I recently had my first visit to a doctor since getting my results from 23andMe. I have only been in New Mexico for six months, and hadn’t yet selected a primary care physician from the list provided by my employer, the University of New Mexico. The health insurance plan has a website with all of the available primary care physicians. There are a lot of them. As a geneticist, I am familiar with the concept of a screen, used to identify interesting genetic variants in an experimental organism. Here was my screen: I needed an internist rather than someone specializing in family medicine or general practice. Although I knew that genetics, let alone genomics, is given very little coverage in medical school, I still wanted someone who had graduated relatively recently from a good medical school with a strong record of externally funded research.
While going through lists of physicians, I had in mind much of the reading that I have done in the area of personal genomics over the last several months, and some of the presentations from the GET 2012 conference in April. Several participants in the Personal Genome Project have brought in very detailed genetic information to their doctors, and recounted their experience. I think that it is fair to say that there is a consensus that most physicians are not prepared to deal well with patients with genomic data. They are not specifically trained to deal with data of this kind. There has also been a fairly high-level reaction from physicians against personal genomics. One of the warning shots came in 2008, when An Unwelcome Side Effect of Direct-to-Consumer Personal Genome Testing by Amy McGuire and Wylie Burke appeared in Journal of the American Medical Association (1).
McGuire and Burke remind us that physicians are accustomed to talking to patients about health information from the Internet and other media. My father, who was a physician, talked about the “Reader’s Digest” effect in medical practice. In the 1960s and 1970s, every month there was a cluster of patients asking to be checked for some specific malady, typically one that had just been covered by a popular article in Reader’s Digest. Of course, this was before the proliferation of cable TV channels and the limitless supply of medical advice, some of it terrible, to be found on the Internet. McGuire and Burke point out that physicians have limited time with patients and are poorly compensated for preventative care. I understand that and sympathize, but if we are ever going to make any progress on containing the costs of health care, patients and physicians are going to have to become partners in preventative care. If the system is not set up to facilitate that, we will have to change the system.
McGuire and Burke write “The clinical value, if any, of most direct-to-consumer personal genome tests remains unproven.” They take particular aim at the long list of risk estimates for specific diseases that is provided by direct-to-consumer genetic testing firms like 23andMe. Here is what the top of my “Elevated Disease Risk” page looks like at 23andMe:
I am only showing the results that place me at increased risk. There is a list of conditions for which I have a reduced risk, and a list for which I have an typical risk (shown later). When you look at my elevated risk list, you would have to conclude that I am a really lucky guy with a great genome. Clicking the links takes you to more detailed information. I discover that my top risk, for Venous Thromboembolism, results from my blood type (I’m AB+). Venous Thromboembolism has a heritability of 55%, which means that 45% of your risk is due to non-genetic factors. There is some advice on prevention. Don’t smoke (always good advice; I have never smoked). Keep your weight in check (good advice for many reasons). Get up and move, because sitting still for long periods of time places you at risk for Deep Vein Thrombosis (“economy class syndrome”). I wish I could get my employer to spring for First Class when I fly, but they won’t.
The other elevated risks are marginally elevated risks for rare conditions. I can see the point that McGuire and Burke are making here. There is no way that I am bringing this list in to a physician. There is nothing here that is medically actionable. I already know that the best general preventative health information that you can currently give to anyone would fit on an index card: Don’t Smoke, Maintain an Ideal Weight, Eat a Balanced Diet, Get Regular Exercise, Reduce Stress.
McGuire and Burke raise the problem of the burden on the health care system of increased testing due to requests by patients. Tests may produce ambiguous, incidental, or false-positive results. This might cause another round of more expensive, invasive, and dangerous tests in the pursuit of nothing. I understand this argument. It is therefore my responsibility as a patient (albeit an overeducated one) to avoid this downward cycle by asking only about genomic findings that are clinically relevant and medically actionable. I am in an excellent position to do that.
The current consensus is that the average person, at this time, will get one medically significant result from having their genome analyzed. Some people get zero (that’s actually good news), some people get two. I got one: increased risk of hemochromatosis. There is a wonderful discussion area on 23andMe where people write about their findings and report new information from the medical literature. I quickly found some highly informative discussion threads on hemochromatosis. I found many people with my genotype (HFE – H63D/C282Y). They described their experiences with their physicians, and gave advice on which blood tests to get done: serum ferritin, serum iron, total iron binding capacity, transferrin saturation. They told me to go see a doctor, and asked me to let them know how things turned out.
My screening of the physician list turned up some promising candidates. I decided to start with Dr. Patricia Morrow, who graduated from medical school in 1986 from the University of Texas at San Antonio. She was accepting new patients, but those appointments were on days that conflicted with my teaching schedule, so we had to set a date after classes were over, a month from when I first called. But that was fine with me, no emergency.
In the month leading up to my appointment, I had a look at my other results (Decreased Risk and Typical Risk) from 23andMe, shown in part below:
Wow, forget my elevated risk for Ulcerative Colitis at 1.1%. Look at my risk for Obesity (63.4%) or Type 2 Diabetes (18.7%). I click through on the Diabetes link and find out that Type 2 Diabetes has a heritability of only 26%. That’s actually good news; 74% of the risk is up to me. This is where it gets familiar. Maintain an Ideal Weight. Eat a Balanced Diet. What about my 50.2% risk of Coronary Heart Disease? This one is a little foggy, with the heritability estimated at 39-56%. What can I do to avoid this? Maintain an Ideal Weight. Eat a Balanced Diet. Don’t Smoke. Exercise Regularly.
So I decided to make my visit to the doctor as productive as possible. I printed out the summary page on Hemochromatosis. I had already modified my diet. I cut down my consumption of red meat, with its high availability of heme iron, to perhaps once or twice a week, a pretty big change for me. I knew the blood tests that I wanted, but because my last physical was in 2009, I decided that I needed the usual reports on triglycerides, HDL, and LDL. The high incidence of Type 2 Diabetes bothered me, so I decided to get a fasting glucose level as well.
Finally, the big day came. I skipped breakfast and lunch to be ready for a fasting glucose level test at 2:00 pm. Because my wife and I are down to one car since we moved to New Mexico, and it was a nice day, I walked the three miles to the doctor’s office.
Dr. Morrow’s office is in a wonderful old building not far from Old Town in Albuquerque. I checked in, filled out the insurance and medical history forms, and presented the summary page on hemochromatosis for my file. A nurse checked by blood pressure (118/80, not bad at all) and asked a few questions before Dr. Morrow came in.
She knew that I was a new patient and that I was there to get a primary care physician to allow me to navigate the health care system here if need be. She also knew that I had come to be evaluated for hemochromatosis. She opened my folder, took out the report from 23andMe, and asked, “What is this?”
“It’s a report from a personal genomics company. I had my genome analyzed, and I found that I’m at risk for hemochromatosis. I’d like to get some specific blood tests,” I said. “I’m from the future,” I continued, “In ten years, most of your patients will be coming in here with reports like this.”
Dr. Morrow took it really well, and we had a great conversation. At one point I told her that she should get CME credits for talking to me, but she knew which activities got her points and which didn’t. She got my medical history, which is unremarkable, and we talked about a few specifics. My family history is uncommonly free of major heritable illnesses. There is no family history of hemochromatosis. I have moderate ocular hypertension, monitored by my eye doctor but never progressing to the point at which it required medication (my mother and my brother have been treated for this). I have Seasonal Affective Disorder, managed by diet and light therapy in our parrot room. Managed is an inadequate word for this, of course. Mitigated would be better. Medical language attempts to be polite, which is why we call it Seasonal Affective Disorder, rather than Having Your Mind Dragged Off to Hell by Demons During the Winter.
“So,” she asked, “What are you going to die of, then?”
“Not boredom,” I immediately replied. We got back onto hemochromatosis. Dr. Morrow pointed out that I didn’t have any symptoms, and asked me what my chances were of developing them. I told her that most people with my genotype never develop any symptoms, but I was likely to have high levels of iron. She asked whether we knew what caused iron to deposit in tissues, and of course I said no. Studies in mice show that there are several genes, some of whose identity is unknown, that affect the level of serum iron in mice lacking a functional HFE gene (2, 3, 4). In humans, there is a wide range in iron levels in people with the same HFE genotype, and there is genetic variation in genes that may modify the development of hemochromatosis. In both humans and mice, it seems likely that there are unknown genes that affect the level of iron accumulation in tissues. I said that I thought that the medical literature at the present time was mostly written backwards: most of the studies are of people with symptoms of hemochromatosis, who are then genotyped. As far as I know, we don’t have any prospective studies that follow a group of people with a genotype like mine to see how many develop symptoms.
We got down to figuring out which blood tests to order. At this point, Dr. Morrow was ticking boxes off on a form: ferritin, serum iron, total iron binding capacity, transferrin saturation. Glucose and lipids. That should do it.
“I need a code,” she said.
All I could think of was the genetic code. Sixty-four triplets of A, T, C, or G. Good for encoding twenty amino acids with some degeneracy, plus start and stop signals. I decided not to say anything about the genetic code, as we had already had a fairly extensive conversation about genetics. So I just asked what sort of code she needed.
“A reason that we are ordering these tests,” she said. “I know. Fatigue.”
“Yes,” I said, “I’m very tired, and I hurt all over.” Actually, I was fine. The walk to her office had lifted my spirits.
She mentioned that one of the consequences of genome analysis might be unnecessary testing. I told her that I was confident that the testing was necessary, and that in the long run we were going to save the health care system a lot of money by engaging in preventative care. If my iron levels were dangerously high, I would be bled on a regular basis to get back to normal levels and prevent the progression of the disease.
We were still talking when the nurse came back in to remind her that she had a patient waiting. We had talked for over half an hour.
About a week later, my results were in. My serum ferritin was 351, at the high end of the normal range of 30 – 400 for males. I have corresponded with people who have my HFE genotype with ferritin levels of 1000; they were bled regularly until they reached 500. I knew right away that I did not have to start a program of leeching. My other iron-related numbers were a bit above normal, but not dangerously so: serum iron, 184 (normal 65-176); total iron-binding capacity 297 (normal 240-450); transferrin saturation 62% (normal 20-50%); hematocrit 51.4 (usually up to 45). Dr. Morris told me that we were not going to have to start a course of phlebotomy. If she was surprised that a genetic test had predicted my blood chemistry in the absence of a family history, she didn’t show it on the phone.
Everything else was fine, as it always has been. My fasting glucose was 94, so I am not pre-diabetic. My triglycerides were 68, HDL was 74, LDL was 121. The last is a bit high, but I haven’t been working out in a gym since I relocated. I am going to have to get back to that.
My experience with Dr. Morris was terrific. She was really interested in learning about how personal genomics was going to impact the practice of medicine. I think that she is glad to have a patient who is going to be an educated partner in preventative care.
So, it’s working out well for me, even though we need to change the system. There is no box to check to tell the insurance company that I need a test as part of a program of preventative care based on the results of having my genome analyzed. We are a long way from the system of personalized medicine that I have been hearing about in seminars for the last ten years.
As I was writing this, I went back into the literature to see if we know anything about genes that interact with HFE. Hemochromatosis is a disease that has incomplete penetrance, which is a fancy way of saying that not everyone who is HFE – H63D/C282Y like me develops symptoms. Do we know anything yet about genetic variation that modifies the risk of developing hemochromatosis given a particular genotype at HFE?
There are some promising studies in mice. The TMPRSS6 gene encodes a transmembrane serine protease that, in both humans and mice, has the opposite effect of the HFE gene on serum levels of hepcidin, a peptide hormone that inhibits dietary iron uptake. HFE–/HFE– mice resemble HFE – C282Y/C282Y humans in that they have high serum levels of iron and accumulate iron in the liver. When HFE–/HFE– mice are heterozygous for a loss-of-function mutation in TMPRSS6, they have reduced iron overload. HFE–/HFE– mice that are homozygous for a loss-of-function mutation in TMPRSS6 actually have an iron deficiency (5). This also suggests a therapy: “Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder.”
It is known that there is genetic variation in human populations for TMPRSS6 (6). People who are homozygous for a loss-of-function allele of TMPRSS6 have an inherited disease called Iron-Refractory Iron Deficient Anemia (IRIDA). In this condition, patients have anemia with no evidence of reduced dietary iron. They fail to respond to oral iron therapy. They respond somewhat to intramuscular iron injection (not a pleasant prospect). This condition is the opposite of hemochromatosis. People with IRIDA may have adequate levels of iron in their diet, but they don’t take it up, and their blood levels of iron are far below normal.
The studies in mice show us that these two genes with opposite effects interact. Let us simplify the situation by considering only normal (HFE+ and TMPRSS6+) and loss-of-function alleles (HFE– and TMPRSS6–). Here is a summary table to show the interaction.
|-/-||+/-||Hemochromatosis, but more normal|
|+/-||-/-||IRIDA (anemia), but more normal?|
So, is there any evidence that I am heterozygous for a protective allele of TMPRSS6? While my 23andMe results show my genotype with respect to SNPs in TMPRSS6, none of these SNPs is associated with loss-of-function alleles. The variant alleles of the HFE gene that I carry, HFE – H63D and HFE – C282Y, are identified in the 23andMe test by specific oligonucleotides that detect these variants, which are common in human populations. The discovery of variation in the TMPRSS6 gene is relatively recent (6), and the 23andMe test does not include results that will predict my genotype at TMPRSS6.
In February, I became part of a pilot program at 23andMe to have my exome sequenced. Most of the human genome does not encode proteins. The small portion of the human genome that does encode proteins is called the “exome.” The exome is only about 2% of the genome. In exome sequencing, genomic DNA is melted to single strands and hybridized to a vast array of oligonucleotides designed with knowledge of the sequence of the human genome. Strands of DNA from the genome being analyzed hybridize to the collection of oligonucleotides that selects for coding sequences, and are then sequenced. The rest of the genome is not. Exome sequencing is the poor man’s way of having the most highly informative parts of the genome sequenced while we wait for the cost of whole-genome sequencing to drop further.
I am still waiting for my exome sequence from 23andMe. They promised a four-month wait, which would give me my results in the middle of June, not long from now. I may very well be heterozygous for a loss-of-function allele of TMPRSS6, or have some other kind of genetic variation that protects me from hemochromatosis despite my HFE – H63D/C282Y genotype.
There is independent evidence to suggest that I carry a protective allele of TMPRSS6 or some other modifier gene. My mother has been borderline anemic all of her life. She tells me that she was given oral iron therapy as a child, and even intramuscular iron injections to treat her anemia. Her current physician has been campaigning to get her to add more red meat and other iron sources to her diet. This does not appear to be having any effect. It may be that my mother has IRIDA, modified by her genotype at HFE. Although she has not had her genome analyzed, she must be at least heterozygous for one of the two HFE alleles that I carry, HFE – H63D or HFE – C282Y, because I had to inherit one of my two alleles from her.
We’ll see when I get my exome results. I will post the findings when I get them.
1. Amy L. McGuire and Wylie Burke (2008). An Unwelcome Side Effect of Direct-to-Consumer Personal Genome Testing. Raiding the Medical Commons. JAMA. 300(22):2669-2671.
2. Joanne E. Levy, Lynne K. Montross and Nancy C. Andrews (2000). Genes that modify the hemochromatosis phenotype in mice. J Clin Invest. 105(9):1209–1216.
3. Mounia Bensaid, Séverine Fruchon, Christine Mazères, Seiamak Bahram, Marie-paule Roth, Hélène Coppin (2003). Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology 126: 1400-1408.
4. Gaël Nicolas, Nancy C. Andrews, Axel Kahn, and Sophie Vaulont (2004). Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice. Blood 103: 2841-2843.
5. Karin E. Finberg, Rebecca L. Whittlesey, and Nancy C. Andrews (2011). Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. Blood 117: 4590-4599.
6. Karin E Finberg, Matthew M Heeney, Dean R Campagna, Yeim Aydnok, Howard A Pearson, Kip R Hartman, Mary M Mayo, Stewart M Samuel, John J Strouse, Kyriacos Markianos, Nancy C Andrews & Mark D Fleming (2008). Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nature Genetics 40:569 – 571.