SNPwatch: The “Jist” on JAK2 and Myeloproliferative Neoplasms

Editor’s note: Pending an FDA decision, 23andMe no longer offers new customers access to health reports referred to in this post. Customers who purchased prior to November 22, 2013 will still be able to see their health reports, but those who purchased after that time will not. Those customers will have access to ancestry information as well as access to their uninterpreted raw data.

Myeloproliferative neoplasms (MPN) have a complicated name but it’s an apt descriptor for the biology underlying this group of rare blood disorders. MPNs result from excessive production of “myeloid” blood cells that originate in the bone marrow, and come in different forms including essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), chronic myeloid leukemia (CML), and systemic mastocytosis. Most forms of MPN are cancerous and all types are rare, with each affecting fewer than 100,000 Americans.

In 1951 a physician named William Dameshek proposed the idea of myeloproliferative disorders, but it wasn’t until 2005 — when four articles were published back-to-back on the V617F mutation in the JAK2 gene — that researchers began to uncover clues about the genetic basis of these diseases. Discovered in blood cells of people with MPN, the V617F mutation is defined as a somatic or acquired mutation, which means that it arises during the course of person’s life as opposed to being a change in DNA that someone is born with. (See sidebar for more about the JAK2 V617F mutation and its clinical use.)

JAK2 in the Clinic
The JAK2 protein is a tyrosine kinase and plays important roles in the cell by directing the activity and movement of other proteins. Although more research is needed to clearly define the role of the JAK2 V617F mutation in myeloproliferative disease, there is strong evidence that cells bearing this mutation are less prone to dying and are very good at making multiple copies of themselves, a hallmark of cancer. The World Health Organization (WHO) has recommended that the JAK2 V617F mutation be used as a diagnostic marker of disease and numerous companies are developing drugs to inhibit the activity of JAK2, though it is too early to tell if they will be successful.

 

This figure shows that people who inherit predisposing JAK2 variants have higher odds of acquiring the JAK2 V617F mutation, which is thought to push the cell to make multiple copies of itself. But it’s not the only factor leading to MPN. Although most people with the polycythemia vera (PV) form of MPN have the V617F mutation, many people with other types of MPN do not.

In addition to the V617F mutation, a number of studies, largely performed in people with European ancestry, have shown that inherited genetic factors may also increase risk for MPN. A cluster of SNPs in the JAK2 gene, called the 46/1 or GGCC JAK2 haplotype, has been associated with MPN and seems to be a strong predisposing factor for acquiring the V617F somatic mutation. People with a G at (equivalent to in the study) had nearly four times higher odds of developing V617F-positive MPN compared to people without the G version. 23andMe recently replicated this association, though we see a smaller effect — in our database, people with a G at have about two times the odds of developing V617F-positive MPN compared to people without the G version.

A more recent study carried out with a Japanese cohort suggests that the association between relatively common variants in the JAK2 gene and MPN also applies to individuals with Asian ancestry. Junko Ohyashiki and colleagues from Tokyo Medical University report that people with an A at in the JAK2 gene (equivalent to reported in the study and highly correlated with ) have about four times higher odds of developing V617F-positive MPN compared to individuals without the A version.

(23andMe customers can view their data for (applicable to people with European ancestry) and  (applicable to people with Asian ancestry) in their MPN Preliminary Research report.)

When they looked more closely, they found even stronger evidence for the association and a larger effect in patients with the polycythemia vera (PV) form of MPN, which is consistent with the fact that over 95% of people with PV have the V617F mutation while only about half of people with essential thrombocythemia (ET) or myelofibrosis (MF) have V617F. The SNP did not appear to be linked to V617F-negative MPN.

Although these findings are still preliminary since they were collected from relatively small studies (Ohyashiki’s findings came from just 95 people with MPN), they are still exciting progress in research on these rare disorders. That relatively common genetic variation might predispose individuals to acquire other mutations during their lifetime is an intriguing concept that will require more research to understand.

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason it is important to remember that like all information we provide, the studies we describe in SNPwatch are for research and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.






  • Jocelyn

    I have PV and participated in the 23andme study, and sure enough – I just looked and I do have “substantially increased odds of developing an MPN.” It’s really great to see progress in the research and hopefully finding a cure!

  • Jennett

    I have CML, and my genome shows:
    JAK2, LOC100129248 5089677 rs3780374 A or G GG

    JAK2 5066691 rs12340895 C or G CC

  • Mary Cotter

    Will there be an analysis of family members of Jak2 positive mpn people? My father submitted his DNA sample and I wonder what his results look like. Which side of my family did this snip ome from? I have thought of having my children submit samples. If they do will they be able to learn if they too have this snip?

    • http://23andme.com Shwu

      Hi Mary,

      The V617F mutation associated with many MPNs is actually an “acquired” mutation, meaning that it’s a spontaneous change that happens in a person’s cells rather than a genetic variant that you’re born with. Someone with this mutation cannot pass it down to their children since their sperm or egg cells do not have the mutation.

      The other SNPs mentioned in the studies, however, are associated with higher odds of acquiring the V617F mutation and these are inherited. You can compare different people’s results for these SNPs like you can with any other SNPs on our chip. If someone has, say, “AG” at a SNP and her mom is “AA” and her dad “GG”, then you know that she inherited the “A” from mom and the “G” from dad. Similarly, if her mom is “AG” and her dad “GG”, you again know that she inherited the “A” from mom and the “G” from dad. In some cases, though, it’s not definitive who passed down what — for this example, this would be the case if both parents are “AG”.

      Hope this helps!

  • http://www.6smarketing.com Robert Lendvai

    My mother has polycythemia vera rubra. She’s 83 and has lived with it for many years. It’s been managed primarily through a drug called hydroxyurea. Thank you 23andme for identifying the fact that I may also develop this disorder.

  • http://www.patientpower.info Andrew Schorr

    I have just been diagnosed with early primary MF, at age 61, after living with CLL with 16 years and doing well. I am happy to participate in any genetic studies if that will help.

    • http://23andme.com Shwu

      Hi Andrew,

      We are sorry to hear of your diagnoses. If you haven’t already, please go to http://www.23andme.com/mpn and enroll in our MPN research initiative. If you have any questions, contact us at mpn-help@23andme.com. Thank you for your interest in contributing to research!

  • Carolyn Reznikoff

    My results show positive for both GG and AA. Is this possible? It doesn’t sound like it from the knowledgable sounding post from Shwu. I do have the JAK2 variant and both ET and SM.

    • http://23andme.com Shwu

      Hi Carolyn,

      My previous reply was with regards to being able to tell which version of SNP someone might have inherited from which parent, apologies if it was unclear. It’s actually expected that if you’re GG at one of the SNPs that you’ll be AA at the other — these two SNPs are highly correlated but one association has been found in studies of people with European ancestry while the other association has been found in individuals with Asian ancestry. You should consider your results at the SNP applicable to your ancestry only.

      @Franco,
      As I wrote above to Carolyn, both of the SNPs we currently report on (rs12340895 and rs3780374) probably represent the same biological signal, however one of the SNPs has been shown to be associated with MPN in several studies in people with European ancestry while the other SNP is specific to people with Asian ancestry, so you should just look at whichever association is applicable to your ancestry. Keep in mind that MPN is still extremely rare, so having higher odds of developing JAK2-positive MPN is still a very low probability overall and there are likely other genetic factors that influence who develops this condition as well. Scientists are still learning more about this set of diseases and the different factors involved!

  • Franco Fiori

    I have both snps markers for myeloproliferative neoplasm that are linked to higher odds of devolping this illness. What should I do as prevention?

  • Bonnie

    I have 2 kids on here with cutaneous mastocytosis (never had the bone marrow biopsy to find out if it is systemic). One child showed high risk of Jak2 mutation, and the other showed normal risk. My question is: is jak2 indicative of systemic mastocytosis? In masto, they typically talk about the c-kit mutation, not jak2. Can we also check for likelihood of c-kit mutation? If so, can someone tell me which gene to look at in the raw data.

    Thanks,
    Bonnie

    • BHromatka

      Hello Bonnie,

      We are very sorry to hear about your children’s diagnoses and wish all of you the best. Although systemic mastocytosis is classified as a myeloproliferative neoplasm (MPN), individuals with this form of MPN do not usually have the JAK2 V617F “acquired” mutation in their blood cells. (A study published in 2009 showed that only 4% of people with systemic mastocytosis had the JAK2 V617F mutation: http://bloodjournal.hematologylibrary.org/content/113/23/5727.long).

      The results discussed in this blog post and in our MPN preliminary research report are for predisposing, inherited variations in DNA that seem to make people more susceptible to acquiring MPN and the JAK2 V617F mutation later in life. As you mentioned, systemic mastocytosis is often associated with KIT D816V, which just like JAK2 V617F, is a mutation that people “acquire” later in life as opposed to being one that they are born with. Since 23andMe only tests for inherited variations in DNA and not for “acquired” mutations, we do not test for KIT D816V. We are not aware of any inherited variants that predispose for acquiring the KIT D816V mutation. Hopefully scientists will learn more about the genetics underlying systemic mastocytosis in the near future! If you would like to learn more about our research efforts on MPN, please go to http://www.23andme.com/mpn. If you have any questions, contact us at mpn-help@23andme.com.

  • Tom

    The report Prevelance of Polycythemia Vera and Esstentional Thrombocythemia lists the occurances of the disease per 100,000 people as 22 and 24.

    What I would like to see is the total number of people listed on this site as rs12340895 GG or CG or AA and rs3780374 the same and broken down per GG,etc.. That way if there were only say a total of 100 rs12340895 and 22 get PV you could better see the rarity. Or say if there were 50,000 and only 22 get PV then even rarer.

    These are some of the things that computer data mining can solve very quickly. the power of a data base can be immense or nothing, depending on how it is used.

    The problem has been presented, I am graciously awaiting the solution. thanks.

    • BHromatka

      Hello Tom,
      You raise a very good point. Since all forms of MPN are very rare, it helps to know what percentage of people have the “riskier” version of the SNP. We know from data collected through the International HapMap Project (http://hapmap.ncbi.nlm.nih.gov/index.html.en) that nearly 50% of people with European ancestry have at least one G at rs12340895 and about 40% of people with Asian ancestry have at least one A at rs3780374. Beyond this, more research is needed to understand why only some people with the inherited variant go on to acquire the somatic mutation or develop MPN, but it’s a question we’re very interested in and have the potential to study given our unique database.

  • Tom

    Thanks for the response BHromatka. So when shall we get to studying this problem as the sooner we do the sooner an answer can be obtained. And possibly how to prevent the somatic mutation. thanks again.

  • http://yahoo Randall Ceaglske

    My son has been diagnosed previously with autism, PANDAS and underwent treatment for ALL — the course was complicated with frequent persistant infenctions, one of which was bartonell grahamii.

    His results show the trifecta GG AA GG when you include rs10974944
    This would make his MPN risk aprox 4096 normal.
    Each parent is heterozygous = 64 fold risk.

    My marrow results are pending.
    Any advice on where to turn?
    When you caculate 4 fold risk for each allele shouldn’t this pop up at the top of the browser?

    • BHromatka

      Hello Randall,

      We are very sorry to hear about your son’s diagnoses and hope that he is doing much better. We also wish you the best with your bone marrow tests.

      Being GG at rs12340895 increases one’s odds of developing JAK2 V617F-positive MPN, but being GG at rs10974944 doesn’t further increase one’s odds. This is because these SNPs don’t individually confer risk and thus the effects are not additive. If a parent is heterozygous at each SNP then he/she still only has ~ 4 fold increased odds of developing MPN. Just for some more background, the SNPs rs12340895, rs10974944, and rs3780374 are almost always inherited together — for instance if you are GG at rs12340895 then you will most likely also be GG at rs10974944 and AA at rs3780374, too. As mentioned earlier, you should only consider the results that are applicable to your ethnicity.

      There are a number of patient support groups for MPN including the MPN Research Foundation (http://www.mpnresearchfoundation.org/) and the Myeloproliferative Disorders Research Consortium (http://www.mpd-rc.org/home.php). You may also direct any questions to mpn-help@23andme.com.

  • MPN SNP

    I have both rs12340895 GG, rs3780374 AA, and rs10974944 GG. This is described as greatly/substantiallly increased risk for MNP. Wondering what the prevalence of these SNP variants in the normal population is, can only find for a single G or single A, respectively, which seems to be quite common (40-50%?).
    Also wondering what the total/combined increase in risk of MNP is in my case with three of the “worst” variants. Also, how common is this triple variant combined in the population? Should I worry?

    • BHromatka

      @ MPN SNP

      As noted in previous comments to this post, you should consider your results at the SNP applicable to your ancestry only. Nearly 50% of people with European ancestry have at least one G at rs12340895 and about 40% of people with Asian ancestry have at least one A at rs3780374. However, only about 5% of people will be GG at rs12340895 (for Europeans) or AA at rs3780374 (for Asians). Although being GG at rs12340895 increases one’s odds of developing JAK2 V617F-positive MPN, being GG at rs10974944 doesn’t further increase one’s odds. In this particular case these SNPs don’t individually confer risk and thus the effects are not additive. See responses to earlier comments for more explanation on these points. I hope this helps!

  • Kristen

    I have the AG Asian variant. I think 23andme is really on to something here. My daughter was diagnosed with acute myelogenous leukemia, subtype acute promyelocytic leukemia when she was two. I was diagnosed with erythromelalgia just a few years ago. I just read that Polycythemia Vera can cause erythromelalgia. To date, aside from positive Lyme tests which I was told were false positive by some doctors, no doctor has been able to give me a definitive diagnosis for the constellation of symptoms I have. I went ahead with Lyme treatment, despite the disapproval from some doctors. Surprisingly, my erythro improved greatly. I still have the erythro, but it is greatly diminished. It does make me wonder if the Lyme bacteria can be one of the causes of the mutation. There are studies that show that the Lyme bacteria does enter the organs of unborn babies so that could explain a mutation with my daughter having the leukemia. I’m just brainstorming. Perhaps the Lyme is a false positive and we have a genetic predisposition. Either way, I find it too coincidental that I have erythromelalgia and my daughter had APL, both of which are rare and both which can fall under this genetic variant.

  • Kristen

    Forgot to mention that I have the CG variant at rs12340895. Both of the variants I carry increase my odds. So while these variants may be found in 50% of persons of European ancestry and 40% of Asians, it is not common to have those variants and already have one AML in my family and erythromelalgia. I think those diagnoses together with the variants definitely paint a little different picture in my case as far as risk factors go.

    I also find it interesting that Randall’s son was found to have an infection, Bartonella, which can also be transmitted by ticks. Researchers are finding that ticks are now passing more than just one bacteria at a time. They are passing Lyme, Bartonella, Babesiosis, Rocky Mountain Spotted Fever, etc.

    Perhaps these bacteria are the triggers that turn these oncogenes on. I would love to see a study with mice with these genetic variants, who are then given these types of bacteria. It would be interesting to see if they would serve as a trigger and the mice end up with MPN. I wish I had all the money in the world so I could fund these studies.

    • BHromatka

      Hi Kristen,

      We are sorry to hear about your diagnoses and hope that you and your daughter are doing better. You raise a good point about combining family health history with genetic results. If you haven’t checked it out already, please visit 23andMe’s Family Health History feature: https://www.23andme.com/family/tree/.

  • Anne

    Hi All,

    I’m new to 23andme, and still making sense of all the info. When flagged for MPN, is there a way to tell from the data available to us, if a mutation has already occurred in V617-F? Or does the data only reflect a predisposition to developing mutation?

    Thanks for your help!
    Anne

    • BHromatka

      Hi Anne,

      Welcome to 23andMe! Our MPN report tells you if you have higher odds of developing MPN and acquiring the JAK2 V617F somatic mutation. It does not, however, tell you if your blood cells have already acquired the V617F mutation. The JAK2 V617F mutation is defined as a somatic or acquired mutation, which means that it arises during the course of a person’s life as opposed to being a change in DNA that someone is born with. I hope this helps!

  • Anne

    Hi BHromatka,

    Yes, that is exactly what I wanted to know. Thank you for your speedy response!

  • MPN SNP

    # BHromatka

    Thank you for your answer, and high quality of answers in general! You say that rs12340895 GG, rs3780374 AA, and rs10974944 GG combined does not pose an additive increase in risk for the JAK2 V617F somatic mutation. Do you have the publication where this information is taken from?

    • BHromatka

      Hello MPN SNP!

      In general, SNPs that are located close to one another (for instance in the same gene) often represent the same biological signal unless proven otherwise. In this case, it just so happened that one particular SNP in the JAK2 gene was the most statistically significant for Europeans and a different SNP in the JAK2 gene was the most statistically significant in Asians. This is more likely a reflection of differences in genetic linkage in the JAK2 region between the two populations rather than a reflection of two separate risk signals. Below are some of the primary papers for the association between SNPs in the JAK2 gene and developing MPN.

      http://www.nature.com/ng/journal/v41/n4/full/ng.341.html
      http://www.nature.com/ng/journal/v41/n4/full/ng.334.html
      http://www.biomedcentral.com/1471-2350/13/6

      I hope this helps and just to reiterate, you should only consider the results at the SNP applicable to your ancestry only!

  • Randall

    I recently went to a conference on Bartonella — interesting pathogen with a propensity to hide in CD34 (marrow progenitor) cells — the most common form of ALL is CD34+. Intra erythrocytic location can make this a difficult pathogen to treat. There is fantastic work being done at NCU by a Dr. Ed Breidtschwerdt. Galaxy labs offers PCR testing. My son was also diagnosed with autism — which seemed to improve with antibiotics — perhaps it was neuroretinitis? Ticks can transmit bartonella — though typically it can be aquired simply through an abrasion — not an uncommon thing for a child. The most recent publication links bartonella and rheumatoid arthritis — a similar situation to post deployment ailments (infectious arthritis) seen after WW1. Also it is a noteworthy pathogen due to it’s interaction with H1N1 (Spanish Flu).

    I suspect that the driving force behind some autoimmune ailments might just be chronic gram negative bacteremia. Broad PCR testing can help (ex spirostat), especially in the situation of chronic immunosuppression. We live in Burnett County WI — recently Mayo Clinic was through looking at Ehrlichia Muris in cancer patients.

    I’m less inclined to blame Lyme — as we learn more about pathogens that clearly have a track record of persistance. If Lyme is there — you get around to treating that too, too much controversy there — and no retractions of any of the old literature.

    Charles Kallick M.D. has a patent for treating aplastic anemia and leukemia with strictly antibiotics — also article in Medical Hypothesis that would support my ramblings here.
    I don’t suppose you’ll ever see an affordable approach to cancer — but treating concomitant bacteremia is a no brainer.

  • Michael

    Very interesting. I have substantially increased odds in both the AG and CG but I have another genetic blood disorder(Familial TTP). I wonder if there is any correlation here. I guess it definitely fits into that rare category.

  • Michael

    Both the ADAMTS13 gene(my disorder) and the JAK2 gene are on the same chromosome(9) but the JAK2 gene is on the short side pretty far away from the ADAMTS13 gene. I guess its more of a coincidence than a correlation. Very interesting research.

  • Gerald Kent

    I’m no expert, but it is clear to me that the overall probability of being stricken with PRV or some forms of ET, is your predisposition (that is, the risk factor GG, GC, CC) combined in some complicated way with the insults your body receives. As has been pointed out, these diseases are rare. Even though a substantial fraction of the population is at increased risk for a JAK2 mutation, not many folks end up with an MPN.

    That said, the insults that are highly suspect are petrochemicals, in particular, toluene and benzene and ionizing radiation. While the levels of these in the general population are small, some may be increasing. For example, some airline security equipment now uses ionizing radiation and extensive use is being made of modern medical diagnostic equipment such as CAT and PET scans. We are always told how low the dosages of these things are, but nobody is willing to make any guarantees.

    The oncologists talk about a “double hit” in relation to an MPN that “migrates” into something more sinister when insulted more than once.

    I take the “pat-down” at the airport when their equipment uses ionizing radiation and I limit my dental and medical exposures to only essential tests. I wear gloves when handling chemicals.

    There is a JAK2 inhibitor that has been or is about to be approved. I don’t like the side effect profile. I am much more disposed to considering waiting for a regime using Pegylated interferon-alpha, which has been shown to actually change the allele burden toward the normal.

  • Ingrid

    Since english is not my native language I have a bit a problem to understand this:
    I have GG Greatly increased odds of developing JAK2 V617F-positive MPN. And AA too.
    But I have already PV for more than 10 years.
    Does that mean I’m JAK2 V617F-positive
    or does it mean I’m still negative but it can mutate every moment?
    I’m a bit confused.

    • BethannH

      Hello Ingrid,
      I’m sorry to hear about your PV diagnosis. It’s important to only consider the results at the SNP applicable to your ancestry only. If you have European ancestry then pay attention to the results for rs12340895. If you have Asian ancestry then consider the results for rs3780374. The “risky” versions of these SNPs are associated with increased likelihood of developing the form of MPN that is JAK2 V617F positive. However, these results do not mean that the blood cells in your body definitely have the V617F mutation. We cannot tell you that information as 23andMe does not currently report on the V617F mutation. I hope this helps.

  • Gerald Kent

    Please see my earlier post in this thread.

    For those at high(er) risk of having the JAK2 acquired mutation without MPNs and for those with MPN who are concerned about what is called a “second hit,” which could lead to a more serious blood disease, the question is, “How do we protect ourselves to the extent possible?”

    For example, dentists and airport security folks tell you how small the dose is from certain equipment, but I suspect that there is some probability they could be less than safe. Likewise, handling petrochemicals without protection could also add risk.

    I am taking the pat down, stretching out the frequency of dental x-rays and wearing gloves instead of adding potential risk. It would be nice to know if these things are doing any good, but they certainly are not going to increase my chances of exacerbating the current status of my health.

  • ariane

    Hello,
    I am diagnose mutation jak2 for 4 years now and take 500mg ( 3 capsules per day) of Hydroxyurea. Did someone know what is the long terms effect to take this medication?
    Thank You!
    Ariane

  • Julie Moore

    Interestingly, I was diagnosed with JAK2 negative ET at the age of 31 and my mother was diagnosed 24 years later with JAK2 POSITIVE ET at the age of 85. My genetic work was assumed to be wrong and was repeated with the same results.

  • Maryellen

    I have been on intron a for 8 years for pv. Would the blood test for Jak2 likely be negative now from the intron treatment?

    • BethannH

      Hello Maryellen,
      I’m sorry to hear about your PV diagnosis. It is my understanding that levels of the JAK2 V617F mutation in blood do not typically go down with treatment, but I suggest that you ask your hematologist about this. He or she should be able to give you a more detailed answer.

  • Christine

    One of my sister’s had been diagnosed with ET 12 years ago and had been prescribed meds to stabilize her platelets. Sadly, she died this past September at the age 67. Two other members of my family has been diagnosed with MPN just this past year. I’m not sure if they have to same form (ET) or one of the other forms. One of the two have been battling Non-Hodgkin lymphoma for the past 10 years and is now 71. I see from my results on 23andme that I am in the “substantially increased odds” group of developing JAK2 V617F-positive MPN.

    There is a total of seven sibs in my family and we’re just lost one to MPN, two others diagnosed with it, I’m likely to develop it – what about the other three???? Are the odds that they will also develop this?

    • BethannH

      Dear Christine,
      I’m very sorry to hear about the loss of your sister and the diagnoses of your other family members. There is some evidence that MPNs can cluster in families, thus suggesting that some people may have a predisposition based on family history. We suggest speaking with a physician about your family history of MPNs.

  • steve

    I’m at increased odds of getting a JAK2 positive MPN, but I have a JAK2 negative MPN. I think you have it wrong here. The risk is the MPN, not the JAK mutation.

    • BethannH

      Hi steve,

      Thanks for your comment. Researchers have found a statistical association between inherited variants of the JAK2 gene and developing a JAK2 V617F-positive form of MPN. But, since this is just an association and not an absolute rule, there are predicted to be exceptions.

      • steve

        Yes, it is clear you found an association, but it is invalid. Since we can also get a non JAK2 positive MPN, then the real risk is of getting the MPN. Since JAK2 seems to be involved either way, there are is likely a similar mutation involved with those of us that are JAK negative.

  • Anne Thomas

    I’m a new participant in the 23andme community and would appreciate any guidance regarding the following results:

    Myeloproliferative Neoplasms:
    Marker rs12340895 = CG (substantially increased odds of developing JAK2 V617F-positive MPN
    Marker 3780374 = AG (substantially increased odds of developing JAK2 V617F-positive MPN

    My mother died of acute myeloblastic leukemia at age 50 and her mother was diagnosed with polycythemia but lived until 92.

    Does manifestation of the MPN in near relatives increase the odds of developing blood disorders beyond the odds/risks displayed for my individual sample? I would be happy to participate in any familial studies of MPN.

    Thank you

    • Anne Thomas

      One more question regarding my inquiry above: If there is a substantially higher risk of MPN, is it advisable to to have stem cells extracted prior to a diagnosis in preparation for a possible autologous transplant should the need arise?

      Thank you!

      • BethannH

        Hello again Anne,
        I suggest speaking with a physician who specializes in MPNs about diagnosing and treating these conditions.

    • BethannH

      Hello Anne,
      Welcome to 23andMe! You should consider your results at the SNP applicable to your ancestry only. The marker rs12340895 is applicable to people with European ancestry and rs3780374 is applicable to people with Asian ancestry. Because MPNs are very rare, most cases are sporadic, meaning they are not usually found in people with a family history of the disease. But there is some evidence that MPNs can cluster in families, thus suggesting that some people may have a predisposition based on family history. We suggest speaking with a physician about your family history of MPNs. We do not currently have any familial studies on MPNs.

      I hope this helps.

  • john woodard

    My Daughter was diagnosed with CML in 2006 at the age of 28, I was diagnosed with PV (Jak2-positive) July 2012, at the age of 60, I also was diagnosed with Hereditary Hemochromatosis in 1998, I have been told very rare for our situation and no connecting dots, so to speak, is there any test or study that can be done on us to find out if there are any connecting dots?

    • BethannH

      Hi John,
      I’m sorry to hear about your diagnoses. There is some evidence that MPNs can cluster in families, thus suggesting that some people may have a predisposition based on family history. We do not currently have any familial studies on MPNs. I am not aware of a genetic or biological connection between MPNs and hemochromatosis. One thing to note is that hemochromatosis is very common in the European population. In people with European ancestry, roughly one in 300 individuals has hereditary hemochromatosis. Rates are even higher in certain European populations including Irish, Norwegian and Australian.

  • Karen Rulli

    FDA recently approved a JAK inhibitor for myelofibrosis, it’s called Jakafi. Effective in both JAK V617F mutation positive and negative patients.

  • Laurie

    I am just now looking over my results and am a bit shocked at my “substantially increased risk”. Now trying to read up – I hate surprises ;) But here is my BIG question….my father passed away from multiple myeloma. Is this related? That condition is also a cancerous blood/bone marrow problem. And I do not trust the medical information he received or the prognosis he got as my research showed something completely different [and mine was accurate in hindsight].

    Is it possible that this is indeed an inherited possibility? I do fit the “European” model….

    • ScottH

      Laurie, I’m sorry about your father. While there is some evidence that MPNs run in families, multiple myeloma isn’t an MPN.

  • Suzette Frederick

    I just received my results this week and these markers show JAK2 V617F-positive myeloproliferative neoplasms but I have not had time to really research yet. However my maternal grandmother died at age 70 in 1968 with what they called myeloproliferative “disorder”. The information in my DNA study does not distress me, but it certainly is good information to have. I have had GCA (continual treatment without remission) for 4 years and have had a positive ANA (low readings with markers consistent with Lupus) since age 30 as well as Hypertension. Since I get blood tests monthly I would assume any abnormalities would show up, but I will let my doctors know about this result. At 67 I live a physically active life, exercising, biking, hiking, and enjoying my grandchildren. I would be happy to participate in any study.

  • Suzanne Hall

    I have both markers for substantially increased risk, since I am not sure how to read all of this yet I am not sure of what this means….do I need to see a genetic counselor? What resources do you recommend for educating oneself about this increased risk?
    SD

    • ScottH

      Suzanne, Remember that these are very rare cancers while it is not uncommon to have the mutation. It might be helpful for you to talk to your doctor or a hematologist about what having these mutations might mean for you. 23andMe collaborates with Informed Medical Decisions, Inc., to give you direct access to board-certified genetic counselors that are familiar with 23andMe’s reports. If you prefer to speak to someone in person, the National Society of Genetic Counselors can help you find a provider in your area.

    • BethannH

      Hi Suzanne,
      A few more helpful pieces of information. First, as noted in previous comments to this post, you should consider your results at the SNP/marker applicable to your ancestry only. This means you can only have one of the markers for substantially increased risk. Also, it’s important to know that these genetic variants are very common — nearly 50% of people with European ancestry have at least one G at rs12340895 and about 40% of people with Asian ancestry have at least one A at rs3780374. However, MPNs are extremely rare — fewer than one in 10,000 Americans is diagnosed with one each year. This means that very few people with the risky versions of rs12340895 or rs3780374 will actually go on to develop an MPN. Finally, MPNs are most often diagnosed in older people; the average age of onset is around 55 years. Sometimes it can be helpful to know if these blood disorders run in your family.

  • Lainey Melnick

    I am a little confused about the info. My husband is:

    • rs12340895: GG
    • rs4495487: AA

    He has a few symptoms, mainly just nose bleeds which he’s had his whole life. Does this mean that he definitely has one of the V617F-positive myelofibrosis disorders. I read that he has “Substantially increased odds of developing V617F-positive MPN”. What does that mean? Does that mean something like 2 in one million vs 1 in one million, or is this something that we need to get tested right away even without a lot of symptoms?

    Thanks,

    Lainey

    • BethannH

      Hi Lainey,

      These markers only tell you about risk for disease, they are not a diagnosis of disease.

      A few other important things. First, only consider your results at the SNP/marker applicable to your ancestry. (There is one marker for European ancestry and one for Asian ancestry). Thus you can only have one of the markers for substantially increased risk. Also, it’s important to know that these genetic variants are very common — nearly 50% of people with European ancestry have at least one G at rs12340895 and about 40% of people with Asian ancestry have at least one A at rs3780374. However, MPNs are extremely rare — fewer than one in 10,000 Americans is diagnosed with one each year. This means that very few people with the risky versions of rs12340895 or rs3780374 will actually go on to develop an MPN. Finally, MPNs are most often diagnosed in older people; the average age of onset is around 55 years.

      So the take home is that depending on which marker your husband has, his risk is about four to 16 times higher than average for developing a very, very rare condition. Most of our customers with this result do not seek further testing unless they are older and have symptoms or a family history of these conditions. I hope this helps.

  • Erika

    I was diagnosed with ET Jak2+ over a year ago. I was on Hydrea for 6 months and my platelets drop into the normal range. Due to no other symptoms my current doctor has me taking a baby aspirin once a day. Because of the diagnosis I was referred to 23andMe for a Mayo Clinic research project.

    • 23blog

      Erika, Thanks for the note and thanks for participating in research.

  • Deetles

    I am GG and AA. Mother died at age 60 from AML. Her sister died in late 80s with CML. Grand-father died from Penious Anemia. Does this mean that we all have the gene? Grandchildren?

  • dave mueller

    Has 23andme published any data on JAK2 negative MPN patients? I think about 50% of us with MF and ET are negative. I think you missed the boat with the JAK2 positive statements. I would like to see the percentages and associations with the genetic markers and the types of MPNs we develop. How about publishing your results in one of the medical journals? There are 3 major mutations now associated with MPNs. JAK2, MPL and CALR. The vast majority of MPN patients carry one or more of these. I think it’s somewhere over 90%. I think the data 23andme has gathered could be used to advance research into new treatments or even a cure, but I have my doubts that this information is in the right hands. I would like to see the raw data made available free to MPN researchers.

    • Scott23H

      Dave,
      We are working on a paper regarding that. Although we’ve presented some of our preliminary findings at conferences, the process of publishing findings takes a little longer. We hope to have something published on this in the near future. Thanks.

  • Scott23H

    These markers only tell you about risk for disease, they are not a diagnosis of disease.

    A few other important things. First, only consider your results at the SNP/marker applicable to your ancestry. (There is one marker for European ancestry and one for Asian ancestry). Thus you can only have one of the markers for substantially increased risk. Also, it’s important to know that these genetic variants are very common — nearly 50% of people with European ancestry have at least one G at rs12340895 and about 40% of people with Asian ancestry have at least one A at rs3780374. However, MPNs are extremely rare — fewer than one in 10,000 Americans is diagnosed with one each year. This means that very few people with the risky versions of rs12340895 or rs3780374 will actually go on to develop an MPN. Finally, MPNs are most often diagnosed in older people; the average age of onset is around 55 years.

    So the take home is that depending on which marker your husband has, his risk is about four to 16 times higher than average for developing a very, very rare condition. Most of our customers with this result do not seek further testing unless they are older and have symptoms or a family history of these conditions.

    • onehotmess

      He’s GG

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