Fiddle, Fiddle, & More Fiddling (a.k.a. “What is a maintenance dose?”)

Pic of the day - Cajun Music Party


This is the distilled down description of what I did, without the explanation, for those who are coming back to this post and just want a quick reference of the numbers. Remember to talk dosing and timing over with your doctors!

mg = milligram
mcg = microgram
1 mg = 1000 mcg

In the Early Days

1 mg 5-L-methylfolate daily in morning
1 b-complex (without folate or folic acid) daily at lunch
1 mg methylcobalamin daily at evening

After Injury

2 mg 5-L-methylfolate daily in morning
1 mg 5-L-methylfolate daily at lunch
1 b-complex (without folate or folic acid) daily at lunch
1 mg methylcobalamin daily at evening

When Healthy

400 mcg 5-L-methylfolate in morning twice a week (usually M/Th)
1 b-complex (without folate or folic acid) daily at lunch
1 mg methylcobalamin at evening once a week


I’ve been taking extra methylfolate for a few years now. I started out following the general ideas from Dr. Ben Lynch’s MTHFR site, but without following his protocol (since that meant buying the vitamins that he sells, and I couldn’t find information about them anywhere other than on his site). So I’ve been cobbling things together on my own, through experimentation and how my own body reacts. This is absolutely the hard way to do things, but I haven’t found a doc who knows enough about it to give me advice. Dr. Lynch makes one very important point in his protocol:

“Now – the supplement recommendations need to be tailored to the individual – again – regardless of which genetic variants you have. Working with a physician trained in this area of medicine is key. The recommendations of supplements are merely suggestions and ones that I may recommend to a patient or physician. They are not flat out must-haves nor must one take all of them.”

Personalize it. Tweak. Fiddle. Refine. Change things up. Experiment. Customize. Listen to your body. Here’s what I’ve found myself doing over the past few years, and what I’m doing now.

When I started, I’d been very sick for a lot of years. Decades. So, my body was in pretty bad shape, and had a lot of healing to do. I wasn’t sure at that point if the methylfolate would actually help, or what was the right dose for me. I started out with small doses (400mcg), and couldn’t even tell I was taking them, so I bumped it up, and up. I ended up taking a daily dose of about 1 mg (1000 mcg) for the first year or so. For a while I felt amazing. Then I started to have some of the side effects mentioned on Dr. Lynch’s site, so I started mixing things up, and added in some methylcobalamine (methyl-B12).

I was feeling decent, but then I had another illness, and felt crummy. I found that when I was sick, I needed a little extra. I bumped the dose up to 2mg (2000mcg), and when I felt better, I bumped it back down to 1mg/day. Then, about two years ago, I had a major injury. It took me a few months to even think of it, but I found again I needed to take a LOT when I was healing from the injury! I ended up taking 3mg a day for a while! And I had to take it all before noon, or it kept me awake at night. I split the doses 2mg when I woke up and another 1mg at lunch. For the record, while this is an enormous amount for me, this is nothing compared to what is typically prescribed by docs. One prescription form of methylfolate is called Deplin, and the lowest dose given for it is 9mg, THREE TIMES what I was taking at the highest level. During this time, I took another methylcobalamin at night, since that was supposed to help with sleep. I cringe at the thought of taking prescription levels of this, and have read innumerable comments from patients on Deplin in various online forums.

I was in physical therapy for almost two years, but finally ‘graduated.’ That’s when I really started to have trouble with the methylfolate. I had settled into a combination of vitamins that worked for me, and I felt pretty good most of the time. But now I wasn’t feeling good. I’d take my vitamins, and feel worse. I’d feel so tired, I’d take an extra methylfolate sometimes just to try to come up with enough energy to get through the day. Then I’d be so severely fatigued that I was convinced I had been glutened and that this was in reaction to hidden wheat in my diet. I was baffled trying to find how I’d been glutened. Sometimes I was so fatigued that I would forget to take my vitamins in the morning. Eventually I noticed that when I forgot to take my vitamins, I actually felt BETTER. I did some digging online and found a new-to-me post from Dr. Lynch about exactly this happening to people, where their bodies would start to have a reverse reaction to the methylfolate. The important part for me was way at the end.

“Just think of a bell-shaped curve. Before you started taking methylfolate, you felt terrible. You began taking it and started to feel good. Day after day goes by and you continue to improve. In time if the above things are not corrected, you will begin to slide down the other side of the bell-shaped curve.”

OK, so I stopped taking methylfolate. Briefly. After a few days, I started to feel awful again. I’ve found that right now, if I take even a small dose of methylfolate every day, I feel awful. But if I don’t take it for 3 or 4 days, I feel awful then, too. So right now, I’m in the process of trying to figure out what is the right maintenance dose for me. There’s these ideas in healthcare of therapeutic dose (what is needed to treat a problem), loading dose (kind of how to get to the therapeutic dose faster), and a maintenance dose (what it takes to feel OK when you aren’t sick anymore but still need at least a little of the med).

Loading Dose vs. Maintenance Dose

So, what I’m doing currently with respect to methylfolate (which will probably need to be tweaked again later) is this. I take the smallest dose I can find (400 mcg) twice a week, and 1mg of methylcobalamin once a week. I exercise a lot now (which is a big difference from what I could do before), and I eat a lot of green leafy vegetables. As I eat more of those, I may need less of the methylfolate. We’ll see.

Now, it’s important to mention that these are not the ONLY vitamins I take. There are several others which my docs recommended as supplements because of my celiac and gluten-free diet. There are vitamins I take for other conditions. They all fit together and there may be interactions between them. Obviously, there are also other conditions that can … intersect with MTHFR. For example, we know that having one copy of the MTHFR defect is protective against some kinds of cancer. That’s a good thing, right? And it helps explain why MTHFR defects are so common and wide spread. But this also could mean that there are possible issues for methylfolate supplementation for people who either have or are at risk of having cancer.

I try to bring up these various issues with my doctor when I have appointments, and I try to sort things out on my own as much as possible. I know, not everyone can do that. It’s really tricky. Part of the problem is that we just don’t KNOW what we need to know yet about this. It’s becoming obvious in the research literature that MTHFR genetic status and testing is important in many many conditions, but this isn’t widely known among clinicians, and what to do about it is even more obscure. Talk to your docs, but don’t leave this entirely in their hands. Join forums at and at Patients Like Me, where many folk generously answer questions. Don’t trust all those answers, but use them as a starting point to learn more, research, and for what questions and conversations you should be bringing to your own doctors.

I Hate Having Conversations Like This With a Doctor

At the Doctor's Office

This is a rant. Just being honest up front. I’m frustrated right now. Part of this touches on a new diagnosis I was going to blog about here, because it derives directly from the MTHFR genetics. I promise, I’ll come back to that more fully later, in another post. Right now, this post is about communication.

First some background. Last week I phoned my clinic to make an appointment for chest pain upon exertion, that stopped when exertion stopped. I was instead (quite properly, but frustratingly) sent to the ER, where I spent another 24 hours insisting that I felt FINE before being transferred to the Cardiovascular Center, where I spent ANOTHER 24 hours. Of course, in those circumstances you are poked and prodded, hooked up to various machines that don’t like you, get a bunch of tests, etc. If you are lucky, like I was, you get to come home with some new diagnoses, a bunch of instructions, and maybe an extra temporary hole or two. Being my kind of luck, I was also seriously glutened by the hospital’s glutenfree food, spent a few days feeling horrid and sleeping, and another few days breaking out in hives (front, back, arm, and face). Jolly.

Now, that was the GOOD part! Because every nurse and doctor I spoke with was knowledgeable, competent, courteous, engaged, and compassionate. Most of them were also informative, interested, entertaining and amusing, which was a definite plus. I had interesting conversations with them, and was honored to hear phrases like, “I didn’t know that! Thank you for teaching me about it.” “You’re more special than you think.” “I’m glad I met you.”

I had gone in with chest pain, a classic presentation but not a classic cardiac cause. One positive stress test and one negative cardiac catheterization later, it was clear that it was time to move on to the next step of the differential diagnosis. In the last couple hours before I was discharged, 1 cardiologist, 1 cardiology resident, 1 nurse practitioner, and 1 nurse all at different times looked me in the eyes and said, “You have an appointment coming up with your primary care doctor. It isn’t soon enough. Get them to move it up.” You see why I thought this might actually be important?

By the time I made it home on the day of discharge it was too late and I was too tired to phone the clinic, so the next morning that was the first thing I did. They couldn’t get me in with my primary care provider, but they found an appointment for someone on her team. That’s where I was this morning, and I came home cranky because I was unhappy with how the communication was handled. I’m venting some examples of the communications that bothered me. Pay attention to the pattern of information sources, and the flow of information in the conversation. That’s probably more important than what was actually said. Think of flipping the clinic, and then think again about just how that ought to work.

[NOTE: These are excerpts from a longer conversation, not a complete transcript.]

Cardiac or Not? Anemia or Not?

DR: Looks like they did a good job. [recites list of what I’ve had done medically in the past week] Do you want a referral to a cardiologist for that left bundle branch block? There really isn’t anything they can do, but I can do that.

ME: I think the cardiology people have done what they can for now.

DR: Well, it really isn’t your heart. And you’re not anemic.

ME: Yes, I am.

DR: No, you’re not.

ME: It’s on my active problem list.

DR: It shouldn’t be. Your hemoglobin is fine.

ME: Of course, it is. It’s the serum ferritin that isn’t.

DR: That’s not anemia, that’s low iron. See what I mean? You don’t have anemia.

ME: My hemoglobin is ALWAYS fine.

DR: Then you were never anemic.

ME: Oh, God!

DR: What?!

ME: [deep breath] OK. My hemoglobin is always fine. And I almost died of carbon monoxide poisoning because all the docs thought hemoglobin was all they needed to check.

DR: Your serum ferritin has ranged from 70 to 40 in the past five years.

ME: Yes, but when this started, my serum ferritin was 11. My fingers were gray. My skin was gray. My eyes were gray. My hemoglobin was low normal. And I almost died of carbon monoxide poisoning before someone would check my ferritin and start treating me for anemia.

DR: But you’re not anemic.

ME: I’m not anemic RIGHT NOW.(*)

DR: I don’t know why this is here.

ME: Please. Don’t. Don’t take it out of my diagnosis list.

DR: Well! I didn’t know you have strong feelings about that.

ME: It serves as an alert to my care providers that this is something that needs to be monitored.

(*) [NOTE: Yes, “Anemia is strictly defined as a decrease in red blood cell (RBC) mass.” So technically, on a simple level, he was accurate enough. The idea of what exactly IS “low normal” hemoglobin is something that is pretty hotly debated in the literature, including findings that “low normal” carries its own risks. For example this statement from UpToDate: “Studies in older adults with hemoglobin levels in the “low normal” range according to WHO criteria have linked these levels to declines in performance as well as increased morbidity and mortality.” And then there is the subtlety of what are differences in types of anemia. What I have/had is Anemia of Chronic Disease, which most likely originated with the then undiagnosed celiac disease and was exacerbated by the also then undiagnosed MTHFR deficiency.

“Hemoglobin values will generally reach a low normal range of 9.5–10.5 g/dL and remain there within this moderately low range until the underlying condition is cured. If disease that results in blood loss is present, the person will develop iron deficiency anemia (IDA). ACD and IDA can be distinguished with a serum ferritin test.” Iron Disorders Institute: Anemia of Chronic Disease.

What I never got a chance to say in this conversation was that the doc who diagnosed me with anemia (assistant department chair of family medicine at the time) told me that in long-standing severe anemia the body throws every scrap of iron it can find into the hemoglobin in an attempt to keep the body alive, and that a chronic reading of low hemoglobin can be a sign of severe anemia. The docs who treated my anemia over several years, getting my ferritin up to that 40-70 range (out of a normal target of 100), are the ones who put in the diagnostic code and active problem list identifications. Unless he has a better and more appropriate code to enter to describe this problem, I personally feel safer leaving it as it was found.

Yes, I’m a bit on the defensive here. It’s a personal safety issue, and feeling safe. I discovered in the hospital that someone had deleted from my medical record my most serious drug allergy, and that scared me.]

New diagnosis

ME: And they added a new diagnosis.

DR: I don’t see anything new.

ME: They added “with homocystinuria” to my MTHFR deficiency diagnosis.

DR: I don’t see that in the computer.

ME: [rummages in bag, pulls out discharge folder from hospital, ruffles through papers, finds the right one] See here, on page three of the hospital encounter description?

DR: That’s just your active problem list.

ME: But this line changed.

DR: Hunh. I don’t know what that is. I don’t know who added that.

ME: Dr. L took the patient history about it, so I’m guessing it was him.

DR: I don’t even know how you would diagnose that.

ME: I did some searching online. The screening questions he asked came directly from the NIH Genetic Home Reference.

DR: I don’t know what that is.

ME: It’s from NIH and National Library of Medicine.

Differential diagnosis

ME: Homocystinuria is associated with embolism and liver disease. I’m already on baby aspirin, but I’m not sure anyone has checked my homocysteine levels. And liver disease was on the differential they mentioned in the hospital.

DR: What do you mean?

ME: The cardiac cath can only check the large vessels. In women, it isn’t unusual for the coronary artery disease to start in the microvessels. But that’s really hard to diagnose.

DR: [Nods.]

ME: The easiest way to diagnose CAD in microvessels is to rule out everything else. In the hospital they ruled out heart and kidney, and liver was another thing I heard them mention. I don’t know what else there should be.

DR: Well, they didn’t check your homocysteine levels, but they did check an indicator for them a year ago, so that’s fine.

ME: I don’t know the last time anyone checked my liver function. There is a blood test for that, isn’t there?

DR: Yes. Hmmm. No one has run that test in five years. Hmmm. OK, I can order that.


[COMMENT: Pay attention. This is where something started to go right, sort of.]

DR: So, how’s that incision?

ME: It’s fine. I had a little problem with it yesterday, but it’s fine now.

DR: Let’s listen to your heart and lungs. Unhunh. Lay back, please. Does that hurt? That? There? Please sit up. Hmmmm. Do you have asthma?

ME: Yes. Well, I did. After the carbon monoxide poisoning, my lungs were badly scarred.

DR: But it went away?

ME: Yes, the scar tissue shrank as it healed.

DR: Do you use an inhaler?

ME: No, I can’t. I’m allergic to them.

DR: What happens?

ME: I pass out.

DR: OH! Well, hmmm. I’m going to request a pulmonary function test, and we’ll mention that. So you don’t use an inhaler?

ME: I used to use Intal, but they quit making it. I stockpiled a couple, but I found the mechanism quit working after a while, even if there was spray left.

DR: Well, you can follow up on that with your regular doctor.


That was pretty much the end of the conversation. And it doesn’t seem quite as awful now that I’ve written it down, but it was very frustrating at the time. Why? The doc listened to me about some things and not others, didn’t seem interested in doing a differential diagnosis, and the impression I came away with was that this doctor didn’t take the other doctors or me seriously. I thought the argument about anemia was entirely unnecessary, and it alarmed me and undermined my trust in the doctor. He could have explained which definition of anemia he was using, and that would have helped, and perhaps opened the conversation to some of the other aspects of anemia that concern me. Since it wasn’t relevant to today’s meeting purpose, it only served to alarm me.

The information and explanations flowed mainly from me to him. He admitted not knowing certain things, but didn’t say he was interested or willing to learn or find out. Still, he didn’t shut me down when I tried to explain. He did listen and integrate the information. I was alarmed again that he wanted to send me right back to the docs I had just left, and I felt I had to work so hard to get him pointed in the direction of continuing the differential diagnosis process. After leaving, in doing more reading, I discovered that testing pulmonary function is indeed a logical next step for differential diagnosis of atypical chest pain, but that wasn’t something he discussed or explained, so I had the impression at the time that he was sidetracked from the purpose of the visit.

The visit wasn’t a total waste, and actually did achieve useful productive goals. I’m pleased to have the pulmonary function test and the liver function test in progress. Something will move forward while waiting for my next appointment with my primary doc over a month from now. It could have been a great deal easier and more clear. I could have gone away AWARE that he was genuinely trying to help, instead of feeling alarmed and distrustful. That would have been nice. Deep down, I think it worried me that I was providing medical information that he didn’t know, and he wasn’t giving me information that I didn’t already know. He wasn’t demonstrating his expertise. The dynamic around the information flow and sharing in these conversation snippets was patient-driven, yes, but imbalanced. Maybe I’m just being nitpicky?

Good Lord, People, 23andMe is NOT Dead!


Good Lord, people, 23andMe is NOT dead! Or closed, or no longer taking orders, or anything like that. I hear this a lot.

“You know, I always wanted to get my genome tested. I was going to try 23andMe, but then the FDA shut them down. Oh, well, missed my chance. [sigh]”

NO! You did NOT miss your chance. Firstly, 23andMe is not closed for business. They still will take your money and your sample. They still will analyze the sample and give you results. From what I’ve been seeing in the results from folk I’ve been helping to look at their data, 23andMe seems to be running the test exactly the same way they always did, for the same SNPs.

They simply are, at this time, not offering their health reports to new customers. It isn’t the data that has changed – it iw what analysis is shared with the customer. Old fogies like me who got their tests done before the FDA folderol” still have access to our old 23andMe health reports, and they continue to improve them.

I have heard nothing to indicate that 23andMe are not working with the FDA to try to make it possible to release health reports again in the future. Issues around that get complicated and I’m going to save them for a later post. Right now, what if you wanted a test for some genetic health information? Can you do it? How long will you have to wait to find out the answers to your health questions?

You can still do it. It isn’t as easy as it was before, but it can be done. I’ve been spending a lot of time talking people through how to do this, and it is time to write it down. If nothing else, it will save me time. This will be the short short version, and I can answer more detailed questions and describe specifics, maybe give an example or two or three.


Risk is Not Just Genes

Making sense of genetic information is complicated even for experts, which most of us are not. Of course, part of the irony of looking at genetics for health conditions is that most of the time what causes the condition is not just the genetics, but genes PLUS something else. If you don’t find the genes for something, that doesn’t mean you can’t get it; if you do find the genes for something, it doesn’t mean you will get it. It is hardly ever a case of this=that.

What Does Risk Mean, Anyway?

There is also the challenge of figuring out how important the risk is, and whether or not to do something about it. So, my personal risk of celiac disease is over 4 times normal. Wow! That sounds like a lot, doesn’t it? But 4 times normal for celiac risk is still only 1 in 20 people, because normal is about 1 in a hundred. I know someone with celiac risk 17 times normal, which is 1 in 4 people. That’s getting to be pretty serious! But, while celiac is dangerous, it isn’t one of those conditions that is immediately deadly or painful. And my friend still has a 3 in 4 chance of NOT getting celiac, and that is a lifetime risk.

On the other hand, my risk of venous thromboembolism (VTE) is 1.5 times normal. That doesn’t sound like much does it? It’s higher, but only a little bit. So we don’t really need to worry about it, do we? Well, yes. VTE can kill you on the spot, and it is incredibly painful. And normal is 1 in 10 people for lifetime risk. For me, the risk is closer to 1 in 7.

Given that, according to 23andMe, my genetic risk of celiac is roughly 1/20 and my risk of VTE is 1/7, and adding in the comparative dangers of the two diseases, my docs got all excited about the VTE, and not terribly about the celiac. I hope you understand why now, and also a bit more about why genetic risk is complicated.

On Asking for Help

Last part of the disclaimer.

For both of these, celiac and VTE, 23andMe looks at SOME of the genes and SNPs known to be associated with the condition, but not ALL of them. So whatever 23andMe tells me about risk is only part of the picture. It looks at the most important genes, but is still only part of the picture. That’s why you need experts to put all the pieces together, and get more information to fill in the gaps from the 23andMe test.

Everyone always says, “Ask your doctor,” when it comes to finding something puzzling, confusing, contradictory, or worrisome in your genetic tests. I did, and found that most of my doctors didn’t have the expertise to make more out of it than I did. Some poohpoohed the 23andMe results, others made clinical decisions based on them without verifying with other tests, some asked for more medical tests to expand upon what 23andMe had, and one said, “You know more about this than I do, but I’m going to learn.” Here is a quote from an NEJM article a few months ago about the risks and benefits of trusting direct-to-consumer personal genomic services such as 23andMe.

“Clinicians will be central to helping consumer–patients use genomic information to make health decisions. Any regulatory regime must recognize this reality by doing more than simply adding the tagline on most consumer ads for prescription drugs: “Ask your physician.” That is insufficient guidance unless your physician has ready access to a clinical geneticist or genetic counselor.” Annas GJ, Elias S. 23andMe and the FDA. N Engl J Med 2014; 370:985-988.

Some of the personal genomics service offer phone-in access to genetic counselors. I tried that, and didn’t get helpful answers there, either. Even worse, one of the answers I got was blatantly wrong. It may have been just the genetic counselor who I happened to be talking with, so don’t judge the whole profession by that one person, but do be prepared to keep looking for info if needed. Where I found the most helpful information was in the 23andMe forums, BUT a lot of the info there was unreliable, and I had to sort out what was helpful and what wasn’t.

So, my recommendation is, absolutely DO ask your doctor, ask a genetic counselor if you can, but that might not be enough. You might need to do more research on your own, or find someone you trust to help you with this.

What Good Is It?

So, what good is it then? It gives you clues. Like a detective, you take the clues and look for more information, or ask for more thorough testing, or raise questions that weren’t being asked or addressed before. Some of the clues will be red herrings. Some of them may lead you to a prized solution. For me, these clues ended up dramatically improving my quality of life, and may have even saved my life.

So, now, the short short version. And PLEASE, if someone more expert than me with genomic data reads this and spots any errors, please say so!


1. Get your 23andMe test done.

Pic of the Day - PGenPGEN, Take 2

2. Log in at the 23andMe web site when you are notified that your results are ready.


3. Click: Browse raw data.
23andMe: Getting to your raw data

It should look like this:

23andMe: Browse Raw Data

4. Click: Download raw data.
23andMe: Download Raw Data

5. Complete security procedure (log in again, answer security questions, etc.). It should look like this.

23andMe: Downloading Raw Data

6. Answer the question about what type of data and format you want. NOTE: I always choose ALL DNA, unless you have something else specifically in mind.

23andMe: Downloading ALL Your Raw Data Or ...

7. Find the file (which will be named something like genome_Firstname_Lastname_Full_12345678901234.txt)

PART TWO (A): Easier Way

Genetic Genie

Now you have choices. You can dig into the information the easier way, or the less easy way. Let’s start with the easier way.

1. Select a tool to do what you want with your data. There are LOTS of tools people have built to do useful things with 23andMe data files. One of my favorites is Genetic Genie, because it tells you about the MTHFR gene which has become so important in my life. I also am spending a lot of time with Promethease because it is so complete compared to most other 23andMe analysis tools. Lets start with these.

2. Go to the tool of your choice, such as:

Genetic Genie:


3. Follow the directions at the tool, but this almost always requires you to upload your 23andMe data file. Here are more details about doing this with Genetic Genie.

4. Last come what is always the tricky part — making sense of the information you get. That’s worth several posts, but for starters the main point to remember is that the 23andMe test is a place to start, not a final answer. In Genetic Genie, the code, analysis, and text are written by engaged amateurs, not by doctors or genetic counselors. They worked hard, collaborated with a lot of other people, and did a lot of research, but it isn’t going to say the same things your doctor might.

More Tools

23andMe: Tools for Everyone
NOTE: When 23andMe took out the health reports, they also edited this page to remove links to tools that provide health data from 23andMe data. So, this is interesting and useful, but not sufficient. You’ll have to look somewhere else for most tools.

23++ Chrome Extension: Get more from your data:

Confessions of a Cryokid: Top 10 things to do with your FTDNA raw data (2011)

Genetic Genealogist: What Else Can I Do With My DNA Results:

International Society of Genetic Genealogy: Autosomal DNA Tools:

Resqua: Q: What should I do after generating my Gene variance report?

Think Exponential: Get SNPd!

PART TWO (B): Less Easy Way

Linking Disease Associations with Regulatory Information in the Human Genome

Actually, there are a LOT of different “less easy ways.” You can open the raw data file in a text editor and search manually for specific pieces of information. Or, if you code, you can write a little program to do some of the hard work for you.

Basically, it comes down to doing a lot of research, the hard way, by hand. But, believe it or not, I am doing it. I’ve had a lot of help from people who offered tips or comments in the 23andMe or forums, on Facebook, on Twitter, and comments on these blogs. I am NOT an expert, but like most readers of this blog, just someone who wants or needs to know more. This is what I’ve learned and figured out on my own, offered as an example, nothing more.

Critical Background

23andMe gives SNP-based data. SNP stands for single nucleotide polymorphism. Polymorphism means something that can be itself but in different ways, our eyes are eyes whether they are blue or brown or hazel or violet or any other natural eye color. I won’t give an introduction to genetics here, but there are several online resources that explain these ideas, with one of the best resources being Genetic Home Reference from the US government. Depending on how much you want to know, you may wish to take the Coursera courses Introduction to Genetics and Evolution (Duke U) or Experimental Genome Science (U Penn).

1. What SNPs do you want to know about? Check here:

RegulomeDB (Stanford): Linking Disease Associations with Regulatory Information in the Human Genome:

I have also found SNPs of interest in research articles, PUBMED, and other places, but this is a good start. The SNP identifier (what you need) will look something like this:


2. Find out which polymorphism is the one considered “healthy” or “normal”, and which one is the one associated with risk of disease? These maybe called “risk alleles” or
simply polymorphisms.

For example, for SNP “rs2187668” (one of the celiac risk SNPs) the risk indicator is (T), while the normal is (C).

3. Open your 23andMe raw data file in a text editor, like WordPad (Windows) or TextEdit or TextWrangler (Macintosh).

4. Search for the SNP you want to know about. The data will be in four columns:
– Chromosome
– Position
– Genotype
You need to know about the first and last columns, RSID and Genotype. It will look a little like this.

… [many other rows of data] …

So, this person (me) has for that SNP one risk allele “T,” (which I happen to know is from my dad, by comparing it to his scan) and one normal allele “C,” (which must, by default, be from my mom, since for every gene pair we have gotten one from each parent).

5. Repeat for all the other SNPs associated with the condition you are researching.

6. Search for more information and articles about those SNPs, the condition, and more. You can’t make sense of this without more information. And ask lots of questions.

More Tools


ENSEMBL Genome Browser:



UCSC Genome Browser:

Trying Out SAM-e (Smart People Can Do Dumb Things)

Screen Shot of image search for SAM-e

Another girlfriend suggested SAM-e, and since it connects to methylation and we know I have mega-MTHFR challenges as well as other methylation problems like COMT, I figured I’d give it a try. Before you read too far, the end of the experiment for me is a big fat “NO, DON’T DO THIS.” But, of course, it isn’t that simple. I’m still not feeling well, so I’m trying to keep this simple. In part, this is an example of how to research something before you decide on a new course of treatment for yourself, and in part it is a cautionary tale.


What is SAM-e used for? The big ones are depression, osteoarthritis, fibromyalgia, and liver disease, but these are also mentioned.

back pain
chronic fatigue syndrome (CFS)
heart disease
lead poisoning
liver disease
multiple sclerosis
premenstrual dysphoric disorder (PMDD)
premenstrual syndrome (PMS)

Well, with a list like that, I figure a lot of folk think the same thing I did: “Gee, several of those apply to me or my family. Who knows? Maybe it might help. Let’s give it a try.” The first piece I looked at clustered these into categories of (1) bone and join problems, (2) nervous system problems, and (3) organ health. Two of those are themes in my life, so it was making sense that it might be part of the picture. And I really really wanted to feel better.


No, I’m not so foolish as to simply dive in and start taking something on a whim. Everything we ingest can have effects like a drug; everything has a minimum and maximum recommended dose; everything has interactions and side-effects, indications and contraindications. I looked it up, in major drug databases as well as Google Scholar, Pubmed, and some drug databases. I looked for the interactions and side-effects (there are LOTS). I looked at signs of an overdose. Turns out there are two kinds of overdose: (1) over-methylation, which makes you jittery, anxious, sleepless, etc.; and (2) serotonin syndrome, which can be fatal, and starts out with agitation, restlessness, confusion, tachycardia, high blood pressure, muscle twitches, sweating, diarrhea, headache, shivering, fever, goosebumps.

I felt pretty prepared at that point, but there were a few more things I wanted to know. The importance of SAM-e in the methylation process was obvious with even a superficial web search. Since I have MTHFR deficiency and that is also a big problem with the methylation cycle, I wanted to make sure the two don’t interact in nasty ways. So I searched for information about interactions between SAM-e and methylfolate, warnings, precautions, etc.

This was more interesting. First off, it turns out that methylfolate helps people make their OWN SAM-e! They are part of the same cycle, and SAM-e is one of the by-products from MTHFR processing. Regarding taking both, there was virtually no solid evidence floating up to the top, but an awful lot of opinion and personal experience. (Guess I’m adding to that body of unclear literature.) I saw a lot of people saying, “If you have MTHFR deficiency, do not ever take SAM-e!” This was balanced by an equal number of folk saying the opposite. The overall picture was unclear. There was a lot that said to take them together, almost nothing about if you have an MTHFR deficiency.

I found one woman who described it as helpful for brief periods, and she described her genetics as similar to mine — heterozygous MTHFR, homozygous COMT (H62H & V158M), and celiac. She described reacting with an over-methylation response after a couple weeks, and I had gone through that when I started taking methylfolate and felt I know what to do. Just to be careful, I started out with the smallest dose I could find – 200mg.


Part of what was motivating this was that general feeling of being unwell that I’ve had ever since I returned from my trip. I really want to feel better, but am feeling crummy. I thought about waiting to start SAM-e until I feel better, but based on what information I’d found I thought I knew what to expect. Either it wouldn’t do much, or I’d feel better.

I took a half dose on Monday. I felt basically the same as I’ve been feeling — generally crummy. Tuesday the same thing. I wasn’t sure if I’d been glutened or not. I took a couple days off, just to see. Then I thought maybe I hadn’t taken enough to notice a difference. [The problem with this was I had forgotten to look at how long it takes to feel an effect, and it varies depending on the problem.]

I was taking Friday as vacation, and thought I’d risk taking a larger dose, since I didn’t want to experiment if I was going to try to work. Instead of 200, I took 400. I continued to feel vaguely crummy, and then I started to feel as if I’d been glutened. I’d been eating “whole foods,” so I couldn’t imagine what it would have been, but I recognized the feeling. Fatigue. Brain fog. Wobbly. But not a hint of any digestive symptoms, no bloating, no hives. I was puzzled, but sleeping too much to figure it out. I had trouble sitting and standing, my joints hurt. I felt too weak to do much. Not normal symptoms included feeling hot, sweaty, feverish, flushed, confused, congested, chilling, spaced out, distractible. Then I got a headache, and my head feels strange in the back. So far, this has lasted three days. Each day has had a couple brief periods when I felt ok, before it would start up again, slightly milder than the day before.


I went back and looked again at SAM-e overdose. Nope, these symptoms don’t match up, except for the headache. My symptoms were more like those indicators that someone needs more SAM-e. Very puzzling. I kept digging into literature about SAM-e. I tried taking extra methylfolate, but didn’t notice a difference. I did notice that my clear-headed time was in late afternoon, and every day I take a B-complex vitamin with my lunch. Then I stumbled into some information that SAM-e can cause problems if someone is deficient in B-vitamins (like me). Basically, it creates a lot of homocysteine, which the body can’t clear out because it needs more B-vitamins to do so.

I put 3 and 3 together. Maybe this was a SAM-e overdose, but my body couldn’t properly process the SAM-e? I tried taking extra B-vitamins to see if this helps clear the fog and confusion and fatigue. I’m not trying to do it all at once. I took a B12 and my usual B-complex, then waited a few hours and took another B-complex. So far it seems to be working. I’ll add an addendum tomorrow.

SOURCES, Alternative Medicine: SAMe, What Should I Know About It?

Mayo Clinic: SAMe: Safety:

Mayo Clinic: Serotonin syndrome:

Natural Database: SAMe:

University of Maryland Medical Center:

WebMD: SAMe: Uses, Side Effects, Interactions, and Warnings.

UPDATE June 24, 2014:

Looks like I probably guessed right. The extra B-vitamins are helping, allowing me to get through the day. I couldn’t find anything about the length of time it takes to clear SAM-e from the body (personal reports range from on day to a couple weeks). I’ll probably have to take extra B-vitamins for a few more days.

Ingredients, Not ‘Food’

Checkerboard Egg CartonOnions

When I was in Chicago for my business trip, I was staying with my friend Rita. She was worried about how to feed me safely, since she isn’t gluten free herself, and since I am what many people have told me is “freakishly hypersensitive.” I told her what I’ve heard other people say, “Stick to whole foods.” But what is whole foods? What does that mean? It isn’t Whole Foods, the grocery chain, it means something different, although there is some overlap. You can say the other meme, “Shop the outside edge of the grocery store,” but that is lot riskier and more vague. I tried to explain, but I wasn’t doing such a good job. She figured it out, and when she did she said, “You know, this isn’t that hard!” No, it isn’t, but it is hard to explain.

Farmer's Market - Sept 6, 2008Making Preserved Lemons

After I came back from Chicago, there was a day I was riding back home from sword practice with my friend, Charles. He was telling me a story about when he was young and one of his friend’s came over to hang out and then got hungry. He told his friend to look in the fridge, and his friend complained loudly, “Where’s the food? You don’t have any FOOD in here, all you have is INGREDIENTS!” To which Charles replied, “Ah, but with ingredients, you can MAKE food.”

“AHA!,” I thought, “That is how to explain it!” The idea of “whole foods,” what is my primary foods, what I usually eat, is actually made up of things that many other people don’t even think of as food. That was a revelation and a hard idea to wrap my head around. Kind of like talking different languages.

Pic of the day - Not Cucumbers, Not SquashOkra

While in Chicago, I was fine as long as I was at Rita’s, but I got into trouble that last day of the trip, after I left Rita’s and was traveling home, eating so-called gluten-free food from restaurants. When I was so badly glutened in Chicago, for some odd reason, I just haven’t been able to shake it since I came back. I’ll feel better for a couple hours here or there, but then something else will set me back, and I’ll feel rotten again. It’ll be a month in two days, I’m very tired of this. I’ve been trying all kinds of things, some of which will turn into other blogposts, I hope.

The past few months I read both Grain Brain by Perlmutter and Gluten Freedom by Fasano. I’d hoped to do a quick review of each of them, but to avoid doing that here, let’s simply say I found Grain Brain frustrating and Gluten Freedom fabulous. One of the things mentioned by Dr. Fasano in his book was “The Fasano Diet” for people who are hypersensitive (like me) or seem to have gluten-induced symptoms no matter how careful they are (like me).

2013-07-06 at 10.12.45Farmer's Market - Sept 6, 2008

I was interested in trying it out, but I didn’t find the description in the book terribly helpful. I read a blogpost by someone who is a patient of Dr. Fasano’s and is on the diet to try to get some insight.

The Gluten Contamination Elimination Diet (Summary Of Dr. Fasano’s Recent Paper)

Frankly, this wasn’t much help either, but it did give a citation to the article for the Fasano Diet.

Justin R Hollon, Pamela A Cureton, Margaret L Martin, Elaine L Leonard Puppa, and Alessio Fasano. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterology 2013, 13:40

The guidelines for the diet are listed in Table 1.

Table 1: Products allowed/disallowed in the Gluten Contamination Elimination Diet (GCED), targeting the elimination of gluten cross-contamination

Allowed: Plain, unflavored, brown and white rice
Not Allowed: Millet, sorghum, buckwheat or other inherently gluten-free grains, seeds, or flours

Allowed: All fresh fruits/vegetables
Not allowed: Frozen, canned or dried

Allowed: Fresh meats, Fresh fish, Eggs, Dried beans, Unseasoned nuts in the shell
Not Allowed: Lunch meats, Ham, bacon; Other processed, self-basted or cured meat products

Allowed: Butter, yogurt (unflavored), milk (unflavored), aged cheeses
Not Allowed: Seasoned or flavored dairy products, Processed cheeses

Oils, vinegar, honey, salt
Flavored and malt vinegars

Allowed: 100% fruit/vegetable
Gluten-free supplemental formulas
Gatorade, milk, water

Hollon et al. BMC Gastroenterology 2013 13:40 doi:10.1186/1471-230X-13-40

I printed off the article, read it, highlighted, read it again. I still feel like the description just doesn’t answer my questions. They say in the article what criteria they use before putting a patient on the diet, what sort of problems patients had trying to stay on the diet, and that before starting the diet it is really important to consult with a dietician.

2013-07-06 at 10.53.492009 - Montebello's Rainy Day

Well. That’s nice. If I had a “real” celiac diagnosis, had had a biopsy, had a clue of the condition of my villi, then I might be able to get help with the symptoms, the ongoing challenges. I might be able to get someone to give me a referral. As it is, I’m on my own for a lot of this. So I’m trying to figure it out on my own.

Here are some examples of the types of questions I’m answering for myself. Please note, I DO NOT KNOW IF THE ANSWERS ARE RIGHT!

Q: No frozen meat?
A: Don’t buy it pre-frozen. You can buy fresh meat and freeze it yourself.

Q: No flavoured vinegars?
A: If you buy plain apple cider vinegar and fresh fruit or garlic, then flavor the vinegar yourself by soaking the flavoring fruit or garlic in the vinegar, since all of it is made from allowed ingredients, the result will also be allowed.

Here’s another example of my twisted flawed logic for trying to stumble through self-guidance for the Fasano Diet. Alright, rice is allowed. But rice makes me feel sick and quinoa makes me feel good. So, me, I’m using quinoa. Fresh chicken is allowed. Fresh onions. Fresh mushrooms. I can use salt. I can use butter. I can sauté the mushroom in butter with salt. I can grate “aged cheese” and use that (but should NOT use pre-grated cheese bought at the store). So then, I can make this, right? And this would count as “whole food” because all the ingredients were bought fresh and whole and then assembled into something by yours truly. And now I have food.

"Whole Food" sort of

On Getting Glutened

Field Training 2
Field Training 2; (US Army photo by Spc. Robert H. Baumgartner); 82nd Sustainment Brigade

People often ask me, “What is it like? What happens?” Some are sheepish or shy about asking, others are avid and openly curious, but either way they want to know. Sometimes they’ve heard it’s like having the flu, but don’t know that it can be different for different people.

Recently, I was traveling for the first time in a few years, and got badly glutened on the last day of the trip. it was the first travel day that I wasn’t able to make my own food, and had no choice but to buy “gluten free” food from restaurants. I will never know which food caused the trouble, but I do now remember quite vividly what my daily life was like before I went GF. I was trying to explain it to one of my best friends. The explanation went something like this.

“Imagine you’re a raw recruit in bootcamp. It’s the third day, and you’ve just realized this is going to be harder than you expected. Then the sergeant comes, and before you know you’re all suited up in 50 pounds of body armor, carrying two backpacks, and miles away from camp with no idea how long the hike will be. You’re dragging, trying to find a second wind, then crumpling; trying to find a third wind; a fourth …”

“I’m sorry,” said my girlfriend.

“No, wait,” I answered, “That’s just the beginning.”

“You realize you aren’t in bootcamp after all. You’re somewhere else, a forest or jungle or something. The weather is strange, hot, then cold. Or maybe you’re sick. You feel queasy, sweating and chilling at the same time. Somehow ants have crawled in under the armor, and they’re biting you, something fierce.

“And you’ve been drugged. You’re confused, not sure where you are, what you’re supposed to be doing, who you’re with. You just keep moving because if you don’t you feel like you’ll never move again. Your eyes keep closing, and half the time you are walking (stumbling, actually) with your eyes closed, catching a quick blurred glimpse, and falling closed again. But you are at least moving! Hey, that’s something to be proud of, right?

“And then you open your eyes. You’re in an office building, surrounded by people. You know you work with them, but you can’t remember their names. They are all looking at you, wary, like you just said something crazy or did something scary. You don’t remember. What did you say? What should you say? You shrug, grin lopsided, ask what’s next, as if it makes sense, and you pray that it does. But you still feel like you’re 200 pounds heavier and drugged.”

That’s what it feels like when I get glutened. How long did it last? This time was especially bad — around a week and a half. I managed to do what I needed to do for work, collapsed when I got home, made it through and made sense most of the time. And I am very, VERY grateful that this is no longer my everyday life. That it stops.

Alzheimer’s, Cognitive Impairment, & MTHFR Genetics

November Trip: Visiting Grandma:

It’s been over a year since I posted here. There are lots of reasons why. In that time, just to touch on the high points, my mother died and I suffered a major injury to my right arm which makes it hard for me to type and write and such. There has been so much happening in this space about which I really WANTED to write! The whole brouhaha with 23andMe and the FDA was a big one. There have been a number of interesting research articles that have come out. I did a presentation about my condition and meant to share the slides here. I may still, someday, write about these things.

For today, I want to talk about the research connecting genetic changes to the MTHFR gene to Alzheimer’s, Mild Cognitive Impairment (MCI), Vascular Cognitive Impairment (VCI), and related cognitive challenges. Because of my ongoing challenges with typing, I’m going to keep this simple, by selecting examples of the research and giving very brief snippets of the key findings. In other words, what’s most important.

The reason why I want to do this is because a friend of mine was recently diagnosed with one of these conditions, and so many doctors are not aware of this connection and don’t look for it. I’ve heard that from a number of places, but have a particular story that really rammed it home for me. As a medical librarian who works with systematic reviews, I’m on a number of medical and library email lists with various medical experts in different disciplines. On one of those lists, a clinician posted a question about this question. He is a recognized expert in his field and an expert in seeking and finding quality medical information. The family of one of his patients had approached him. Their mother has Alzheimer’s and they were wondering about giving her methylfolate supplements to help slow or arrest her memory loss. He wasn’t convinced, and was reluctant to support the family with this request. But he found enough evidence in support of the idea that he wanted to ask other professionals about the idea, and whether any of them had strong feelings about this. I sent him my search strategy and a few selected citations, and hoped for the best. I wondered, though, if someone as expert as he is was unaware of this, and reluctant to go along with a family’s request, what hope do others have with doctors who may very well not even ask the questions he was asking.

That was someone far away, in another country. I have no idea what happened. Now it is my friend, and I’m not close enough to talk with her clinicians. I’m hoping that someone will show this to her doctor, and if that doesn’t happen, maybe it will help someone else.

For the record, this is also a topic I follow because of personal concerns. When I was 12 I was briefly a significant part of my grandmother’s caregiving team. I was told at the time that she had Alzheimer’s, and it frankly terrified me. Years later, following brain damage from longterm carbon monoxide poisoning (another story for another day), I not only had amnesia but seemed to be developing mild cognitive impairment. It took me years to admit this to my doctor, and then brought it up at every appointment for the next few years. I won’t bore you with what didn’t work, but when I serendipitously discovered the MTHFR deficiency and began taking methylfolate, all my memory problems disappeared. Poof! Just like that. It was pretty amazing, and they haven’t come back. (Well, as long as I don’t get glutened.) Then, in the final part of her life my mother had cognitive decline. We don’t know her MTHFR status because we couldn’t get her genome tested, but we do know from testing other family members that she had at least one copy of the A1298c polymorphism. So, yes, I have a personal bias regarding this. That’s an excellent reason for me to stick to the evidence and what it says instead of trying to interpret it for you.



There are several MTHFR variations which are considered potential problems. The big ones are C677t and A1298c, with newer and less well understood, the MTHFR 03 P39P. The SNPs (snips) for these are:
* MTHFR C677t = rs1801133
* MTHFR A1298c = rs1801131
* MTHFR 03 P39P = rs2066470
Each of these is associated with different health impacts. A study that shows that one of them does something (or does not) says absolutely nothing about the other variants. There isn’t enough research yet to look at all of them together across the board. For many of the MTHFR variations, one common association is for increases in homocysteine (hyperhomocysteinemia), which in and of itself causes much damage in the body.

The Search

So, to start off, here is the Pubmed search strategy I’m using to try to get to just high quality research on this topic.

(mthfr OR methylfolate OR L-methylfolate OR Methylenetetrahydrofolate OR 5-mthf OR l-5-mthf) (“alzheimer disease”[MeSH Terms] OR “Mild Cognitive Impairment”[MeSH Terms] OR “dementia, vascular”[MeSH Terms] OR “dementia”[MeSH Terms] OR “Cognition Disorders”[MeSH Terms] OR “memory disorders”[MeSH Terms] OR “amnesia”[MeSH Terms])

Today, that results in 121 citations. Since this topic actually has fairly deep roots in the literature, going back to at least the early 1990s, I’ll be selective and focus on newer articles. To be even more selective, I am limiting this to systematic reviews and meta-analyses, the very top quality evidence available, and only the most recent of those available in English. Systematic reviews and meta-analyses distill the best evidence available into recommendations for clinical practice. In other words, they look through the whole puzzle and say, “This is what doctors need to know, and what they should consider doing.” After that, I may add just a couple very new research studies that would not have been included in the reviews.

For me, I will say that while some of these show a strong connection and others only a weak connection, there aren’t any that show no connection or the opposite. The gathering of these large aggregated studies together confirms a solid connection in some populations and is suggestive that may not have enough data to know yet about other populations. If it was me or my loved one, I’d wonder if it is worth at least doing a test and considering possible low levels of supplementation with methylfolate as a low-cost, low-risk intervention, and then seeing how the patient responds.


Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007 Jan;39(1):17-23.

In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles).

Laumet G, Chouraki V, Grenier-Boley B, Legry V, Heath S, Zelenika D, Fievet N, Hannequin D, Delepine M, Pasquier F, Hanon O, Brice A, Epelbaum J, Berr C, Dartigues JF, Tzourio C, Campion D, Lathrop M, Bertram L, Amouyel P, Lambert JC. Systematic analysis of candidate genes for Alzheimer’s disease in a French, genome-wide association study. J Alzheimers Dis. 2010;20(4):1181-8. doi: 10.3233/JAD-2010-100126.

We selected twenty genes from the “Top Results” list on the AlzGene database website and assessed their association with risk of developing Alzheimer’s disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses.

Liu H, Yang M, Li GM, Qiu Y, Zheng J, Du X, Wang JL, Liu RW. The MTHFR C677T polymorphism contributes to an increased risk for vascular dementia: a meta-analysis. J Neurol Sci. 2010 Jul 15;294(1-2):74-80. doi: 10.1016/j.jns.2010.04.001. Epub 2010 May 2.

RESULTS: A total of 11 studies, comprising 672 cases and 1038 controls, were included worldwide. Publication bias was not observed. This meta-analysis demonstrated that the MTHFR T allele or TT genotype had an increased risk for VaD in general populations (OR, 95%CI: 1.27, 1.01-1.59; 1.41, 1.06-1.88, respectively), and a significant association was found in allele contrast, recessive, and dominant model in Asian populations, but not in Caucasian populations.
CONCLUSION: The MTHFR C677T polymorphism (mainly TT genotype) is associated with developing VaD in general populations or Asian populations.

Zhang MY1, Miao L, Li YS, Hu GY. Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to Alzheimer’s disease. Neurosci Res. 2010 Oct;68(2):142-50. doi: 10.1016/j.neures.2010.06.011. Epub 2010 Jun 30.

No clear consensus has been reached at the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and Alzheimer’s disease (AD) risk. Thus in this meta-analysis, a total of 19 case-control studies was assessed to evaluate the possible association. The data demonstrated that the frequency of T677 allele (T vs. C) was significantly associated with susceptibility to AD in all subjects (OR=1.15, 95% CI=1.06-1.26) and in East Asians (OR=1.22, 95% CI=1.08-1.39). … A subgroup analysis in the subjects without APOE epsilon4 alleles showed T677 allele significantly increased risk of AD in all subjects (OR=1.21, 95% CI: 1.04-1.42) and in East Asians (OR=1.28, 95% CI: 1.06-1.55). However, no association was found in Caucasians. In conclusion, this meta-analysis supports that MTHFR C677T polymorphism is capable of causing AD susceptibility in East Asians, not in Caucasians.

Hua Y1, Zhao H, Kong Y, Ye M. Association between the MTHFR gene and Alzheimer’s disease: a meta-analysis. Int J Neurosci. 2011 Aug;121(8):462-71. doi: 10.3109/00207454.2011.578778. Epub 2011 Jun 10.

RESULTS: This meta-analysis demonstrated that the MTHFR T allele or dominant model for T allele (CT + TT) had an increased risk for AD in combined populations (OR, 95% CI: 1.13, 1.05-1.21; 1.18, 1.07-1.31, respectively), and a significant association was found in allele contrast, recessive, and dominant model in Asian populations, but not in Caucasian populations.
CONCLUSION: The MTHFR C677T polymorphism is associated with AD in Asian populations, but not in Caucasians.

Dwyer R, Skrobot OA, Dwyer J, Munafo M, Kehoe PG. Using Alzgene-like approaches to investigate susceptibility genes for vascular cognitive impairment. J Alzheimers Dis. 2013 Jan 1;34(1):145-54. doi: 10.3233/JAD-121069.

Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer’s disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. … Associations of increased risk for VCI were found for APOE ε4 (1.818 (95% CI = 1.611-2.053), p < 0.001; n = 3,554 cases, n = 12,277 controls) and MTHFR rs1801133 (1.323 (95% CI = 1.061-1.650) p = 0.013); n = 659 cases, n = 981 controls). There was marginal evidence of a protective effect for APOE ε2 (0.885 (95% CI = 0.783-0.999), p = 0.048; n = 3,320 cases, n = 10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI.

Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS, Steinthorsdottir V, Bjarnason H, Gudbjartsson DF, Magnusson OT, Sparsø T, Albrechtsen A, Kong A, Masson G, Tian G, Cao H, Nie C, Kristiansen K, Husemoen LL, Thuesen B, Li Y, Nielsen R, Linneberg A, Olafsson I, Eyjolfsson GI, Jørgensen T, Wang J, Hansen T, Thorsteinsdottir U, Stefánsson K, Pedersen O. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet. 2013 Jun;9(6):e1003530. doi: 10.1371/journal.pgen.1003530. Epub 2013 Jun 6.

Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer’s disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.


Mansouri L1, Fekih-Mrissa N, Klai S, Mansour M, Gritli N, Mrissa R. Association of methylenetetrahydrofolate reductase polymorphisms with susceptibility to Alzheimer’s disease. Clin Neurol Neurosurg. 2013 Sep;115(9):1693-6. doi: 10.1016/j.clineuro.2013.03.015. Epub 2013 May 6.

RESULT: Genetic analyses did not indicate a significant association between the MTHFR C677T mutation and AD (C/T: 63.15% versus 39%, p=0.087). However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3)). Our data suggest an association between the MTHFR A1298C mutation and AD; however, the MTHFR C677T mutation did not contribute to susceptibility for AD.
CONCLUSION: The MTHFR A1298C polymorphism is a possible risk factor for Alzheimer's disease.

Farkas M1, Keskitalo S, Smith DE, Bain N, Semmler A, Ineichen B, Smulders Y, Blom H, Kulic L, Linnebank M. Hyperhomocysteinemia in Alzheimer’s disease: the hen and the egg? J Alzheimers Dis. 2013;33(4):1097-104. doi: 10.3233/JAD-2012-121378.

Hyperhomocysteinemia is associated with Alzheimer’s disease (AD). The causality of this association is controversial. … In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF.

Jin P1, Hou S, Ding B, Li D, Liu L, Li H, Li L, Zhao G, Shao Z, Liu X. Association between MTHFR gene polymorphisms, smoking, and the incidence of vascular dementia. Asia Pac J Public Health. 2013 Jul;25(4 Suppl):57S-63S. doi: 10.1177/1010539513492819. Epub 2013 Jul 15.

This study investigated the relationship between N5,N10-methylene tetrahydrofolic acid reductase (MTHFR) polymorphisms, smoking, and vascular dementia (VD). … The T allele frequency was significantly higher in the VD group than in the control group (P < .05). Among patients who smoked, the relative risk of VD in patients with the TT genotype and T allele was higher than in the control group (P < .05). Therefore, the smoking group with the T allele has the highest risk of VD, and synergy appears to exist between the MTHFR gene polymorphisms and smoking in susceptibility to VD.