Circadian rhythms, both in plants and animals, are endogenous and self-sustaining in stable environmental conditions where light and temperature remain fairly consistent. Even without the daily re-setting, or entrainment, of that rhythm, most organisms maintain an endogenous circadian period that is approximately, but usually not exactly, 24 hours. In the early 1900’s experiments showed that the leaf movements of plants kept in the dark varied just a little from being 24-hour cycles. The concept that endogenous cycles are not always exactly 24-hours is known as the organisms free-running time and applies to both plants an animals. (McClung 2006) Light, as a zeitgeber (German for time giver), entrains the core circadian rhythm each day, resetting a slightly longer or shorter free-running time back to 24-hours.

Plant circadian rhythms have been studied for hundreds of years. Charles Darwin wrote a book on plant movement in 1880.  In it, he postulates that heredity (genetics) is involved in the movement of plants. Some of the observations he made include the inherited movement of the hypocotyl arching and breaking through the ground as certain plants germinate. (Darwin 1880)

Groundbreaking genetic discoveries in the 1970’s and 80’s paved the way for understanding the genes that drive circadian rhythm.  While the first circadian gene to be cloned was the Per (period) gene from the Drosophila melanogaster, a fruit fly (Bargiello and Young 1984), the genetic basis for plant circadian function was not completely elucidated until the 1980’s. The circadian function of the Cab-1 gene was discovered in 1985 in peas and replicated in 1988 in wheat. (Nagy et al., 1988) A series of experiments in the ‘90’s and early 2000’s showed that there are three interlocking feedback loops in most plant circadian rhythms with the genes TOC1, CCA1, and LHY playing integral roles. (McClung 2006)

Human Circadian Rhythm
The human core circadian clock is governed by the feedback loop of the transcription of CLOCK and ARNTL (Bmal1) genes that rise during the day and are then repressed during the night by rising levels of the PER (period family) and CRY (cryptochrome family) of genes. When CRY and PER levels reach a certain level they inhibit their own transcription, forming the basis of the 24-hour oscillation of our molecular circadian pacemaker.  The region of the brain that controls the core circadian rhythm is called the suprachiasmatic nucleus (SCN) and is located in the hypothalamus. Light, specifically in the ~480nm blue wavelengths, hits the melanopsin-containing non-image forming photoreceptors in the retina, signaling to the SCN that it is daylight. This entrains the core clock genes each day to the 24-hour rhythm, and it also stops the production of melatonin, an antioxidant and signaling molecule that rises during the dark.(Xu and Lu 2018)

Research is increasingly showing how intertwined our circadian rhythm is with our health. Circadian dysfunction has been implicated in many chronic diseases including depression, bipolar disorder, heart disease (Thosar et al. 2018), certain cancers, Alzheimer’s disease, and other dementias. (Xu and Lu 2018)

Disruptions to our natural circadian rhythm are ubiquitous in modern life.  Artificial lighting at night, especially in the short blue wavelengths, disrupts the core circadian clock through activating melanopsin and signaling to the SCN that it is still daytime. Blue light in the evenings or at night from TVs, cell phones, computers, and CFL/LED bulbs creates havoc within our circadian system.

Our 24/7 society demands shift work, and we now have food readily available in any season and any time of the day. These two things come together in modern times to increase the risk of many chronic diseases that are dependent on metabolism. Feeding and fasting times regulate circadian metabolism, and mouse studies have shown that time of eating influences adiposity regardless of caloric intake. (Potter, Gregory D. M. et al. 2016) Not only does the time of day impact metabolism, but the overall number of hours in the feeding window, or time from the first food of the day to the last, also impacts metabolism. This was clearly shown by Hatori, et al. in a mouse study that restricted the mice to eat only during an 8-hour window during their normal active time at night. The time restricted feeding mice ate the same number of calories as the mice allowed to eat ad libitum, but they gained less fat and were protected from getting hyperinsulinemia and fatty liver. (Hatori I 2012)

While the body’s core circadian rhythm is governed by the oscillation of CLOCK, BMAL1 and PER, CRY in the SCN, there are also peripheral clocks governing circadian patterns in organs such as the liver, pancreas, and adipose tissue.  Twenty percent of proteins in the liver are under circadian control, varying in the time of day that they are expressed. (Ribas-Latre, Aleix, et al. 2015b.)

Polyphenols
While the term polyphenol is often used in health and nutrition articles, the formal definition of the term has been debated and changed over the years. Polyphenols are generally defined as phenolic molecules that contain one or more benzene rings linked to a hydroxyl group. Plants produce polyphenols in response to either UV radiation or as a defense against various different pathogens. (Beckman 2000, 101-110) Historically, polyphenol was a general term given to plant compounds capable of tanning (a tannin).

Large, epidemiological studies link the consumption of higher amounts of polyphenols to various health benefits including reduced risk of cardiovascular disease, cancer, and neurodegenerative diseases. Food sources that are high in polyphenols include tea, red wine, olive oil, and most fruits and vegetables. Tea is one of the most widely consumed sources of polyphenols, and drinking three or more cups a day has been found to reduce the risk of cardiovascular disease by 11%. (Vauzour et al. 2010)

Polyphenols can be categorized into several main types including flavonoids, phenolic acids, and phenolic amides.  Flavonoids, which often act as antioxidants, have a standard ring structure of C6-C3-C6 with the two C6 rings being phenols. They can be further categorized base on different ways of bonding with the ring structure, with subcategories including proanthocyanidins, flavonoids, flavones, and flavonols. (Tsao 2010, 1231-1246)

The category of flavonoids called proanthocyanidins includes several compounds that have been found to favorably affect human health. Proanthocyanidins, which are polymers of flavonols, include catechins, (Tsao 2010) epigallocatechin (e.g. EGCG from green tea), and grape seed extract. The most common sources of proanthocyanidins in the US diet are apples, chocolate, and grapes, with the 2 – 4-year-old age group eating the most proanthocyanidins.  (Gu et al. 2004)

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol known as a stilbenoid, which is produced by certain plants when they are attacked by fungus or another pathogen.  High levels are found in knotweed, grape skins, pine trees, berries such as blueberries, raspberries, cranberries, mulberries. (Tsao 2010) Resveratrol is a phytoalexin, which is a compound formed by a plant when under stress due to attack by pathogens such as fungus.  Red wine is known for its high resveratrol content, with resveratrol concentrated in the skin of grapes as a way of fighting off the fungus. The grape variety Vitis vinifera is well known for its high concentrations. (Jeandet, Bessis, and Gautheron 1991) Specific cultivars of grapes are higher in resveratrol and thus have a greater natural capacity to resist fungal infections. (Dercks and Creasy 1989)

Effects of Polyphenols on Circadian Rhythm
When looking at how polyphenols affect the expression of core circadian genes either in the SCN or in peripheral systems, there are two elements at play: the effect of the compounds and the timing of the compounds. A compound that causes a rise in one arm of the circadian clock could possibly be a negative at certain times and positive at other times.

Resveratrol
Oike and Kobori in 2008 found that 100um of resveratrol increased the expression of Per1, Per2, and Bmal1 genes. Although a cell study using rat cells, this was one of the first to show that gene expression can be altered by resveratrol. (Oike and Kobori, 2008)  In 2011, Pifferi, et al. used a primate model to determine the effects of resveratrol on circadian period.  The mouse lemurs were kept in the constant dark for two weeks, with a control group and a group fed resveratrol.  The resveratrol group had a shorter circadian free-running period and a lower body temperature compared to the control group. (Pifferi et al. 2011)

Miranda, et al. compared a rat model of obesity (given high-fat diet chow) with a group fed resveratrol plus the high-fat diet (HFD). They found that resveratrol targeted the clock related gene Rev-Erba in adipose tissue and it reversed the changes normally induced by HFD. (Miranda et al. 2013)

A mouse study by Sun, et al. in 2015 found that adding resveratrol to the obesity-inducing HFD attenuated the weight gain. The mice fed a high-fat diet with resveratrol (11-week study) had weight gain about halfway in between the regular high-fat diet group and the control mice. The high-fat diet obese mice had nearly flat daily circadian rhythms of Per2, Clock, and Bmal1; adding resveratrol to the HFD restored the circadian rhythm to that of mice in the control group on a normal chow diet. (Sun et al. 2015)

The timing of resveratrol consumption may be important to reap positive health effects.  Mouse study on resveratrol measured antioxidant effects based on time of day of dosing.  Resveratrol given during the active period (dark for mice) acted as a fairly strong antioxidant in a dose-dependent manner.  Doses ranged from 0.8 to 5 mg/kg, which converts to a physiological dose for humans.  Conversely, when resveratrol was given during the inactive period (light for mice) it actually became a pro-oxidant, increasing oxidative stress in a dose-dependent manner. (Gadacha et al. 2009)

Tea Polyphenols and EGCG
Mi, et al. examined the effects of EGCG, a phenolic component of green tea, on circadian rhythm in mice.  The study used a high-fat, high fructose diet (HFFD), which disrupts normal circadian rhythm by dampening or decreasing the amplitude of Clock, Bmal1, Cry1, Per2, and Per3 gene expression as well as increases triglycerides and total cholesterol.  Adding EGCG to the HFFD diet during the active phase (at night for mice) reversed the changes in lipid metabolism and clock gene expression that was found in HFFD only mice.  The EGCG was added at the beginning and middle of the active period.  Additionally, the group fed HFFD plus EGCG gained less weight than the HFFD group with similar food intake and calorie intake.

In 2017, Qi, et al. studied the effects of tea polyphenols on circadian disruption using a mouse model kept in constant darkness. The constant darkness group had higher insulin levels at certain time points, similar to other studies on circadian rhythm disruption and diabetes. In the group that was given tea polyphenols, there was a suppression of the dysregulation of insulin levels. When comparing the circadian gene expression of the group in constant darkness versus the group in constant dark plus tea polyphenol, the group without added polyphenols had decreased Clock and Bmal1 levels while the group kept in the dark but given polyphenols had circadian gene expression similar to that of the control group kept in a regular light / dark cycle.(Qi et al. 2017)

Passionflower Extract
Passionflower extract (passiflora incarnata) is an herbal folk remedy often used for anxiety and insomnia. Passionflower is a woody, climbing vine that that is native to the southeastern United States. A placebo-controlled study found that passionflower extract was as effective as oxazepam, a benzodiazepine, for the treatment of generalized anxiety disorder. (Akhondzadeh et al. 2001)

Toda et al. found that passionflower extract increases the amplitude of Per1, Per2, and Cry1 about 12 hours after treatment. Treatment at 0 hr showed that it affected the circadian genes over next 20 hours as well as changing the corticosterone rhythm. For the study, the floral parts of passionflower were extracted from dried flowers from France.  The flavonoids in the plants included isovitexin, isovitexin 2″-O-glucoside, schaftoside, isoschaftoside, and homoorientin. Homoorientin specifically was found to separately increase Per2 the most, although the other compounds added to the effect. (Toda et al. 2017)

Proanthocyanidins
Grape seeds are high in proanthocyanidins, and grape seed extract has been used to study the effects of proanthocyanidins on circadian gene expression.  A mouse study by Ribas-Latre, et al. looked at the effect of chronic consumption of grape seed proanthocyanidin extract (GSPE). The results showed increases in the gene expression of CLOCK and PER2 at a dosage of 25 and 50 mg/kg/day in both the liver and in white adipose tissue. Additionally, Nampt was also increased at those doses in white adipose tissue. Nampt expression correlates with nicotinamide adenine dinucleotide (NAD) levels, which activates Sirt1 and affects the expression of Bmal1. (Ribas-Latre 2015a)

A second study by Ribas-Latre, et al. looked at the timing of GSPE administration.  The rats were fed GCPE either at ZT0 (when the lights come on) or at ZT12 (lights off).  The protein expression in the liver was recorded, and it was found that grape seed extract given at ZT0 decreased the expression of Nampt. When given at ZT12, grape seed extract increased the expression of Nampt, which correlates to NAD levels.  NAD activates Sirt1, which is a sirtuin that acetylates Bmal1, thus affecting the expression of Bmal1.  Bmal1 forms a heterodimer with CLOCK, so increasing Bmal1 is only important if there is CLOCK available also. (Ribas-Latre et al. 2015b)  

A final study by Ribas-Latre, et al. examined the effect of GSPE on circadian gene expression using liver cells.  The liver is both under the influence of the core circadian clock genes in the SCN as well as maintaining a peripheral clock influenced by the timing of meals and diet composition. The study found that GSPE altered the expression of BMAL1, increasing the expression at 1 hour and 15 hours after application in comparison to control.  The study also examined the impact of melatonin on BMAL1 as well. The results showed that melatonin at 10umol/L had a very similar impact on BMAL1 expression as GSPE. The researchers further looked at the impact of blocking the melatonin receptor, MT1, and found that GSPE is not acting through the melatonin receptor. (Ribas-Latre et al. 2015)  

Nobiletin
Nobiletin is a polymethoxylated flavonoid found in citrus fruit rinds.  In 2016, He, et al. found that nobiletin increases the amplitude of core clock genes and decreases the effects of metabolic syndrome in a circadian-related manner.  The study found that nobiletin is acting on ROR to enhanced PER2 amplitude in peripheral tissue systems but not in the SCN.  In a mouse model of diabetes and diet-induced obesity (db/db mice fed HFD), nobiletin was effective in blocking the weight gain through decreasing the size of the fat mass and the size of the adipocytes. The nobiletin was administered at 8-10 ZT 200mg/kg every other day.  This blocking of weight gain was accomplished even though the amount of food the mice ate was the same as the obese mice. A second arm of the study looked at the effect of nobiletin vs. a diet-induced obesity model strain of mice that were bred to be deficient in the Clock gene.  The nobiletin group with deleted Clock gene had the same weight gain as the HFD obese mice, reinforcing the circadian rhythm impact of this flavonoid. (He et al. 2016)

Discussion
Plant polyphenols can have a remarkable effect on animal metabolism; part of their benefit may come from their ability to modulate circadian rhythm.  The studies on polyphenols in mice, rats, and primates clearly show that the compounds affect both metabolism and circadian function. More studies are needed to elucidate the role of plant polyphenols on human circadian function. Future studies of polyphenols should include the timing of consumption as well as the daily circadian cycle of the study participants.

The importance to human health of a robust circadian rhythm is becoming abundantly clear with the many studies linking circadian dysfunction with chronic health problems such as mood disorders, cancer, obesity, type 2 diabetes, and dementia. As it is doubtful that our society will go back to a time of only firelight at night, the ability to manipulate circadian gene function with natural polyphenols could have a large impact on the health of the whole human population.

The polyphenols discussed here, with the exception of nobiletin, are readily available as supplements. The timing of taking those supplements may affect the health benefits received from them. For example, passionflower extract, which increases the amplitude of PER1, PER2, and CRY1, should be timed to maximize the expression of the genes that rise during the evening and night. In fact, one of the uses of passionflower in herbal teas is for promoting sleep. Resveratrol, well known as an antioxidant, was shown to actually exhibit pro-oxidant properties when administered during the inactive period. This leads to the idea that resveratrol may be better to take during the day rather than in the evening to reap the benefits as an antioxidant.

The changing effects of polyphenols based on the timing may also explain some of the differing results in studies on them. For example, resveratrol supplement studies may show different results depending on the time of day that the participants took the supplement. Further studies into the timing of supplemental polyphenols could strengthen their protective effects against metabolic disorders also associated with circadian rhythm disruption.

 

References

Bargiello, Thaddeus A., and Michael W. Young. 1984. Molecular genetics of a biological clock in Drosophila. Proc Natl Acad Sci USA 81, no. 7:2142.

Beckman, Carl H. 2000. Phenolic-storing cells: keys to programmed cell death and periderm formation in wilt disease resistance and in general defence responses in plants? Physiological and Molecular Plant Pathology 57, no. 3:101-110.

Darwin, Charles. 1880. The Power of Movement in Plants. London: John Murray.

Dercks, W., and L. L. Creasy. 1989. The significance of stilbene phytoalexins in the Plasmopara viticola-grapevine interaction. Physiological and Molecular Plant Pathology 34, no. 3:189-202.

Gadacha, Wafa, et al. 2009. Resveratrol opposite effects on rat tissue lipoperoxidation: pro-oxidant during day-time and antioxidant at night. Redox Report 14, no. 4:154-158.

Gu, Liwei, et al. 2004. Concentrations of Proanthocyanidins in Common Foods and Estimations of Normal Consumption. The Journal of nutrition 134, no. 3:613-617.

Hatori, Megumi, et al. 2012. Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet. Cell Metabolism 15, no. 6:848-860.

He, Baokun, et al. 2016. The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metabolism 23, no. 4:610-621.

Jeandet, Philippe, Roger Bessis, and Bernard Gautheron. 1991. The Production of Resveratrol (3,5,4′-trihydroxystilbene) by Grape Berries in Different Developmental Stages. American Journal of Enology and Viticulture 42, no. 1:41.

McClung, C. R. 2006. Plant Circadian Rhythms. Plant Cell 18, no. 4:792.

Mi, Yashi, et al. 2017. EGCG ameliorates diet-induced metabolic syndrome associating with the circadian clock. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1863, no. 6:1575-1589.

Miranda, Jonatan, et al. 2013. Effects of resveratrol on changes induced by high-fat feeding on clock genes in rats. British Journal of Nutrition 110, no. 8:1421-1428.

Nagy, Ferenc, Stephen A. Kay, and Nam-Hai Chua. 1988. A circadian clock regulates transcription of the wheat Cab-1 gene. Genes & development 2, no. 4:376-382.

Pifferi, Fabien, et al. 2011. Resveratrol Dietary Supplementation Shortens the Free-Running Circadian Period and Decreases Body Temperature in a Prosimian Primate. Vol. 26.

Potter, Gregory D. M. et al. 2016. «Nutrition and the circadian system». British Journal of Nutrition 116 (3): 434–442. doi:10.1017/S0007114516002117.

Qi, Guoyuan, et al. 2017. Dietary tea polyphenols ameliorate metabolic syndrome and memory impairment via circadian clock related mechanisms. Journal of Functional Foods 34, 168-180.

Ribas-Latre, A., et al. 2015a. Chronic consumption of dietary proanthocyanidins modulates peripheral clocks in healthy and obese rats. The Journal of nutritional biochemistry 26, no. 2:112-119.

Ribas-Latre, Aleix, et al. 2015b. Dietary proanthocyanidins modulate BMAL1 acetylation, Nampt expression and NAD levels in rat liver. Scientific Reports 5, 10954.

Ribas-Latre, Aleix, et al. 2015. Dietary proanthocyanidins modulate the rhythm of BMAL1 expression and induce RORα transactivation in HepG2 cells. Journal of Functional Foods 13, 336-344.

Song, Young H., Shogo Ito, and Takato Imaizumi. 2010. Similarities in the circadian clock and photoperiodism in plants. Current opinion in plant biology 13, no. 5:594-603.

Sun, Linjie, et al. 2015. Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice. Biochemical and biophysical research communications 458, no. 1:86-91.

Thosar, S. S., Butler, M. P., & Shea, S. A. (2018). Role of the circadian system in cardiovascular disease. Journal of Clinical Investigation, 128(6), 2157-2167.

Toda, Kazuya, et al. 2017. Passionflower Extract Induces High-amplitude Rhythms without Phase Shifts in the Expression of Several Circadian Clock Genes in Vitro and in Vivo. International Journal of Biomedical Science : IJBS 13, no. 2:84-92.

Tsao, Rong. 2010. Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 2, no. 12:1231-1246.

Vauzour, David, et al. 2010. Polyphenols and Human Health: Prevention of Disease and Mechanisms of Action. Vol. 2.

Xu, Tao, and Baiyi Lu. 2018. The effects of phytochemicals on circadian rhythm and related diseases. Critical reviews in food science and nutrition1-30.

 

 

 

Autophagy Genes

Autophagy is a general term for cellular pathways that move something from the cytoplasm of the cell into the lysosome for degradation. The term comes from the Greek ‘auto’ (self) and ‘-phagy’ (to eat).  So when you see articles touting ‘autophagy diets’ as the latest and greatest for longevity or beautiful skin, realize that the term is just a general one that applies to a cellular process that goes on all the time in our cells.

Let me see if I can explain a bit of the biology behind this, and then I’ll go into how your genes play a role in autophagy.

Back to high school science class:  Inside almost every cell in the body is an organelle called a lysosome. It is made up of a membrane that surrounds a bunch of different enzymes for breaking down proteins.  This is a way our cells can clean up after themselves, and also how they get rid of foreign invaders like bacteria. Continue reading “Autophagy Genes”

CYP3A4 and CYP3A5: Genes that Impact Drug Metabolism

Our bodies break down (metabolize) drugs and other toxins through a group of enzymes known as the CYP450 family. Different CYP enzymes break down different substances, and we all carry genetic variants that can impact whether we metabolize a drug quickly or slowly.

The CYP3A genes (which code for enzymes of the same name) is a subfamily of CYP 450 and is involved in the metabolism of about half the drugs on the market today as well as other xenobiotics and steroids.  There are several major genetic polymorphisms in the CYP3A family that can play a role in how a person reacts to a medication.

Several fruits – grapefruit, noni, pomegranate – are potent inhibitors of CYP3A4.  Eating or drinking these can cause adverse effects on drug metabolism, either increasing the efficiency of the drug or decreasing the effect. Continue reading “CYP3A4 and CYP3A5: Genes that Impact Drug Metabolism”

Lipoprotein(a): A big genetic risk for heart disease

It is often tempting to think that people who exercise, are thin, and look healthy are at a low risk for heart disease. But beneath all the healthiness can lurk a genetically driven risk factor for a heart attack: elevated lipoprotein a.

Heart disease is the number one cause of death in the US and in most countries around the world. Statistics show that one in four people in the US will die of heart disease.

We often have a picture in our heads of someone at risk for a heart attack: obese, older man who looks unhealthy, perhaps with a stressful job. Looking at the statistics, being overweight increases the risk of heart disease by 35% and being obese (BMI >35) can double the risk.[ref] Compare this to the healthy looking person who has no signs or symptoms but yet has a 3x risk of heart attack due to a genetically elevated lipoprotein(a) — Lp(a) — level.

The Biggest Loser host and fitness trainer, Bob Harper, has been open about his recovery from a very serious heart attack that he had in 2017. He was the epitome of healthiness – fitness trainer, nutritional guru, athlete, and only in his early fifties. But he also had genetically elevated levels of Lp(a). Here is a Today show interview where he explains some of his recovery and what he is doing to prevent a second heart attack.

Family history is always mentioned by the doctor as an important indicator of your risk of heart disease, especially if you have a close family member who had a heart attack fairly young. One big way that researchers have found that family history plays a role is through the inheritance of a genetic variant that increases lipoprotein(a).

Lipoprotein(a) or LP(a) — called L P little a — is a blood particle that carries LDL cholesterol and proteins. Elevated levels of Lp(a) are a strong risk factor for having a heart attack due to atherosclerosis.  Read more about Lp(a) on the Lipoprotein(a) Foundation website.

There are questions and controversy on the role that cholesterol plays in heart disease, and that may lead people to dismiss Lp(a) as just the latest number to talk about. (Lots of people on a low carb or keto diet like to point out the flaws in the studies on cholesterol.) I think it would be a big mistake to dismiss the research on Lp(a).  There is abundant and really good research on the increased risk for heart attack, narrowing of the arteries, and stroke  (i.e. cardiovascular disease) being caused by elevated lipoprotein (a).[ref][ref]


LPA gene variants: 

The LPA gene controls the formation of the lipoprotein(a) molecule. Variants in the gene, specifically variable number tandem repeats (VNTR), cause the body to create more Lp(a). About 25% of the population carries one or more risk alleles (listed below) that correlate to the VNTR.

Check your 23andMe results for rs3798220 (v4, v5):

  • CC: risk of elevated Lp(a), increased risk for heart disease – 3.7x risk of aortic stenosis [ref]
  • CT: risk of  elevated Lp(A), increased risk for heart disease, increased risk of aortic stenosis
  • TT: normal

Check your 23andMe results for rs10455872 (v4, v5):

  • GG: likely elevated Lp(a), increased risk for heart disease – 2x risk of aortic stenosis [ref][ref]
  • AG: likely elevated Lp(A), increased risk for heart disease
  • AA: normal

Studies also showed that carrying one risk allele for both of the above — compound heterozygous — also doubled the risk of aortic stenosis.[ref]


Lifehacks:

So what do you do if you carry the risk alleles?  Knowledge is power here.

First:
Keep in mind that this is a fairly common genetic risk factor, so it isn’t a reason to stress out or be anxious.  It is an excellent reason to do what you can from a lifestyle perspective to lower your risk of a heart attack: stop smoking, don’t drink too much, be active, eat healthily, reduce stress. You know all of these things, and now you know that they apply to you.

Get educated:
Read more about lipoprotein (a): Lipoprotein(a) Foundation,  European Atherosclerosis Society,

Doctor:
Talk to your doctor about getting an Lp(a) blood test done.

Quantify:
If you are one of those people who always ignores the “talk to your doctor” advice, you can also order a lipoprotein (a) test done through Walkinlab.com for about $45.  There are other online companies that you can order lab work through as well, and they all offer specials and coupons, so shop around.

How high is high?
One study shows a 3x risk of aortic valve stenosis for those with Lp(a) levels greater than 90 mg/dl.[ref]  Another source says normal Lp(a) levels are less than 30 mg/dl (or 75 nmol/L)[ref]  while others put it at less than 50 mg/dl.[ref] Again – this is something to talk to a doctor about and keep up with the research as it comes out.

Therapies:
There are a couple of therapies for high Lp(a) that have been well studied as well as new drugs coming out to target it.[ref]

  • Apheresis, where they run your blood through a machine to remove the LDL particles,  is considered effective, but expensive and inconvenient.[ref]
  • Niacin (vitamin B3) has been used for decades to lower the risk of heart disease. Studies show that 1 -3 g/day lowers Lp(a) levels by an average of 30-40%.[ref][ref][ref]  Most studies use the type of niacin that causes flushing.
  • Overall, lowering your LDL cholesterol numbers can help lower Lp(a) some since Lp(a) is the carrier for LDL. Here is a good article on it from the Cleveland Clinic.  How do you lower your cholesterol with diet? That seems to be the million dollar question.  A more whole food, plant-based diet, in comparison with a higher meat and fat based diet, works to lower cholesterol for some people.  It may be that you need to try out several diets – Mediterranean, DASH, etc – and test to see what works for your body.
  • One study showed Gingko Biloba reduced Lp(a) levels. The study used 120mg, twice a day and showed a 23% decrease in Lp(a). [ref]

More to read/watch:

 

Vitamin K: CYP4F2 and VKOR Genetic Variants

Vitamin K1 is a fat-soluble vitamin that is needed by our bodies to synthesize the proteins responsible for blood coagulation.  Without vitamin K1, also known as phylloquinone, bleeding is hard to control.  We get vitamin K1 from eating green plants, as phylloquinone is a part of the photosynthesis process.

Vitamin K2 comes in several different forms (MK-4, MK-7, MK-8, MK-10) and helps maintain bone strength.  Additionally, higher levels of K2 has been shown to reduce calcification in the arteries [ref], as well as possibly playing a role in mitochondrial function.[ref]

We get the highest amounts of vitaminK2 from pasture-raised eggs, dairy, and organ meat as well as from fermented soy (natto). We can also convert K1 toK2 in some organs of our bodies, and certain residents of our gut microbiome (E. coli especially) convert K1 to K2 for us. Continue reading “Vitamin K: CYP4F2 and VKOR Genetic Variants”

How light at night could double your risk of cancer.

The World Health Organization listed ‘light at night’ as a possible carcinogen in 2007. That is an eye-opening statement for something that affects almost all of us. From streetlights to the lamp in the living room, from accent garden lighting to the glow of TV’s and cell phone… artificial light at night is truly ubiquitous.

An often stated fact is that 80% of people in North America cannot see the milky way at night.  What was more surprising to me was that the Milky Way was supposed to be visible!  Who knew?  Oh, wait – people with no light pollution know…

So how can light possibly be a carcinogen? Will turning on the TV or a light in the living room after dinner suddenly cause cancer?  Let me start with two recent, contradictory studies, and then I’ll get into the science of why I think that artificial light at night is a fundamental health problem. 

Continue reading “How light at night could double your risk of cancer.”

Genetic variants that increase susceptibility to Lyme disease

Lyme disease is caused by being bitten by a tick that carries the bacterium Borrelia burgdorferi  in North America or other Borrelia species in Europe.  General symptoms after being bitten can include a bulls-eye rash, fever, headache, pain, and general malaise. The majority of people recover after a few weeks, but some have symptoms (neurological, cardiovascular, fatigue, arthritis) that can last for months or even years.

Whether you are one of the ones who recover quickly or have chronic symptoms including joint pain or arthritis may be due to genetic variants that you carry.

Immune Response:
The innate immune system reacts quickly to pathogens, giving us the initial inflammatory response to fight off bacterial invaders.  One part of the innate immune system is the toll-like receptor (TLR) family, which helps the body to recognize specific bacteria, like Borrelia.

The simplified picture is that the innate immune system recognizes the Borrelia bacteria, raises an alarm bringing in inflammatory molecules to destroy it. It is the front line of the body’s army, quick to rise and fight a short battle.

Part of our individuality is found in different genetic variants in our innate immune system. It makes sense for a population to carry different variants – some may be better at fighting off leprosy, others good at surviving cholera.  While variation is good on whole, for an individual, though, it can end up causing increased susceptibility to a pathogen like Borrelia.


TLR1 (Toll-like Receptor 1) -Check your Genetic Variants:

One variant in TLR1, rs5743618 or T1805G, causes a decreased TLR1 functionality for people carrying the CC genotype.  This is an advantage when it comes to leprosy and cuts the risk of severity. [ref] But when it comes to Lyme disease, this variant is linked to an increased risk of ‘antibiotic refractory Lyme arthritis’ which basically means that joints still ache after taking several rounds of antibiotics.[ref]

The C variant for rs5743618 is found in about 50% of the Caucasian population, less than 10% of African populations, and is rarely found in Asian populations. [ref]

Check your 23andMe results for rs5743618 (v4, v5)

  • CC: 1.9x more likely to have antibiotic-refractory Lyme arthritis (but better off if you get leprosy)
  • AC: normal Lyme risk
  • AA: normal Lyme risk

There is another (uncommon) TLR2 genetic variant that is not covered by 23andMe testing. It is interesting because it cuts a person’s risk of Lyme disease by more than half and reduces the risk of long-term effects from Lyme even more substantially.[ref] This again shows the impact that our genetic variants in our immune system can have on our susceptibility to diseases.


HLA-DRB1 gene:

The HLA genes code for another part of our innate immune system known as the major histocompatibility complex. One variant, HLA-DRB1 *0401 has been linked to a greater susceptibility to antibiotic-resistant Lyme arthritis as well as being a risk factor for rheumatoid arthritis.[ref][ref][ref][ref]

So why am I going on about the link to rheumatoid arthritis, an autoimmune condition? There have been quite a few different studies over the past 20 years looking at the link between Borrelia infection and subsequent autoimmune diseases. There doesn’t seem to be a smoking gun study that definitively shows Borrelia causing autoimmune diseases (that I could find), but an interesting 2017 study looked at patients with Lyme arthritis who were diagnosed with autoimmune joint diseases within 4 months of getting Lyme.  The study results showed: “Most systemic autoimmune patients had positive tests for B. burgdorferi IgG antibodies by ELISA, but they had significantly lower titers and lower frequencies of Lyme-associated autoantibodies than LA patients. Prior to our evaluation, the patients often received additional antibiotics for presumed Lyme arthritis without benefit. We prescribed anti-inflammatory therapies, most commonly disease modifying anti-rheumatic drugs (DMARDs), resulting in improvement.” [ref]

HLA-DRB1 *0401

Check your 23andMe results for rs660895 (v4, v5):

  • GG: increased risk of Lyme arthritis, rheumatoid arthritis.
  • AG: increased risk of rheumatoid arthritis
  • AA: normal risk

 


Other factors affecting Lyme:

A study found that age is a factor in susceptibility to Lyme with elderly people likely to have a less vigorous immune response to the pathogen. The study also found that BMI, gender, vitamin D levels, and previous exposure to Borrelia had no effect on Lyme susceptibility.[ref]


Lifehacks:

Antibiotics are, of course, the first line of defense against Borrelia. Your doctor can give you more information on the effective antibiotics.

Below are some herbal remedies that are often recommended for chronic Lyme symptoms that persist after antibiotic treatment:

Stevia, an herbal sweetener, has been shown in the lab to kill Borrelia about as well as antibiotics do.[ref] I question whether this holds true in people rather than just in Petri dishes. But if you like stevia, it is probably a safe bet to use it when you have Lyme disease and it may help.

Andrographis paniculata is an Asian herb used in traditional medicine for respiratory infections and other ailments. It is recommended as an herbal remedy (combined with other herbs) for chronic Lyme disease.  While I didn’t find any studies on its effectiveness against Borrelia, there are quite a few studies on it for other diseases.  Studies have found it to be somewhat effective in the treatment of ulcerative colitis,  changing TH1/TH17 immune response, decreasing fatigue from MS, and as an antibiotic. [ref][ref][ref][ref]

Cat’s Claw (Uncaria tomentosa) is a traditional Peruvian herbal medicine that is often suggested for Lyme disease.  Again, I didn’t find any studies specifically showing that Cat’s Claw was effective for chronic Lyme disease symptoms. Studies do show that it is an antiviral and immunomodulator and that it may be effective for Dengue fever. Other studies show it affecting TNF-alpha and IL-1B levels in the immune response.[ref][ref][ref] You can get Cat’s Claw on Amazon or at most health food stores.

Japanese Knotweed (Polygonum multiflorum) is traditional Chinese herbal medicine sometimes recommended for Lyme. No Lyme specific studies, but there is a very good review of the effectiveness and safety of knotweed for a variety of ailments. Two constituents of knotweed are resveratrol and emodin.[ref]

Emodin, found in knotweed (above), is an anthraquinone that has been shown in a cell study to be effective against Borrelia.[ref] It is also found in rhubarb and is what causes the ‘gastrointestinal effects’ from eating too much rhubarb at once. Another source for emodin is cascara sagrada (also a laxative). There are quite a few studies on emodin, and it is possibly effective as an antimicrobial and as an anticancer agent. Studies also show that long-term, high doses may not be completely safe — so read up on it and know what you are getting into before you go overboard on this one.[ref] [ref]

All in all, there isn’t a ton of research on herbal remedies for chronic Lyme disease, even though there is a lot of discussion on various websites touting their effectiveness (and sometimes selling the products).  My guess is that emodin may be the most effective constituent of some of the herbal remedies.  Rhubarb pie with some stevia?

Dads matter: MTHFR variants in fathers affect miscarriage risk

There are quite a few studies showing that women carrying certain MTHFR variant combinations are at a somewhat higher risk for miscarriage, but I recently ran across a study that added a new twist to the topic.  It turns out that the father’s MTHFR variants can also play a role in recurrent miscarriages.

The study from 2015 looked at 225 couples with more than three consecutive pregnancy losses compared with 100 control couples with successful pregnancies.  All 225 mothers in the pregnancy loss group carried either compound heterozygous MTHFR C677T and A1298C variants or homozygous C677T or homozygous A1298C. The study defined carrying just one copy (heterozygous) of either C677T or A1298C as being at a low risk for miscarriage.

When the researchers looked at the fathers MTHFR variants, they found that in the pregnancy loss group the men were more likely to carry the risk variants.[study]  This backs up the work of other, smaller studies that also found that the male’s MTHFR status combined with the mother’s MTHFR variants does seem to statistically increase the risk of miscarriage.[study]

 

 

How to check your MTHFR variants on 23andMe

Check your 23andMe results for rs1801133 for the MTHFR C677T:

  • GG: normal (wildtype)
  • AG: one copy of C677T allele (heterozygous), MTHFR efficiency reduced by 40%
  • AA: two copies of C677T (homozygous), MTHFR efficiency reduced by 70 – 80%

 

Check your 23andMe results for rs1801131 for the MTHFR A1298C:

  • TT: normal (wildtype)
  • GT: one copy of A1298C allele (heterozygous), MTHFR efficiency reduced
  • GG: two copies of A1298C (homozygous), MTHFR efficiency reduced

 

 

 

There are a couple of things that could be going on here:
First, fathers who carry the MTHFR variants are likely passing them on to the baby.  There are a couple of studies showing that the baby’s MTHFR variants may play a role in miscarriages, but there are other studies showing no effect from the baby’s MTHFR gene. Overall, the meta-studies tend to show little to no effect from the baby’s MTHFR status, so this is probably not the reason.[study]

The second possibility of why the father’s MTHFR variants matter could tie in with the fact that men carrying homozygous MTHFR variants are also at a higher risk for infertility.  A meta-analysis pooled the results of 20+ studies and showed that men carrying either the homozygous MTHFR C677T or A1298C variants were at a higher risk for infertility (29 – 63% increase).  Statistics here…  Keep in mind that this is the just the increase in the risk of infertility compared to the normal risk. For example, if the risk of male infertility is 1 in 20, a 69% increase would make the risk 1.69 in 20.[study]

Dads matter – in conception, pregnancy, and throughout life! It is easy to see how prospective moms need to clean up their diets, exercise, and sleep well before getting pregnant, but I think these studies are a good reminder that prospective fathers need to pay attention to their own health as well!

MTHFR variants (read more here) increase the need for ensuring adequate folate consumption. This means leafy green veggies, legumes, and other organic food sources of folate need to be eaten daily. If you won’t make the necessary dietary changes, there are methyl folate supplements as well. A quality B12 is also important, and many people find it convenient to take a B-complex to cover all the bases.  Here is one that I like: Jarrow B-Right. But you may find other options that are a better fit for you.

This may be a ‘talk to your doctor’ situation if you have a physician working with you on family planning.  I know – telling some guys to talk to a doctor is like banging your head against the wall, but if recurrent miscarriages or infertility are a problem, this really may be a time to get some professional help.

I didn’t find any specific studies looking at men supplementing with folate for recurrent miscarriage, but there are studies showing that it is effective for women. One recent (small) study found that 5mg of methyl folate along with B6 and B12 decreased the risk of miscarriage.[study]

Please note that methyl folate is likely the better form of supplemental folate vs. folic acid,[study]  but that some studies show that a folate-rich diet is as effective as either methyl folate or folic acid. [study]  One reason for methyl folate instead of folic acid is that there have been several recent studies linking high doses of folic acid to things like an increased risk of allergies[ study] and some epigenetic changes that are a bit of an unknown.[study]

Studies on miscarriage risk for women carrying MTHFR variants: