With November proclaimed to be Family History Awareness month, I thought I would write about a medical condition that runs in my family. But to what extent my relatives had this disease, or what it means for my risk, I’m not sure. If a doctor were to ask me if I have a family history of heart disease, my first response would be no. I’m not aware of any 1st, 2nd, or even 3rd degree relatives who have had heart attacks. But wait… My father did have that double bypass 12 years ago… It’s funny how I don’t think about it much. Maybe I should.
Dad didn’t seem to be the type that was at risk. A non-smoker, non-drinker, slender, and active, he started to feel chest pain at age 63 whenever he did something physical. The pain increased gradually over time, and Dad put off seeking medical attention until it became serious. A procedure in the cardiovascular catheter lab revealed a dangerous blockage the coronary arteries. He was immediately rushed into surgery.
It was determined that his blockage was caused by cholesterol (ding, that bell is ringing for me). His double bypass included a stent. What is interesting though is that he mostly remembers the psychotic reaction he had after the surgery (which happens to patients 10-20% of the time) because they used a heart/lung machine.
One More TimeNine years later he started having chest pain again, but thought it was indigestion. (What do former hospital CEOs know about medicine anyway). Sometime later he was in the hospital for a MRI that was looking for a neurological problem. In the middle of that procedure, his chest pain returned and was very severe. Knowing his history, the clinical people determined he was having a heart attack – in the hospital, thank God. His blockage had returned and a new stent was installed.
Any Other History?So I began asking my mother questions about any other family history of heart disease. Both of my grandfathers died (their hearts stopped) immediately following surgery that was not heart-related. They were 78 years old. Mom says her father may have had a heart arrhythmia. I know mom does. She had a procedure called a cardiac ablation, which seems to be a successful treatment. I haven’t experienced any arrhythmias yet, but wonder if any of this affects my risk. Besides my father, nothing is really clear about a family history of heart disease. And what should I discuss about this with my seven siblings?
23andMe Heart Disease Reports Fall Under a Different CategoryInformation on the 86 health and traits included in the 23andMe Research Reports section reside there because they do not establish a large enough increase in risk to be included in the Clinical Reports section. For a disease to be included in Clinical Reports, the riskiest combination of genotypes must increase a person's odds of developing the condition by a factor of three or greater and elevate absolute lifetime risk to at least 5%. The Research Reports section also includes studies that still need to be confirmed by the scientific community, and includes topics where there may be contradictory evidence. The results of these studies may not be conclusive.
Heart Attack in the Research Report SectionThe heritability of death from a heart attack is estimated to be 38% for women and 57% for men. The Odds Calculator tells me my risk is 2.4 out of 100 for my age, but that risk increases more than 5 times in the next 25 years.
Click image to enlargeIt’s In the SNPsNumerous SNPs associated with one's chances of a heart attack have been found in the chromosomal region 9p21.The reported SNP is not in a known gene, but it could affect a gene in a neighboring stretch of DNA. I think this is the first time I’ve heard that a possible pathogenic SNP is not part of a gene.
Click image to enlargeWhat About High Blood PressureLet’s look at four other heart-related 23andMe reports. Left untreated, severe hypertension can lead to heart failure, stroke, vision loss or kidney problems. Environmental risk factors such as age, weight, inactivity, diet and stress can contribute to hypertension, but genetics also contributes.
Click image to enlargeI learn from 23andMe that from several studies, with the total number of subjects of 5,500 individuals of European ancestry, each T at the SNP rs3754777 increased subjects' systolic blood pressure about 2 mm Hg and diastolic blood pressure about 1 mm Hg. This doesn’t seem to make that much of a difference. I have never been hypertensive, so I think I’m OK here.
If I Was Prescribed Beta BlockersBeta-blockers are given to people who have had a recent heart attack, or who have high blood pressure.
Click image to enlargeAfter development of the beta-blocker bucindolol was halted, the authors of one study found that people with the CC genotype who were given bucindolol had a 38% reduction in mortality compared to placebo. This might be an example of using pharmacogenomics to find if certain drugs can be effective for people of a particular genotype. I may need to remember this in the future.
Or Prescribed a StatinStatin drugs are prescribed to reduce cholesterol levels in people who have a high risk of cardiovascular disease.
Click image to enlargeMyopathy (experiences muscle pain and/or weakness) is a very rare side effect (one person in 10,000) of statins, even among those with genotypes that increase their odds of experiencing it. Having two C copies of the SNP increases a person's odds of myopathy by about 17 times, but the overall risk is still very small. If I’m ever prescribed a Statin, I won’t have to worry about this one-in-10,000 risk increasing. But My Problem Is Cholesterol From talking with the source of all family medical knowledge – Mom – I’m fairly convinced high cholesterol will be my problem.HDL, or high-density lipoprotein, is the “good” cholesterol that is considered protective against heart disease, and is another 23andMe ‘Research’ report.
Click image to enlargeMy HDL is good at 50 (normal range 40-63). But my total cholesterol has been between 267 and 295 (normal range 158-199). There is no report from 23andMe on LDL or bad cholesterol and my genotype. I would like to see this.
Doing My Own ‘Research’When I searched for a study on LDL levels and genetics, I found a paper titled “The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol”.
The study genotyped 2,037 adult individuals and measured their total cholesterol, high-density lipoprotein (HDL) cholesterol and glucose, blood pressure, body mass index and waist-hip ratio, for the lead SNPs in the seven CAD-associated loci. SNP rs599839, representing the locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1p13.3, showed a strong association with total cholesterol. The association of the A allele with higher total cholesterol was confirmed in an independent cohort of 847 healthy adults, and related to an effect on low-density lipoprotein (LDL) cholesterol.
Click image to enlargeWhen I entered SNP rs599839 into the Browse Raw Data feature of my 23andMe report, I found that I have the A allele. The study concluded that the findings support further investigation of the role of these genes in cholesterol metabolism and coronary risk. So at this point, I don’t have any analysis for my genetic risk for high total cholesterol.
He’s Still Throwing Utah Snow
Dad is still active at age 75. His favorite thing to do (besides reading my blog) is running his snow-blower multiple times a week during the winter. It's my favorite thing for him to do also. It means his ticker is still strong.
Maybe I should ask Dad to take the 23andMe test so we could compare our 9p21 SNPs and further validate my familial risk. But the longer he hangs in there is good for me - and good for me again.
Perspective from a medical geneticistTrue confessions of the heartAs I read Grant’s post, my first thought was that I should ask one of my cardiology colleagues to write the response. His approach to this issue is a clear indication of what a motivated consumer can do to generate information about risk as well as defining ways to impact this risk. The stark reality is that cardiovascular disease of all types is the leading killer of Americans—responsible for 1 out of every 2.8 deaths in 2005.
As opposed to many of the other conditions we’ve talked about, there are lots of preventive measures that can reduce one’s risk of coronary artery disease and hypertension including exercise, smoking cessation, weight loss, dietary changes and many classes of medication. I faithfully take a baby aspirin every night for this very reason.
Rather than provide a “geneticist’s perspective” on Grant’s post, I’ve decided to confess my risk and behaviors following Grant’s template as I see them from my perspective as a patient who hasn’t been genotyped.
Family HistoryThree of my four grandparents lived into their mid-90s. My paternal grandfather died before I was born of what I think was a hemorrhagic stroke. My recollection is my father told me he had severe hypertension and smoked—two major risk factors. Of the three that lived to a ripe old age, none had any interventions or procedures for coronary disease.
In fact, my maternal grandfather died suddenly one day at age 96 (I presume of a cardiac arrest) after literally never being sick a day in his life. His only medication was a daily baby aspirin (which he began taking after his grandson, the medical student, suggested it might be a good idea). My mother is alive and extraordinarily active at age 83. She has no heart issues or hypertension. My father died in his 60s of mesothelioma due to asbestos exposure when he was an engineer; chalk one up for environment over genetics. He never experienced any cardiac issues although he had elevated cholesterol.
Examination of the extended family identifies a paternal uncle who had bypass surgery in his late 60s and another with coronary artery disease in his 70s, although he died of a blood disease. Another paternal uncle had a stroke, but - like his father - smoked and had hypertension. My maternal aunt and uncle have had no cardiac issues in their 80s (and my uncle being a lifelong smoker). I find this information to be very reassuring—perhaps too much so.
Risk of Heart AttackWhile I’ve not been genotyped, according to my internist my risk for heart attack is average. This risk is based on risk assessments such as the Framingham study and the ATPIII guidelines. In my own mind, I consider myself to be at below average risk given my family history. The family history information collected by the clinical risk stratification tools noted above is rudimentary compared to my 3 generation pedigree!! I rest comfortably in my cloud of delusion and denial!
Grant mentions the 9p21 SNP that 23andMe genotypes. This is clearly the best characterized risk predicting SNP for cardiovascular disease, although there may be as many as 10 others that independently reclassify risk for coronary artery disease (according to deCODEme’s Chief Scientific Advisor Jeffrey Gulcher.) These are not currently part of the 23andMe risk stratification.
What is interesting and counterintuitive to me is that these genomic markers confer risk that seems to be completely independent of family history and clinical markers such as cholesterol. What is not known is whether modification of lifestyle or use of medications will attenuate the risk conferred by these genomic markers. So, no genotyping for me, at least for the present.
High Blood PressureI am proud to say that I am a hypertension carrier. That is to say my presence seems to induce hypertension in others while mine remains blissfully normal (with the exception of a systolic elevation immediately prior to my recent colonoscopy but that’s a story for another day). This is in spite of a zealous aversion to regular exercise and a penchant for salt consumption that drives Janet crazy (she has hypertension that is well controlled by medications despite much better health habits). So, no issues here (nor as best as I can determine for any of my 1st or 2nd degree relatives).
This does bring up an interesting point relative to 23andMe—if I have my blood pressure checked regularly, does my rs3754777 genotype status really matter? Would I do anything differently based on my genotype status? I think not. I would like to think that if my blood pressure was elevated it would lead to modifications in my life, at least to the extent of taking a medication.
CholesterolLest you think that my heart will never give out, I will confess that cholesterol is an issue for me (and for my father, daughter and my mother to a lesser degree). My total cholesterol is elevated (last value was 235) with a borderline HDL of 40 and an elevated LDL of 179. I do drink a glass of red wine every evening, but this does not appear to elevate my HDL significantly L. I think I’ll continue this anyway.
I actually took a statin medication for a couple of years with a spectacular impact on my numbers (total cholesterol of 141, HDL 37 and LDL of 88). I experienced no problems with the drug including no muscle symptoms and normal liver function studies. A couple of years ago I lost a significant amount of weight and my internist and I decided to see how this impacted my numbers. It had a beneficial effect with a total cholesterol of 206 and LDL of 152—not perfect, but probably adequate to stay off statins. Of course my weight has crept up since the low point leading to worsening of my numbers. So, should I try to lose weight again (almost certainly yes) or should I go back on a statin given my excellent clinical response and tolerance? (Again, probably yes).
The reality is that I should probably do both given the increasing evidence of benefit of statins for a number of circumstances. I am deleted for the medication aversion gene located on the Y chromosome, so compliance has never been an issue. I would not pursue genotyping given that I’ve tolerated the drugs in the past.
Given the importance of statins in the treatment armamentarium, I would argue that given the rarity of severe reactions to statins, genotyping could lead to harm if an individual chose not to take a statin based on an increased risk of a reaction given that most individuals with the ‘at risk’ genotype would still tolerate the medication just fine. My mother, in contrast, developed muscle aches with every statin she tried so despite her mild cholesterol abnormalities, she has elected not to take these drugs and I wholeheartedly agree. Besides, living to 83 without any heart problems is probably telling us more about her risk than any test, genetic or otherwise.
I did want to comment on a functionality of 23andMe that we’ve not explored before. Grant did extensive research about factors that influence cholesterol levels and identified information about genetic factors. He was able to enter these into the raw data browser and retrieve his genomic status. This clearly demonstrates how a sophisticated and highly motivated consumer can go beyond what is presented by the testing service. As to how it will alter Grant’s health behavior, well that’s up to him isn’t it?
My Health BehaviorWe all have our beliefs about health and wellness. I somewhat facetiously make two statements about exercise and eating well: 1) Regular exercise does lead to longer life, but you only extend life by how much time you have spent exercising. Stated another way, if you exercise you will live longer but you will have spent all your extra time exercising!! 2) I also believe that eating a healthy diet doesn’t help you live longer, however it will seem a lot longer. Verily my epitaph will read, “He died in search of the perfect bacon cheeseburger.” I also believe that mental well-being and stress reduction are strongly protective despite a dearth of evidence. Therefore, my music making, art business and golf take up the time that I could otherwise devote to exercise. However, I think that if I substituted exercise for these activities I would be substantially less happy.
So, I admit I’m not the best role model for healthy behaviors as we currently understand them. I would like to believe that if there was compelling information, genotypic or not, that I would use this to modify my health behaviors. Realistically, I think it may take a more significant event, i.e. a heart attack, for me to be more serious about these issues. Not the most intelligent approach given the high percentage of men that don’t survive their first MI.
There is another reality which is that no one gets out alive!! All of us will die of something (the Life Extension Institute’s beliefs to the contrary) so would dropping dead of a heart attack be so bad compared to a lingering chronic disease like cancer or my personal worst nightmare-dementia? Not in my mind, but then the choice isn’t all mine is it?
