PEMT and BHMT SNPS, Choline and Cancers, with a nod of thanks to ppodhajski

[Kathevans]

Many of you have provided both advice and support in my healing journey and I am enormously grateful. You’ve helped me to feel not quite so alone, have taken the edge off a very scary process and given me tools to move forward. Most of all you’ve made me feel less stuck.

Because of my family history—my mother and an older sister dead from breast cancer far too young, my baby sister living with it, I have a particular interest in approaches to this challenging disease. Though genetic counseling has shown I do not have the BRCA2 gene, both my sisters have/had it (not my mother, most likely, as she developed it post-menopausally, whereas my father’s sister, like my own, developed it pre-menopausally, leading counselors at Dana Farber to suggest it was most likely passed down by my father).

In any case, it’s this clear-cut effect of genetics that has led me to PR’s methylation protocols and one of the threads here where @ppodhajski happened to mention the University of North Carolina’s work on Nutrigenomics. For this bit of serindip, a bow to him. My own curiosity led me along the path of the head of the Department of Nutrition at that school, Dr. Steven Zeisel, whose credentials are stellar: Harvard Medical, MIT PhD in Nutrition.

It’s Dr. Zeisel’s work I want to bring to the awareness of members who are interested. In my research, which has been in no way exhaustive, I came upon enough pertinent journal articles co-authored by him to make me aware of the importance of choline for those struggling with breast cancer.

I want to share the work I’ve compiled which includes information about Dr. Zeisel (all highlighted print is my own), and four articles he has helped to pen: ‘Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans,’ ‘Choline metabolism and risk of breast cancer in a population-based study,’ ‘High intakes of choline and betaine reduce breast cancer mortality in a population-based study,’ and ‘Common genetic polymorphisms affect the human requirement for the nutrient choline.’

If I can manage to upload this file, it’s nearly 50 pages of information. I hope some of you find it useful. Just fyi, from other threads on choline, I ultimately came to the conclusion that Jarrow’s Citicoline (I think I’m right in calling it an intermediate form of choline) was the supplement I wanted. My sister is now taking it and being hale and hearty in ways I am not (yet!) having no reactions whatsoever. I took ¼ capsule two days in a row and by the second, couldn’t sleep much at all—even with my usual crutches!!

I’ll try again as I increase my MeB-12 and Folate levels…

The very best to each of you.

 

[Gondwanaland]

most young women need little dietary choline while men and post menopausal must eat this nutrient or become sick

@mariovitali

 

[Gondwanaland]

@Oci

 

[ahmo]

Great job @Kathevans thanks for sharing. I've also settle on citicholine, + sunflower lecithin. Best wishes to you.

 

[Oci]

@Kathevans Yes, many thanks!!! I have experienced a lot of cancer both in myself and family members too. I fear for my children and grandchildren considering their possible genetics. I am so sorry to hear of the toll it has taken on your family too.

I have been wading through what you sent! Unfortunately I have some genes that increase my chances of cancer and so I need to do whatever I can. Also some of the ones studied have not been tested by 23andme.

So, it seems we need moderate amounts of choline or we risk CDV risk increase. And that dietary choline (free) gives the most protection. I guess I need to learn to like beef liver!

What dose are you all using of sunflower lecithin? I'd really appreciate your help on this.

It looks like we don't want too high an amount either. Also how does this supplementation affect those of us - including myself and Kath - who have COMT++ and react to excess methyl groups?

Many thanks, Ann

Here are some excerpts I am working on. Bold is my doing.

"Dr. Zeisel's research team discovered that 45% of women have a
genetic variation (snp) in the PEMT gene that makes them unresponsive to estrogen
and therefore they require dietary choline."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775010/
"Table 3 shows the association between nutrient intakes and survival (all-cause mortality and breast
cancer-specific mortality) among the cohort of case women in the LIBCSP. Higher betaine,
phosphocholine, and free choline intakes were associated with reduced all-cause as well as breast
cancer-specific mortality in a dose-dependent fashion. Women in the highest betaine intake group had
a 35% decreased risk of dying from breast cancer (HR, 0.65; 95% CI, 0.41–1.00). Although high
intake of phosphocholine reduced breast cancer mortality by ∼40% (HR, 0.61; 95% CI, 0.38–0.99), a
close to 50% reduction (HR, 0.54; 95% CI, 0.32–0.93) was observed among women with a high free
choline diet."

So, how do we manage a high choline diet? It has been suggested below that we need 550 mg/day for men and 425 mg/day for women). I may be getting close to that in my diet some days...days I start with 2 soft boiled eggs. Other days not.

http://lpi.oregonstate.edu/mic/other-nutrients/choline
Table 2. Some Food Sources of Choline
Food Serving Total Choline (mg)
Beef liver, pan fried 3 ounces* 356
Wheat germ, toasted 1 cup 202
Egg 1 large 147
Beef, trim cut, cooked 3 ounces 97
Scallop, cooked, steamed 3 ounces 94
Salmon, pink, canned 3 ounces 75
Chicken, breast, cooked, roasted 3 ounces 73
Atlantic cod, cooked 3 ounces 71
Shrimp, canned 3 ounces 69
Brussel sprouts, cooked, boiled 1 cup 63
Broccoli, cooked, boiled 1 cup, chopped 63
Milk, skim 8 fluid ounces 38
Peanut butter, smooth 2 tablespoons 20
Milk chocolate 1.5-ounce bar 20
Peanuts 1 ounce 15
*A 3-ounce serving of meat or fish is about the size of a deck of cards.
Supplements
CDP-choline (citicoline) and choline salts, such as choline chloride and choline bitartrate, are available as supplements. Phosphatidylcholine supplements also provide choline; however, choline comprises only about 13% of the weight of phosphatidylcholine (79). Therefore, a supplement containing 4,230 mg (4.23 grams) of phosphatidylcholine would provide 550 mg of choline. Although the term "lecithin" is synonymous with phosphatidylcholine when used in chemistry, commercial lecithins are usually prepared from soybean, sunflower, and rapeseed, and may contain anywhere from 20%-90% of phosphatidylcholine. Egg yolk lecithin is a more unlikely source of lecithin in dietary supplements. Moreover, the nature of phosphatidylcholine-containing fatty acids depends on whether lecithin is produced from vegetable, animal, or microbial sources. In particular, soybean lecithin is richer in polyunsaturated fatty acids than egg yolk lecithin (80).

Safety
Toxicity
High doses (10,000 to 16,000 mg/day) of choline have been associated with a fishy body odor, vomiting, salivation, and increased sweating. The fishy body odor results from excessive production and excretion of trimethylamine, a metabolite of choline. In the inherited condition, primary trimethylaminuria (also known as “fish odor syndrome”; see the article on Riboflavin), a defective flavin containing monooxygenase 3 (FMO3) enzyme results in impaired oxidation of trimethylamine in the liver. Disease management includes the use of choline-restricted diets in affected individuals (81).

Taking large doses of choline in the form of phosphatidylcholine (lecithin) does not generally result in fishy body odor, because its metabolism results in little trimethylamine. A dose of 7,500 mg/day of choline was found to have a slight blood pressure lowering (hypotensive) effect, which could result in dizziness or fainting. Choline magnesium trisalicylate at doses of 3,000 mg/day has resulted in impaired liver function, generalized itching, and ringing of the ears (tinnitus). However, it is likely that these effects were caused by the salicylate, rather than the choline in the preparation (27).

In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established the tolerable upper intake level (UL) for choline at 3,500 mg/day for adults (Table 3). This recommendation was based primarily on preventing hypotension (low blood pressure), and secondarily, on preventing the fishy body odor due to increased excretion of trimethylamine. The UL was established for generally healthy people, and the FNB noted that individuals with liver or kidney disease, Parkinson's disease, depression, or inherited trimethylaminuria might be at increased risk of adverse effects when consuming choline at levels near the UL (27).

Table 3. Tolerable Upper Intake Level (UL) for Choline
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-8 years 1,000
Children 9-13 years 2,000
Adolescents 14-18 years 3,000
Adults 19 years and older 3,500
*Source of intake should be food and formula only.
Do high choline intakes and/or phosphatidylcholine supplements increase the risk for cardiovascular disease?
Oral supplementation with phosphatidylcholine (250 mg of total choline from food plus 250 mg of supplemental phosphatidylcholine) has been found to result in detectable concentrations of trimethylamine and trimethylamine N-oxide (TMAO) in the blood (23). The intestinal microbiota is directly implicated in the generation of trimethylamine from dietary choline, phosphatidylcholine, and carnitine. Trimethylamine is subsequently converted into TMAO by flavin-containing monooxygenases in the liver. The prospective study that followed 4,007 individuals,with or without cardiovascular disease (CVD) for a three-year period found baseline concentrations of circulating TMAO to be positively correlated with incidence of death, nonfatal myocardial infarction, and stroke − described as major adverse cardiac events (MACE) (23). In the same cohort, MACE risk was found to be about 30% higher in individuals in the highest vs. lowest quartile of choline or betaine plasma concentrations (82). However, depending on gut microbiota composition, the risk of having an adverse cardiovascular event may be lower in individuals with low vs. high circulating TMAO even though choline and/or betaine concentrations in the blood are elevated (82).

Elevated TMAO concentrations have been reported in subjects at increased risk of CVD, such as those with diabetes mellitus (83) or end-stage renal disease (chronic kidney failure) (84), and in patients with cardiac insufficiency (chronic heart failure) (85). Yet, in the latter patients, high plasma concentrations of choline, betaine, and TMAO were not associated with a poorer survival rate after five years of follow-up (85). Finally, supplementation with choline, TMAO, or betaine was found to result in the formation of macrophage-derived foam cells in atherosclerosis-prone mice (24). Foam cells are known to contribute to the development of atherosclerotic lesions (i.e., atherogenesis) by accumulating excessive amounts of lipids within the arterial walls and triggering the secretion of pro-inflammatory cytokines.

Further research is needed to understand how the composition of intestinal microbiota influences the metabolic fate of ingested choline. At present, there is no evidence that dietary choline increases the risk of cardiovascular events.

Linus Pauling Institute Recommendation
Little is known regarding the amount of dietary choline required to promote optimum health or prevent chronic diseases in humans. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 550 mg/day for adult men and 425 mg/day for adult women. A varied diet should provide enough choline for most people, but strict vegetarians who consume no milk or eggs may be at risk of inadequate choline intake.

Older adults (>50 years)
Little is known regarding the amount of dietary choline most likely to promote optimum health or prevent chronic diseases in older adults. At present, there is no evidence to support a different recommended intake of choline from that of younger adults (550 mg/day for men and 425 mg/day for women).

 

[Gondwanaland]

I guess I need to learn to like beef liver!

Not so easy if histamines are a problem... What is your DAO status?
From my Sterling's report I am:
DAO rs2070586 A GG -/-
DAO rs3741775 C CC +/+
http://suzycohen.com/articles/histamine_intolerance_dao_genes_hashimotos/

 

[Oci]

Many thanks, Gondwanaland. I have certainly been having symptoms of high histamine of late. I tried taking high doses of probiotics and my brain became terribly foggy.
I have had a lot of migraines in my life although not as many lately. I have never done well on fermented foods.
It looks like histamine is possibly a problem for me.
rs3741775 DAO A14747C C AC +/-
rs3918347 DAO A24464G G AG +/-
rs2070586 DAO G8864A A GG -/-
rs1049742 DAO/ABP1 C995T T CT +/-
and
rs1049793 ABP1/DAO C1933G G CG +/-
rs10156191 ABP1/DAO C47T T CT +/-

Suzy Cohen says
Another SNP in the HNMT gene (histamine-N-methyl transferase) will cause histamine to build up. This is the gene that encodes for an enzyme that reduces histamine into another compound called N-methylhistamine, which subsequently requires the MAO (monoamine oxidase) enzyme to further break it down. MAO runs by having enough riboflavin (actually the biologically active form called FAD).

Fortunately the snps for the following are negative.
rs1378321 HNMT A47507G G AA -/-
rs1050891 HNMT T939C G AA -/-

Suzy says: "As you can see from my diagram, the DAO enzyme is dependent on vitamin B6, B12, iron, copper and vitamin C.
........The problem is that fermented foods are extremely high in histamine."

So liver is high in histamine?

 

[Kathevans]

@ ahmo I think it was your analysis of choline that settled me on the citicoline! Good work!

@ Oci So far I haven't been able to tolerate the citicoline and haven't even tried lecithin. But I did increase my MeB12 to 2mg and the Folate to 800mcg yesterday and these increases are certainly getting both larger and easier to tolerate, so I'm thankful for that. The B12, I believe will have an effect on stomach acid production as I increase it, and that's good since betaine has also been impossible for me to take for the moment. I also think that the magnesium I take--probably about 500mg/day in 2 doses,has helped my COMT++ to overcome whatever methylation difficulties may be associated with that. Or perhaps it has just been getting the ratio of B12 to Folate right at roughly 2:1. It's so hard to know what makes anything in the body work the way it does.

As to food sources of choline, I have to say I never did like beef liver, but I love eggs. I have two poached eggs a day and that, along with some chicken at night or a veggie that's high in choline brings me up over 400mg, which is the target. That doesn't seem so hard, really. If you can't get it in your diet, but can tolerate the supplement, which is 250mg, that could work, too.

@Gondwanaland My DAO are both heterozygous, but I don't seem to have histimIne problems, or at least not any overt ones, and again, it may be the high B6 I take, or the B12, or the vit C that help to moderate any affects.

 

[Oci]

@ Oci So far I haven't been able to tolerate the citicoline and haven't even tried lecithin.

As to food sources of choline, I have to say I never did like beef liver, but I love eggs. I have two poached eggs a day and that, along with some chicken at night or a veggie that's high in choline brings me up over 400mg, which is the target. That doesn't seem so hard, really. If you can't get it in your diet, but can tolerate the supplement, which is 250mg, that could work, too.

Just wondering why you are trying citicoline when it appears you are getting enough food sources of choline? My desire is to get as much as I can from food and decrease the huge number of supps I have taken over the years!

The B12, I believe will have an effect on stomach acid production as I increase it, and that's good since betaine has also been impossible for me to take for the moment.

I also cannot take betaine Hcl - it burs my stomach - and am wondering how to increase betaine. I think my stomach lining is weak - I cannot tolerate anything like ibuprofen, aspirin, pain meds. I don't feel stomach acid is low however.

@Gondwanaland My DAO are both heterozygous, but I don't seem to have histimIne problems, or at least not any overt ones, and again, it may be the high B6 I take, or the B12, or the vit C that help to moderate any affects.

I'm wondering how much of B 6 and which ones you are taking? I've played around a bit but don't have a feel for what is needed.

Many thanks once again! Ann

 

[Kathevans]

Just wondering why you are trying citicoline when it appears you are getting enough food sources of choline?

Support for the snps for the moment in the event my digestion isn't working as efficiently as it ought to be for absorption. And because choline affects betaine and that might be a way of improving digestion as well.

I'm wondering how much of B 6 and which ones you are taking? I've played around a bit but don't have a feel for what is needed.

I'm getting 20mg of B6 in my daily Seeking Health B-Minus, and an additional 12 mg from a 50mg capsule by Pure Encapsulations which I divide 4 ways. I agree there doesn't seem to be much 'feel' for the B6 as far as my body goes. I know it has to do with neurotransmitters and I wanted to see if more helped and initially, it seemed to contribute to more dreams. That initial response has faded and I haven't made any changes for the moment. There is also the issue of oxalates for me, and the B6 is good for that.

Mornings at my house, I'm the kitchen chemist! I'd like to take fewer supps, too, but till I manage to bathe my muscles and tendons with Folate--which may take very large doses--I'm afraid my approach is going to be more, not less!