Deep vein thrombosis (DVT), sometimes called “economy class syndrome” is the formation of a blood clot in a vein deep within the body, usually in the legs.  Not only can DVT be painful, but it can also lead to a potentially fatal condition called pulmonary embolism if the clot breaks free and travels through the circulatory system to the lungs.

In addition to environmental factors, there are genetic variations that can raise a person’s chances of having DVT.  But providing genetic testing to everyone is not feasible, leading researchers from the Leiden University Medical Center in the Netherlands to question whether a family history of DVT could also be of value as a risk indicator.

The researchers looked at records and family histories of 3,764 people – 1,605 who had had DVT and 2,159 who had not.  Their results, published online this week in the Archives of Internal Medicine, show that in people with no environmental or genetic risk factors, having a first-degree relative (parentor sibling) with DVT increased the odds of having a first episode of DVT by 2.5 times.  This was about the same as the increase in odds (2.3 times) caused by genetic risk factors in people with no family history or environmental risk factors.

(The researchers considered several genetic risk factors, including the factor V Leiden and prothrombin variations reported in the 23andMe Venous Thromboembolism Clinical Report. A table summarizing the results of the current study is included at the end of this post.)

Only 29.7% of people with family history of DVT carried a known genetic risk factor, but a family history was more common in DVT patients than controls with similar known genetic and environmental risk factors.  This suggests that there are unknown, probably genetic, factors at work.  The researchers say that unknown genetic factors probably have small effects that contribute to DVT only when other, larger risk factors are present, such as the factor V Leiden genetic variation or an environmental risk factor such as surgery, immobilization or oral contraceptive use.

Based on the fact that a positive family history increases the risk of DVT to about the same degree as known genetic risk factors, and the fact that most people with a family history of DVT don’t actually carry a known genetic risk factor, the researchers conclude that genetic testing for variations associated with DVT is of little additional value compared to collecting family history alone.

However, while a cost-effectiveness argument might be made, the authors’ own data shows that known genetic risk factors substantially increase the odds of DVT whether or not a person has a family history of the condition.  A family history of DVT or a known genetic risk factor alone increases the odds of DVT by about two and a half times, but the presence of both increases the odds by 6.3 times.  The presence of an environmental risk factor raises the odds of DVT about nine and half times.  Add in a positive family history and the odds go up to more than 16 times those of someone who lacks known risk factors (both genetic and environmental) as well as a family history of DVT.  But in those unlucky enough to have a family history of DVT, an environmental risk factor and a known genetic risk factor, the odds of DVT are increased a whopping 64 times.


Notes on the results table:

• Odds are given relative to someone with a negative family history and no known risk factors for DVT.
• A family history of DVT is the presence of the condition in any parent, brother or sister.
• Environmental risk factors considered were surgery, injury, immobilization and pregnancy or delivery within three months of the study, use of oral contraceptive or hormone therapy at the time of the study, and cancer diagnosis within five years before or within six months after the start of the study.
• Genetic risk factors considered were the factor V Leiden variation, the prothrombin 20210A variation, and low levels of antithrombin, protein C or protein S.

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Sometimes you can have too much of a good thing.

Stem cells in your bone marrow are responsible for producing red and white blood cells and platelets.  But in cases of myeloproliferative neoplasm (MPN) the stem cells go overboard and begin producing too many of one type of cell.  There are several types of MPN – polycythemia vera, essential thrombocythemia and primary myelofibrosis.  While all are treatable, these conditions put the approximately 140,000 people in the United States who are affected at higher risk for blood clots and leukemia.

In 2005 researchers discovered that a mutation in the JAK2 gene, called V617F, is responsible for almost all cases of polycythemia vera and about half of all cases of essential thrombocythemia and primary myelofibrosis.  People are not born with this mutation, but instead develop it in their bone marrow cells sometime later in life.  Now, three new research reports show that while the JAK2 V617F mutation itself is not passed down from parent to child, there is an inherited genetic predisposition for developing this mutation and, therefore, MPN.  These findings, published online yesterday in the journal Nature Genetics, have implications not just for this collection of blood disorders, but for the way scientists think about the genetics of diverse types of cancer.

Three separate research groups (their papers can be found here, here and here) found that, in people with European ancestry, the V617F mutation is more likely to occur in copies of the JAK2 gene that contain the C version of rs10815149.  One of the studies found that 80% of V617F mutations occur in the context of a C at this SNP.

Based on their findings, the researchers behind all three studies say that the odds of developing JAK2 V617F-positive MPN are increased in people with one or two Cs at rs10815149.  Although the exact increase varied between studies, it appears that there are at least three times greater odds of the disease in people with the riskier version of the SNP.

(Each study actually looked at several different SNPs in the JAK2 gene, but rs10815149 is a good proxy for all of them. 23andMe customers can check their data for rs10815149 using the Browse Raw Data feature.)

The authors of all three studies suggest that the C version of rs10815149 may somehow make the JAK2 gene more susceptible to mutation.  It is also possible that the V617F mutation is equally likely to occur in all versions of the JAK2 gene, but something about the C version of rs10815149 causes the mutation to actually cause MPN.

Regardless of how rs10815149 is affecting the JAK2 gene, the authors of all three reports conclude that their results have important implications not just for understanding MPN.  They all suggest that many of the genetic variations that have been found to be associated with increased cancer risk may in fact be acting by increasing the odds of later-in-life mutations.

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