37 replies to this topic

[ymc]

I am a self proclaimed personal genomics expert. Feel free to ask me all related questions.

Please don't ask me for credentials. You can judge my qualification based on the quality of my replies.

I am not promoting any commercial services. So please don't ask me to recommend any of them in this thread.

[niner]

I am a self proclaimed personal genomics expert. Feel free to ask me all related questions.
Please don't ask me for credentials. You can judge my qualification based on the quality of my replies.

Ok, I have a question: Which SNPs (rs numbers) should I look at to tell if I can use folate effectively, or if I need to take a methylated version?

[ymc]

I am a self proclaimed personal genomics expert. Feel free to ask me all related questions.
Please don't ask me for credentials. You can judge my qualification based on the quality of my replies.

Ok, I have a question: Which SNPs (rs numbers) should I look at to tell if I can use folate effectively, or if I need to take a methylated version?

http://en.wikipedia....evomefolic_acid

According to wikipedia, if your rs1801133 is TT or CT, then you should get the methylated version for better bioavailability.

[ymc]

http://www.ncbi.nlm....ph0158-2014.pdf

This small study suggests people to use methylated folic acid irrespective of their genotype. Of course, if you are TT, then the benefit is greater.

[e Volution]

Great initiative, thank you!

I have a couple questions. Like many others here on the forum I purchased the $99 special from 23andMe earlier this year.

1) My 23andMe data reports this:
Gene: MTHFR
Position: 11778965
SNP: rs1801133
Versions: A or G
My Genotype: AG

Am I correct that my rs1801133 is CT? If so, what does this mean I should do in laymen terms?

2) Are you familiar with the information 23andMe provides? If so, what other things are there that an average person such as myself can lookup that may directly impact lifestyle/diet/supplementation such as the rs1801133 example?

[ymc]

Great initiative, thank you!

I have a couple questions. Like many others here on the forum I purchased the $99 special from 23andMe earlier this year.

1) My 23andMe data reports this:
Gene: MTHFR
Position: 11778965
SNP: rs1801133
Versions: A or G
My Genotype: AG

Am I correct that my rs1801133 is CT? If so, what does this mean I should do in laymen terms?

2) Are you familiar with the information 23andMe provides? If so, what other things are there that an average person such as myself can lookup that may directly impact lifestyle/diet/supplementation such as the rs1801133 example?

23andme always report the genotype in the forward direction. But in dbSNP, if the SNP is inside a gene, the alleles will be reported as the same direction as the gene. In this case, MTHFR is in the reverse strand of chromosome 1, so it is either C or T.

Besides folate metabolism (and hence Neural Tube Defect in fetus), rs1801133 associates the most with Ischemic Stroke and methotrexate (a chemotherapy drug that is also used to treat Rheumatoid Arthritis) metabolism. If you are TT, you may want to do more to prevent stroke. You may also want to tell your doctor of your MTHFR status such that he/she can skip methotraxate when prescribing a cancer/autoimmune drug

[AgeVivo]

Hi ymc. Great initiative. What would be your top 3 (/5 /10 depending on your knowledge and time) genetic information for one's adult health? Are you aware of serious projects to use such information to lower mortality at a macro level?

I'll give my top one: sensitivity to blood thinners (warfarin in particular) is largely genetic and it seems any retired person should know their cooresponding genotype /informtheir medical doctor and relatives, such that in case of stroke a correct dose of blood thinners is used, to hopefully avoid entering long-term-care. The FDA recommends specific dose for different genetic profiles; to my knowledge there is not one place yet to report the result of the test (there should!)

[ymc]

Hi ymc. Great initiative. What would be your top 3 (/5 /10 depending on your knowledge and time) genetic information for one's adult health? Are you aware of serious projects to use such information to lower mortality at a macro level?

I'll give my top one: sensitivity to blood thinners (warfarin in particular) is largely genetic and it seems any retired person should know their cooresponding genotype /informtheir medical doctor and relatives, such that in case of stroke a correct dose of blood thinners is used, to hopefully avoid entering long-term-care. The FDA recommends specific dose for different genetic profiles; to my knowledge there is not one place yet to report the result of the test (there should!)

The single most important is obvious the APOE SNPs rs429358 and rs7412. They explained almost all the heritability of Alzheimer Disease. They are also the most important SNP to determine whether you can live to 100 (the distinct second being the FOXO3 SNPs).

A distinct second goes to SNPs in the 9p21 region, e.g. rs10757278. It is related to almost all cardiovascular diseases.

My third place will be the Type 2 Diabetes SNP rs7903146. It is the strongest T2D SNP to date. Given the rising prevalence of T2D, this is a very important SNP.

The medical community is very conservative. So far only very strong genetic signals go to the guidelines, e.g. abacavir, carbamazepine. The other obstacle is most physicians are not well trained in genetics and preventive medicine itself has no place in the medical establishment now. For now, it is better to take your genetic destiny in your own hands.

Of course, if you are constantly taking drug or about to do so, the pharmacogenetic SNPs will be very important for you.

[ymc]

Another important thing to know is your HLA-B27 status which is linked to ankylosing spondylitis. For Northwestern European ancestry people, this status can be approximated by the A allele of rs4349859.

[Brainbox]

No specific question at this time. But I'm still looking for a good introduction in genetics and interpretation of measurements (in my case 23andme).
The genetics 101 provided by 23andme is already to trivial for me. I'm not a medical professional nor student, but have some basic knowledge.

Do you have any links or books I might want to read?

Cheers!

[ymc]

No specific question at this time. But I'm still looking for a good introduction in genetics and interpretation of measurements (in my case 23andme).
The genetics 101 provided by 23andme is already to trivial for me. I'm not a medical professional nor student, but have some basic knowledge.

Do you have any links or books I might want to read?

Cheers!

For me, I read an earlier version of this book

http://www.amazon.co...12944617&sr=1-2

[Invariant]

Thanks ymc, great initiative!

The single most important is obvious the APOE SNPs rs429358 and rs7412. They explained almost all the heritability of Alzheimer Disease. They are also the most important SNP to determine whether you can live to 100 (the distinct second being the FOXO3 SNPs).

Could you elaborate on the role of the FOXO gene(s) in aging, and let us know what SNPs to check?

[ymc]

Thanks ymc, great initiative!


Could you elaborate on the role of the FOXO gene(s) in aging, and let us know what SNPs to check?

For people who are interested in the state-of-art regarding the pathways and genes of ageing, this is a very good review paper:

http://www.ncbi.nlm....pubmed/20336132

As to FOXO3 SNPs, if you are an East Asian, check rs2802292

http://snpedia.com/index.php/Rs2802292

If you are a European, check

http://snpedia.com/index.php/Rs2802288

[Danail Bulgaria]

Is there a way an usual person to receive a full transcript of all his/her chromosomes, something like ATGCTATG..... of all of his/her chromosomes, and how much it will cost?

[ymc]

Is there a way an usual person to receive a full transcript of all his/her chromosomes, something like ATGCTATG..... of all of his/her chromosomes, and how much it will cost?

The cheapest reputable vendor should be BGI from China (genomics.cn).
I don't know about the pricing. But the cost of reagent is about US$3,000/sample. They also need assemble the data into 46 chromosomes computationally. I suspect the price is around US$4,000-5,000.

[niner]

I'm not sure what I'd do with a full sequence. Unless you're skilled in bioinformatics, you would mostly be looking at interesting SNPs, and you can get that information more cheaply off of a gene chip. 23andMe's latest chip has about a million snps. If you got the complete sequence, then you wouldn't have to wait for the next chip to come out to learn about a hot new snp. But you would need appropriate software to access your data. This is probably available by now. Then there's the question of the error rate of all of these methods. We don't talk about that enough.

[treonsverdery]

I just read at http://www.health.ha...ancerous-tumors Harvard online that inhibition of cox2 enzymes prevents or reduces cancer risk 20 to 50 pct Are there haplotypes or SNPs of the cox2 gene that are detected with personal genomics like 23andme. If there is variation then a person could find out if using aspirin had anywhwere from a marvelous 90 pct cancer prevention effect to a "nope, I'm already immune to cancer"

cox2 (haplotypes or polymorphisms) www.http://pubmed.org

Edited by treonsverdery, 21 October 2011 - 06:26 PM.

[treonsverdery]

SNPedia has a number of items about cox2 genes as well as SNPs http://snpedia.com/index.php/Rs20417

23andme does describe Rs20417

Also a suggestion of the cancer resistant COX2 SNP variant is at http://snpedia.com/index.php/Rs4648261 where the

Pubmed describes particular COX2 genes that give greater resistance to cancer of a particular type thus it is possible the 23andme data could be used to prevent cancer with aspirin

http://www.ncbi.nlm....pubmed/21976545 Coghill, Ulrich
We investigated the association between CRC survival and genetic variation in pro-inflammatory pathways among patients from the Puget Sound SEER registry. Single nucleotide polymorphisms were genotyped in five genes (PTGS-1, PTGS-2, MRP4, NFkappaB, IkappaBKbeta). Vital status was ascertained through linkage to the National Death Index. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals. The false discovery rate method of Benjamini and Hochberg was applied to address multiple testing.
RESULTS:

Four PTGS-1 variants were associated with CRC survival. One, G>A intron 9 (rs1213266), was associated with ~50% lower CRC mortality (HRAA/AG vs. GG:0.48; 95% CI 0.25-0.93). Three variants, including L237M, resulted in significantly elevated CRC mortality risk, with hazard ratios ranging from approximately 1.5-2.0. Two variants in IkappaBKbeta, including R526Q, were significantly associated with CRC survival. Correction for multiple testing indicated that variants in both PTGS-1 and IkappaBKbeta are reproducibly associated with CRC survival.

Edited by treonsverdery, 21 October 2011 - 08:29 PM.

[ymc]

Interestingly, the abstract of the paper makes no mention of rs20417 and rs4648261 or any variants in PTGS2 gene

[ymc]

I'm not sure what I'd do with a full sequence. Unless you're skilled in bioinformatics, you would mostly be looking at interesting SNPs, and you can get that information more cheaply off of a gene chip. 23andMe's latest chip has about a million snps. If you got the complete sequence, then you wouldn't have to wait for the next chip to come out to learn about a hot new snp. But you would need appropriate software to access your data. This is probably available by now. Then there's the question of the error rate of all of these methods. We don't talk about that enough.

If you know bioinformatics, one of the biggest differences the whole sequence can give you is to let you get a definite diagnosis of genetic diseases. It is not possible for SNP chips to do this because they can only test a few common variants in a gene.

[mag1]

I have Alzheimer's disease.

On the weekend, I read a pharmacogenetic study of MCTs for the treatment of Alzheimer's.
The study found that APOE epsilon 4 negative Alzheimer patients benefit from MCTs. I am an APOE epsilon 4 negative
Alzheimer patient.

Further, it was found that APOE epsilon 4 negative Alzheimer patients with the TT genotype at rs1143627 in the
IL1B gene improved substantially while taking MCTs. Unfortunately, I have the CC genotype (this genotype did not improve
substantially while using MCTs.)

It was also found that APOE epsilon 4 negative Alzheimer patients with the CT or TT genotype at rs2251101 improved while
using MCTS. The CT genotype improved by a very substantial 8 points on the ADAS cog score (from baseline). I do not know
my rs2251101 genotype. My genome scan did not include this SNP. However, I have been doing my best to determine it.

My genome scan did provide me with my rs1887922 genotype (CT). The rs1887922 genotype appears to be related to the rs2251101 genotype.
All the genotyped people on HapMap (Phase2) with a C allele at rs1887922 had a C allele at rs 2251101. I am pretty sure that I must have at least one C allele at rs2251101.

In over 90% of the examples of the Hapmap genotypes with a T at rs1887922, there was a T allele at rs2251101. I am fairly sure that
my rs2251101 genotype is CT. It would be very helpful to me if someone could point me to a website where I could become more sure
of having this genotype. If I did have this genotype, it could improve my life considerably. (By 8 ADAS cog points to be exact!)

It would also be helpful to me if any software suggested did not need the Unix operating environment. I have found it a great struggle trying
to use Unix genetic programs on Windows.

[ymc]

I have Alzheimer's disease.

On the weekend, I read a pharmacogenetic study of MCTs for the treatment of Alzheimer's.
The study found that APOE epsilon 4 negative Alzheimer patients benefit from MCTs. I am an APOE epsilon 4 negative
Alzheimer patient.

Further, it was found that APOE epsilon 4 negative Alzheimer patients with the TT genotype at rs1143627 in the
IL1B gene improved substantially while taking MCTs. Unfortunately, I have the CC genotype (this genotype did not improve
substantially while using MCTs.)

It was also found that APOE epsilon 4 negative Alzheimer patients with the CT or TT genotype at rs2251101 improved while
using MCTS. The CT genotype improved by a very substantial 8 points on the ADAS cog score (from baseline). I do not know
my rs2251101 genotype. My genome scan did not include this SNP. However, I have been doing my best to determine it.

My genome scan did provide me with my rs1887922 genotype (CT). The rs1887922 genotype appears to be related to the rs2251101 genotype.
All the genotyped people on HapMap (Phase2) with a C allele at rs1887922 had a C allele at rs 2251101. I am pretty sure that I must have at least one C allele at rs2251101.

In over 90% of the examples of the Hapmap genotypes with a T at rs1887922, there was a T allele at rs2251101. I am fairly sure that
my rs2251101 genotype is CT. It would be very helpful to me if someone could point me to a website where I could become more sure
of having this genotype. If I did have this genotype, it could improve my life considerably. (By 8 ADAS cog points to be exact!)

It would also be helpful to me if any software suggested did not need the Unix operating environment. I have found it a great struggle trying
to use Unix genetic programs on Windows.

Interesting. I find a paper that might be the one you refer to
http://www.ncbi.nlm....7?dopt=Abstract

You are right that for Caucasians, a C in rs1887922 is linked to a C in rs2251101 but a T in rs1887922 is only linked to a T in rs2251101 for 90% of time.

I used the HaploView program to look for higher linkage SNP but it seems like rs1887922 is the best I could find. This is a free java program that can be run in Windows. You can try it and see if you can find better rs2251101 predictor.

If you can't find a perfect predictor, you can do a better job of prediction by using SNP imputation software. However, unless you are skilled in computer, it is not trivial to set up and run SNP imputation.

Anyway, in your case, consuming MCTs seem to be not a negative thing to do regardless of your genotype. I don't think you should sweat over your genotype too much. Good luck!

[ymc]

I looked into the MCT Alzheimer paper further and noticed that the first author is an employee of Accera, Inc which makes the MCT products used in the paper.

Then I examined the claims made in the paper by searching pubmed.

The paper is trying to show that Alzheimer patients of certain genetic profile might benefit from taking MCT. Unfortunately, the study is small and I couldn't find any replication of it. It is also a suspect of confllct of interest.

The research was carried out because of two claims:

1. Ketosis can help APOE-negative Alzheimer patients
2. Consumption of MCT can induce ketosis

2. is a well established claim and you can find plenty of support in pubmed. However, 1. is only supported by research conducted by the first author Samuel Henderson and his friends.

Therefore I have to say we shouldn't put too much faith into this line of research. However, if you just want to give it a try and don't want to put money into Henderson et al's pocket, then I would suggest trying MCT-rich coconut oil.

[mag1]

The results with MCTs in subgroups of Alzheimer's patients appears to be persuasive.

For medical fraud to be successful, claims of efficacy must be guarded and the testing
of these claims must be difficult. With the extraordinary claims made for MCTs and the
ease in which these claims could be verified, it is very unlikely such a misrepresentation
could be sustained. In the pharmacogenetic article for MCTs, a claim is made that a certain
subgroup of patients improved by almost 8 ADAS cog points over baseline within 90 days of
treatment. This is a very substantial claim. Current Alzheimer drugs might only provide
a point or two of benefit. If an Alzheimer patient were to have all three genotypes noted in
the article that confer benefit, such a patient would be expected to improve by over 13 points
versus baseline and have an almost 19 point advantage relative to placebo at day 90. I am
not aware of any Alzheimer medication that has made such an overwhelming claim of efficacy.

The claims made in the article could be readily tested in almost any memory clinic. It would only require
a few patients with very favourable (or unfavourable) genotypes to conclusively verify the efficacy of MCTs
in Alzheimer's disease. This is the age of pharmacogenetics.

It is also interesting to note that there isn't a substantial hidden financial motivation behind the MCT
research. It would cost me more to buy MCT on the internet than to buy the patented product.

There is a growing awareness of the importance of insulin pathways in Alzheimer's dementia. One
of the SNPs in the recent pharmacogenetic study was near the IDE gene. In certain haplotypes,
IDE rivals APOE in explaining ALzheimer disease risk. There are several other drugs in the neuronal
metabolism class that have also generated strong results in Alzheimer's dementia.

Edited by mag1, 07 April 2012 - 03:47 PM.

[mag1]

I appear to have APOE epsilon 4 negative, rs2251101 CC and rs1143627 CC genotypes. This means that I am in the bottom 1 to 2% of
responders to MCT oil treatment on the basis of the pharmacogenetic study.

I had to infer my rs2251101 genotype by comparing my genotypes at other locations near rs2251101 with those of published genotypes
on the internet. My CT genotype at rs1887922 gave me 17 to 1 odds in my favour of having a CT genotype at rs2251101. I was very
disappointed when I found that I likely had CC genotype at rs2251101. A CT at rs2251101 would have meant that my ADAS cog score
would have been expected to improve by almost 8 points.

I would be very interested in hearing suggestions of how I might override my genotype and obtain benefit from MCTs. The 2 genes involved
in MCT benefit are IDE and IL1B. IDE is insulin degrading enzyme. Increasing IDE helps lower insulin and increase ketone body metabolism
leading to cognitive improvement. What might I do to increase my IDE levels? What might I do to decrease my insulin levels?
IL1B is interleukin 1 beta which is involved in inflammation. Decreasing IL1B helps lower inflammation, decrease insulin levels, increase ketone body
metabolism which leads to cognitive improvement. What might I do to decrease my IL1B levels. If I could increase my IDE levels and decrease my
IL1B levels, in order to duplicate the levels achieved by the patients with the correct genotypes in the recent pharmacogenetic study, I could receive
overwhelming benefit from MCT oil.

I would be very grateful for any suggestions.

[ihatesnow]

http://www.newswise....nctional-genome

[albedo]

 

Hi ymc. Great initiative. What would be your top 3 (/5 /10 depending on your knowledge and time) genetic information for one's adult health? Are you aware of serious projects to use such information to lower mortality at a macro level?

I'll give my top one: sensitivity to blood thinners (warfarin in particular) is largely genetic and it seems any retired person should know their cooresponding genotype /informtheir medical doctor and relatives, such that in case of stroke a correct dose of blood thinners is used, to hopefully avoid entering long-term-care. The FDA recommends specific dose for different genetic profiles; to my knowledge there is not one place yet to report the result of the test (there should!)

The single most important is obvious the APOE SNPs rs429358 and rs7412. They explained almost all the heritability of Alzheimer Disease. They are also the most important SNP to determine whether you can live to 100 (the distinct second being the FOXO3 SNPs).

....

 

 

Just pop into this interesting old thread. A more recent meta analysis of FOXO3 and longevity relationship is here. "Analysis stratified by gender indicated significant associations between rs2802292, rs2764264 and rs13217795 and male longevity"

 

Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis.

http://www.ncbi.nlm....pubmed/24589462

 

[ymc]

Hi ymc. Great initiative. What would be your top 3 (/5 /10 depending on your knowledge and time) genetic information for one's adult health? Are you aware of serious projects to use such information to lower mortality at a macro level?

I'll give my top one: sensitivity to blood thinners (warfarin in particular) is largely genetic and it seems any retired person should know their cooresponding genotype /informtheir medical doctor and relatives, such that in case of stroke a correct dose of blood thinners is used, to hopefully avoid entering long-term-care. The FDA recommends specific dose for different genetic profiles; to my knowledge there is not one place yet to report the result of the test (there should!)

The single most important is obvious the APOE SNPs rs429358 and rs7412. They explained almost all the heritability of Alzheimer Disease. They are also the most important SNP to determine whether you can live to 100 (the distinct second being the FOXO3 SNPs).

....

Just pop into this interesting old thread. A more recent meta analysis of FOXO3 and longevity relationship is here. "Analysis stratified by gender indicated significant associations between rs2802292, rs2764264 and rs13217795 and male longevity"

Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis.
http://www.ncbi.nlm....pubmed/24589462

Good to see more research confirming the significance of FOXO3A gene.

Ultimately, to get the most out of againg genomics, functional analysis on the most common haplotypes (ie combo of mutations on one chromosome) of APOE and FOXO3A genes should be studied. But I suppose the funding is not there

Typically, functional analysis of drug metabolism genes are conducted. Possibly due to the drug companies and the resource and $$$ to do that.

[albedo]

 

 

 

....

The single most important is obvious the APOE SNPs rs429358 and rs7412. They explained almost all the heritability of Alzheimer Disease. They are also the most important SNP to determine whether you can live to 100 (the distinct second being the FOXO3 SNPs).

....

Just pop into this interesting old thread. A more recent meta analysis of FOXO3 and longevity relationship is here. "Analysis stratified by gender indicated significant associations between rs2802292, rs2764264 and rs13217795 and male longevity"

Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis.
http://www.ncbi.nlm....pubmed/24589462

Good to see more research confirming the significance of FOXO3A gene.

Ultimately, to get the most out of againg genomics, functional analysis on the most common haplotypes (ie combo of mutations on one chromosome) of APOE and FOXO3A genes should be studied. But I suppose the funding is not there

Typically, functional analysis of drug metabolism genes are conducted. Possibly due to the drug companies and the resource and $$$ to do that.

 

 

Yes, I guess so. The following very recent study (published Feb. 25, 2016) reconfirms strongly APOE (and FOXO3) across many ethnicities. They also reconfirm other human cohorts longevity pathways, in particular MAPK, immunity and calcium signaling.

 

Novel loci and pathways significantly associated with longevity

http://www.nature.co...icles/srep21243

[ymc]

....

The single most important is obvious the APOE SNPs rs429358 and rs7412. They explained almost all the heritability of Alzheimer Disease. They are also the most important SNP to determine whether you can live to 100 (the distinct second being the FOXO3 SNPs).

....

Just pop into this interesting old thread. A more recent meta analysis of FOXO3 and longevity relationship is here. "Analysis stratified by gender indicated significant associations between rs2802292, rs2764264 and rs13217795 and male longevity"

Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis.
http://www.ncbi.nlm....pubmed/24589462

Good to see more research confirming the significance of FOXO3A gene.

Ultimately, to get the most out of againg genomics, functional analysis on the most common haplotypes (ie combo of mutations on one chromosome) of APOE and FOXO3A genes should be studied. But I suppose the funding is not there

Typically, functional analysis of drug metabolism genes are conducted. Possibly due to the drug companies and the resource and $$$ to do that.

Yes, I guess so. The following very recent study (published Feb. 25, 2016) reconfirms strongly APOE (and FOXO3) across many ethnicities. They also reconfirm other human cohorts longevity pathways, in particular MAPK, immunity and calcium signaling.

Novel loci and pathways significantly associated with longevity
http://www.nature.co...icles/srep21243

Well, in the long run, when we sequence enough samples, it wouldn't be surprising to see that almost all genes related to age-related diseases will be found to be associated.

IMHO, the really interesting mutations are the ones that are rare but when they show up, they significantly increase the chance of longevity. An example is rs121911886 that improve oxygen carrying capacity by 50% that significantly boost the endurance of atheletes.