What does it mean when I have genes that increase my “risk” of disease? Like Alzheimer’s?

The last few posts (here and here) have been about people who have carrier mutations.  These people have one recessive gene mutation that they could pass on to their child.  If the child inherits two recessive genes (one from each parent), they will get the disease.  That’s how it works with recessive diseases that are caused by one gene.  About 4,000 diseases are caused by mutations in one gene (either in dominant or recessive genes).  But that leaves all of the other diseases…

Since we’re still talking about genetics, let’s stick to diseases that are caused at least in
part by gene mutations as compared to diseases caused by infection, for example.  There are many diseases that are caused by mutations in multiple genes (the technical word for this is polygenic). In these cases, no one gene can be identified as the single cause of the disease.  The genes that are involved in causing the disease can be on many different chromosomes in many different locations on these chromosomes and only if mutated in combination will someone get the disease.  And these mutations may only cause the disease if exposed to a certain environmental factor (like cigarette smoke).

disease_polygenic

If this sounds confusing and complicated to you – it is.  Scientists find it confusing and complicated too. It’s much more difficult to pinpoint the exact genes that cause a  disease if there is more than one mutation in more than one gene.  It’s like a puzzle, but you don’t know the number of pieces in advance or what the puzzle looks like.  So if you fit two pieces together (or identify two genes that are mutated), you don’t know if you have completed the puzzle and figured out what is causing a disease or if you need to look deeper.

Scientifically, this is a complicated question, but for the patient who doesn’t care how many genes cause the disease, what does it mean to them? What does this mean for risk?  If a gene is found to be associated with a polygenic disease, mutations in this gene may increase or decrease your risk of that disease.  But unlike genes cause by dominant or recessive genes, no one can say for sure 100% either way if you have a particular gene mutation that you will or won’t get a disease.

A great example of this is Alzheimer’s disease.  Only in early onset Alzheimer’s (0.1% of all cases), one dominant genetic mutation the cause of the disease. However, in 99.9% of Alzheimer’s Disease cases, more than one gene is involved (at least three genes, but probably more).  One gene that is well studied in association with Alzheimer’s Disease risk is the gene apolipoprotein E (ApoE, for short).  There are three different versions of the ApoE gene called ApoE2, ApoE3, and ApoE4 – each representing a different mutation in the ApoE gene.  The E2 version (found with 8.4% frequency in the population) is protective against Alzheimer’s Disease.  The E3 version (found with 77.9% frequency in the population) is essentially neutral (neither causing or protecting from disease).  The E4 version (found with 13.7% frequency in the general population) is the one that causes the problems and and increase the risk from 20% in a person who has zero copies of E4 to 91% risk in a person with two ApoE4 copies.  The more copied of E4 the more likely a person is to get Alzheimer’s disease at a younger age as well. And if you’re wondering, this is ABSOLUTE risk, not relative.

alzheimersAlzheimer’s disease is a particularly tricky example to use because there are few, if any, preventative treatments for the disease.  So even if you know that you have two copies of ApoE4, there isn’t much that you can do.  However, there are other diseases, where certain genes increase risk for a disease (like I described for the BRCA mutations and breast cancer risk).  In this case there are potential preventative treatments, though even after those treatments, the decrease in risk is significant but cannot be eliminated.  Overall, it’s important to understand the complexity of disease and how many factors (including unknown factors) can contribute to disease risk and onset. For scientists, knowing the risk factors can help to detect disease early or develop targeted therapies to treat the disease. For doctors, it helps to predict disease risk and tailor treatment.  And for the patient, it helps to know that diseases are complicated and risk isn’t 0% or 100%.

 

What can you do if you’re a genetic carrier?

In my last post, I talked all about what is means when you are a genetic carrier of a recessive gene.  To recap, the recessive gene will not cause disease, but your partner also has that recessive gene, you may have a child with a disease. Let’s think about the options, using a capital letter (G) as the normal gene and a lower case letter (g) as the recessive mutated gene.

carrier-noncarrier youandpartnercarrierIf you are a carrier, you’re have one copy of G and one copy of g (or Gg).  What if you have a child with someone who isn’t a carrier (GG)?  If you look at the possibilities (to the left) you have a 50/50 chance of having a child who isn’t a carrier or one who is.  But you will not have a child who has the disease.  On the other hand, if both you and your partner are carriers (see the picture on the right), you have 25% chance of having a child who isn’t a carrier, 50% chance of having a child who’s a carrier, and 25% chance of having a child who has the disease.

If you’re a carrier and your partner is a carrier, you know your odds.  So what are your options?  Before I start, if you’re dealing with this personally, please discuss all of this with a trained medical professional.  I can explain the biology of why things happen, but only your doctor can give you medical advice and treatment options.  Also, these decisions are all personal to you.  There is no one answer, and what works for you may not work for someone else – and this is often what we face when making these very personal medical decisions.

CVSOptions:

  • If you know that you and your partner are both carriers for a particular disease, you can choose not to get pregnant and avoid the risk altogether
  • Alternatively, you can get pregnant and  monitor the pregnancy closely.  Go ahead and roll the dice!  There is a 25% chance of having a child with that disease and a 75% chance that they won’t.  Having the knowledge in advance, you will know the likelihood and can monitor the pregnancy accordingly
  • There are tests like chorionic villus sampling  (CVS) that can test for genetic diseases (such as Tay-Sachs disease) before birth, if both you and your partner are carriers for a recessive gene that causes disease
  • If the developing child is found to have a genetic disease, depending on the disease and severity (e.g., if they will or will not survive at birth), there is the option to terminate the pregnancy. There also may be options for treatments while the child is developing or immediately at birth that may help decrease the severity of the disease right away.
  • You can choose instead to use a sperm or egg donor from someone who doesn’t carry that recessive gene.
  • You can use in vitro fertilization and check the genes of the embryo pre-implantation to select those that do not have two copies of the recessive genes.
  • Choose to adopt

As an aside, I asked my primary care physician about carrier testing a few years ago.peopleDNA  Without a family history of any genetic diseases, she was resistant (if not downright hostile) about me wanting to get carrier testing, and mentioned that insurance likely wouldn’t pay for the testing.  I’m hoping that my experience was not the norm, however, I don’t think that most primary care physicians have a deep understanding of genetics and genetics diseases and may be uncomfortable suggesting this type of screening because they would not know how to best interpret the results.  Interestingly, a number of companies now exist that will perform the carrier testing for you for a nominal fee, such as Pathway Genomics, Counsyl, and Natera.  I cannot recommend or discourage you from using or not using these services, however you generally need to work with your doctor to order these tests.

Again, these are all options, not medical advice, and all up to you as to what works best for you and your partner.  But with the knowledge of what may happen and why it may happen, you are at least armed with information to ask meaningful questions about yours and your non-existent child’s potential genes before or during your pregnancy,

What is risk? Absolute versus Relative

riskMy mom and I were talking this afternoon – we talk every day on my drive home from work (I celebrated the day I got Bluetooth in my car) – about Angelina Jolie.  It was difficult to miss the news this past week about her New York Times opinion piece describing why she decided to remove her ovaries and Fallopian tubes.  There have been a number of interesting articles both praising (here or here or here) or criticizing or clarifying her choice.  That’s not what I want to talk about and it’s not what my mom and I talked about.  What we talked about was risk.  Most stories talking about Angelina Jolie mention that because of the gene mutation she had, there was an 87% risk of her developing breast cancer.  Despite the fact that 87% is awfully specific (and based on limited data from a certain number of women with this mutation that were studied over time), what I want to focus on isn’t the number, but what the number refers to.  In particular, I want to point out that there are different ways of talking about risk – and this is important when reading about any scientific information in the news.

coin_flipLet’s start with a quick definition – risk is the chance that something will happen.  These are usually percentages.  There is a 50% chance when you flip a coin that it will land on heads.  The risk is 50%.  Of course, when applied to the chance of developing a disease, or having a particular treatment outcome, or surviving an accident, the numbers are a lot more difficult to calculate than a coin flip.  But they are also more confusing when describing the risk as well.

 

rosk_tableI’m sure you’ve read news stories that say something like “Drinking more than 3 caffeinated drinks a day increases your risk of a heart attack by 50%” (this is a completely fictional example!!!) Fifty percent. What a HUGE risk.  Except what they don’t tell you is that without drinking caffeinated drinks, your risk of having a heart attach is only 1%.  So a 50% increase means your risk only increases to 2%.  This is the difference between relative versus absolute risk.  50% is the risk relative to what the actual baseline risk, whereas the absolute risk tells you the actual chance of something happening.

Let’s look at another example.  “This new drug decreases the risk of blindness in diabetic patients by 50% over 5 years”.  This is promising news!  Except, again, the 50% is relative risk – what you want to know is what the chance of a diabetic patient going blind?  If the chance that a diabetic patient goes blind is 60%, then a decrease of 50% is huge. There is only a 30% chance of blindness now.  Ont he other hand, if like the previous example, the actual chance of going blind is 2%, the 50% decrease is less impressive.  This makes the decrease in risk no less important to the patients who take the drug and don’t go blind – but it does affect how you read a news story describing the effect of the drug and whether or not you may want to take an expensive drug.

Now let’s get back to Angelina Jolie. The actual risk for breast cancer in the general population over a lifetime is ~12%.  If you have the mutations in the genes (called BRCA1/BRCA2) that Angelina Jolie has, it increases the risk to 40-80%. This is the absolute increase in the chance of getting breast cancer.  And as you may notice – the risk has a range (based on a number of factors – family history, health history, etc that we’ll get into in another post).

So how can you be a more savvy reader? You can be tipped off to relative risk by phrases like “increased by”, “decreased by”, “more than” or “less than”.  This only tells us the difference compared to baseline, but gives NO indication of what that baseline risk is. Absolute risk, on the other hand, provides the best estimate of what the overall likelihood of something happening will be.

risk_cartoon