<img loading="lazy" decoding="async" class="aligncenter wp-image-17528 size-full" title="Tetralogy_of_Fallot.svg" src="http://35.88.189.111/wp-content/uploads/2013/02/Tetralogy_of_Fallot.svg_-e1682537405785.png" alt="" width="477" height="323" srcset="https://blogcms.23andme.com/wp-content/uploads/2013/02/Tetralogy_of_Fallot.svg_-e1682537405785.png 477w, https://blogcms.23andme.com/wp-content/uploads/2013/02/Tetralogy_of_Fallot.svg_-e1682537405785-300x203.png 300w" sizes="auto, (max-width: 477px) 100vw, 477px" />Image by Mariana Ruiz LadyofHats [Public domain], via Wikimedia Commons
By Bethann Hromatka, Ph.D.
New research suggests that a once-fatal <a href="https://en.wikipedia.org/wiki/Congenital_disorder">congenital</a> heart defect – sometimes called “blue baby syndrome” – is influenced by genetic factors that are broadly found in the general population.
Different heart malformations lead to poor oxygenation of the blood and a bluish discoloration of the skin, but the most common culprit (affecting three in 10,000 births) is a condition called tetralogy of Fallot (fah-LO), or TOF. Before the first heart surgery was pioneered for this condition in the mid 1940s, about 80 percent of affected children died before the age of ten.
<h6>Genetic Factors and non-genetic factors</h6>
Like most heart malformations that arise in the womb, it’s not possible to point to a single causative factor for TOF. A number of non-genetic factors increase risk – alcoholism and diabetes in the mother as well as poor nutrition and certain infections during pregnancy.
But there are also <a href="http://circgenetics.ahajournals.org/content/3/2/122.long">hints</a> that TOF is more common in some families, raising the possibility that genetics also plays a role.
<h6>A new study on TOF</h6>
The new <a href="http://hmg.oxfordjournals.org/content/early/2013/01/08/hmg.dds552.long">study</a> led by Dr. Heather Cordell from the Institute of Genetic Medicine in Newcastle provides insight into the genetic underpinnings of TOF. Dr. Cordell and colleagues carried out the first genome-wide association study (GWAS) on this condition in around 1,600 people of European ancestry and found two genetic variants associated with TOF. Their findings were published in the journal Human Molecular Genetics.
The first variant is located in a region of chromosome 12 (12q24) that has previously been associated with numerous complex conditions including coronary artery disease and autoimmune disease. The second variant is located in a gene called GPC5 that encodes a protein called glypican 5.
<h6>Other previously identified variants</h6>
Previous <a href="https://www.sciencedirect.com/science/article/pii/S1769721208001365">studies</a> have linked deletions near this gene with heart malformations including TOF.  A few other markers were also suggestively linked to TOF and it’s possible that future, larger studies might solidify their involvement.
This is the first study to suggest that common genetic factors in developing fetus play a role in TOF. Roughly 30 percent of people have at least one risky version of the SNPs discussed here, but each variant only increases risk slightly. Combine these genetic factors with environmental cues and the scale might tip towards TOF.
February is American Heart Month.

Bethann Hromatka

Genetic Associations with “Blue Babies”

<img loading="lazy" decoding="async" class="alignright wp-image-17426 size-medium" title="heart health infographic" src="http://35.88.189.111/wp-content/uploads/2013/02/heart-health-infographic-300x263.jpg" alt="" width="300" height="263" srcset="https://blogcms.23andme.com/wp-content/uploads/2013/02/heart-health-infographic-300x263.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2013/02/heart-health-infographic-768x673.jpg 768w, https://blogcms.23andme.com/wp-content/uploads/2013/02/heart-health-infographic-880x771.jpg 880w, https://blogcms.23andme.com/wp-content/uploads/2013/02/heart-health-infographic.jpg 897w" sizes="auto, (max-width: 300px) 100vw, 300px" />
February is American Heart Month and a time to focus on what remains the nation’s number one killer – heart disease – which is responsible for one in three deaths in the United States every year.
Why heart disease is so deadly has a lot to do with lifestyle and diet in America. Obesity, even among the very young, is increasingly commonplace, and the <a href="http://www.heart.org/HEARTORG/GettingHealthy/PhysicalActivity/StartWalking/The-Price-of-Inactivity_UCM_307974_Article.jsp">majority of Americans</a> do not get enough exercise, according to the American Heart Association.
Fortunately, we can all reduce our risk of heart disease. We can exercise more, eat right and reduce stress in our lives. But it’s also important to understand, that like many health conditions, genetic factors contribute to heart disease risk.
Understanding how your genetics plays a role can help you craft the most effective plan for a healthy heart.
23andMe reports on several genetic factors that impact heart health, such as those associated with coronary heart disease and atrial fibrillation, as well as a rare heart condition called hypertrophic cardiomyopathy. We also have reports on how your genes affect your response to anti-clotting drugs to reduce the risk of heart attack.
The role genetics plays in these different conditions varies greatly. In some cases, such as in coronary heart disease, many of the genetic factors involved are not yet fully known.
While you can’t change your genetics, you can do a lot to change your risks for heart disease by changing your lifestyle. Cutting out smoking, lowering cholesterol, exercising more and eating right can go a long way towards keeping your heart healthy.

23andMe Blog

23andMe Blog Team

Genetics and a Healthy Heart

<img loading="lazy" decoding="async" class="aligncenter wp-image-2804 size-full" title="smoking" src="http://35.88.189.111/wp-content/uploads/2009/02/smoking.jpg" alt="" width="350" height="260" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/02/smoking.jpg 350w, https://blogcms.23andme.com/wp-content/uploads/2009/02/smoking-300x223.jpg 300w" sizes="auto, (max-width: 350px) 100vw, 350px" />
You probably know that smoking and excessive drinking are bad for you. But did you know that your genetics also factor into how much those vices can impact your health?
Healthy lifestyle choice – like avoiding cigarettes – make you less susceptible to a host to diseases. For instance, non-smokers live, on average, a decade longer than smokers. Genetics aside it just makes a lot of sense to avoid lighting up.
But genetics also plays a role. Your genes – regardless of your health habits – may put you at higher risk for certain diseases associated with smoking and drinking.  That can make the healthy choices you make that much more important.
Your genetic information, when taken together with information about your lifestyle and environment, will give you the most complete picture of your health risks.
But, in a few cases, your genetics can increase the risks of smoking and drinking by much more than either risk factor alone. Heightening the importance of making healthy choices. Here are a few examples.
A variant in a single gene, <a href="http://www.23andme.com/topics/health-predispositions/alpha-1-antitrypsin-deficiency/">alpha-1 antitrypsin</a>, leads to deficiency in a protein that protects fragile lung tissue. This can put one at more risk for emphysema and liver disease. Because smoking can further reduce the levels of the protective protein, it can further increase the risks for lung disease.
Another variant in the ALDH2 gene causes a deficiency in its enzyme product – aldehyde dehydrogenase. Those lacking this enzyme are at increased risk for esophageal cancer, especially for those who smoke or drink.
The magnitude of the combined effect varies from study to study, but the basic finding that these three risk factors synergistically increase the risk of esophageal cancer is definitive.
In the case of smoking, a variant in the CHRNA gene is strongly associated with how many times you light up in an average day. In people with European ancestry, each copy of an A at the single-nucleotide polymorphism (SNP) rs1051730 is associated with smoking one more cigarette per day on average. It’s unclear if the association also holds true for people of African or Asian ancestry.
As for drinking, a number of previous studies found an association between the SNP rs1800497 and alcoholism, with each copy of A at that location increasing a person’s odds of being alcoholic by 1.2 times.
Keep in mind that there are many of other conditions associated with smoking and drinking that are also impacted by your genetics. For instance, if you light up regularly, you’re putting yourself at a higher risk for such things as lung cancer, esophageal cancer, age-related macular degeneration, multiple sclerosis, psoriasis, rheumatoid arthritis, venous thrombosis and coronary heart disease.
Heavy drinking increases your risk for esophageal cancer, colorectal cancer, and atrial fibrillation 
esophageal cancer, colorectal cancer and atrial fibrillation.

Barfly Genetics

<img loading="lazy" decoding="async" class="alignright wp-image-4013 size-full" title="geneticresearch7" src="http://35.88.189.111/wp-content/uploads/2009/07/geneticresearch7.jpg" alt="" width="350" height="268" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/07/geneticresearch7.jpg 350w, https://blogcms.23andme.com/wp-content/uploads/2009/07/geneticresearch7-300x230.jpg 300w" sizes="auto, (max-width: 350px) 100vw, 350px" />
Team 23andMe will again have a strong presence at the annual meeting of the American Society of Human Genetics.
We’ve been at this gathering of geneticists and those interested in human genetics ever since 23andMe launched, but this year with the 62nd annual meeting being held in San Francisco – sort of our backyard – we’ll be there en masse.
Each year the annual meeting attracts the best and brightest in human genetics with thought-provoking displays of research results and stimulating discussions. This year is no different and more than 6,000 people are expected to attend over the four days starting on November 6th.
Along with the 24 scientific sessions – including panel discussions featuring our Senior Director of Research Dr. Joanna Mountain, who will discuss research partnerships between academics and private companies, and Science Content Manager Dr. Shirley Wu, who will speak on the use of social media in research  – there are also 400 presentations drawn from abstracts submitted by scientists from around the world.
This year 23andMe submitted almost two dozen abstracts on a wide range of topics including our groundbreaking and first-ever genome-wide association study on sexual orientation, as well as preliminary findings from our<a href="../announcements/exomes-the-first-of-many/"> Exome Pilot</a>, which is the first exome sequencing offered directly to consumers. (We will link to these abstracts when they’re available on the ASHG website.)
Also reported in one of the abstracts are some of our findings from a full-genome sequencing project on 50 people with the LRRK2 G2019S mutation associated with Parkinson’s disease. We’ll also have details of a study that looks at an association with hypertrophic cardiomyopathy, the leading cause of sudden cardiac death in young athletes.
Being 23andMe we also have some less serious – but no less interesting – abstracts looking at such things as genetic associations with motion sickness, over 250 genetic associations with common traits such as baldness and unibrow, whether DNA can explain why some women get stretchmarks and others don’t, as well as why some people love cilantro and others think it tastes like soap.
We’re pretty excited by the upcoming conference.
We are particularly proud of our colleague, Dr. Uta Francke, who will deliver a presentation as recipient of the 2012 ASHG William Allan Award. As always the gathering will not just be a chance for us to present some of the interesting results from our research, but also to learn from others. There’s some fun stuff too, including a symposium on “Human Genetics in Contemporary Poetry, Fiction, and Art: How Humanists View our World,” and meeting will close with a forward looking symposium on the future of human genetics.
The preliminary 2012 Meeting schedule is now available. While we can’t wait for the meeting, we’re even more excited about sharing some of the interesting findings and breakthroughs we’ve made with the help of our customers. In the coming weeks we’ll collect information on all the 23andMe presentations onto a single web page so you can find them easily.
Stay tuned for more information about 23andMe’s presence at ASHG.
We’ll have a booth in the Exhibit Hall, and knowing our scientists, they’ll manage to squeeze a party in there too.

Highlighting 23andMe Research at ASHG 2012

<img loading="lazy" decoding="async" class="aligncenter wp-image-13489 size-full" src="http://35.88.189.111/wp-content/uploads/2012/06/FatherBikeKid.jpg" alt="" width="416" height="288" srcset="https://blogcms.23andme.com/wp-content/uploads/2012/06/FatherBikeKid.jpg 416w, https://blogcms.23andme.com/wp-content/uploads/2012/06/FatherBikeKid-300x208.jpg 300w" sizes="auto, (max-width: 416px) 100vw, 416px" />
You claim that Junior is giving you gray hairs, but is he really? In actuality your kids may be adding years to your life &#8212; one recent <a href="https://www.ncbi.nlm.nih.gov/pubmed/21946940">study</a> suggests that fatherhood may actually reduce a man’s risk of dying from a heart attack.
The study, which was conducted last year and led by Michael Eisenberg at Stanford and Mark Pletcher at the University of California, San Francisco, addresses the relationship between heart health and fatherhood. Nearly 138,000 men between the ages of 50 and 71 participated in the study, which used data from the NIH-AARP Diet and Health Study, a national survey in retired persons. Only men free of heart disease and stroke at the beginning of the study were included, and the heart health of these individuals was followed for over ten years, on average. After adjusting for income, education, health habits, and age, men without children died from heart disease 17% more frequently than men who were fathers.

One possible explanation for this heart health discrepancy is a difference in testosterone production. Studies have shown that low levels of androgen hormones, such as testosterone, result in both a higher risk for cardiovascular disease and for infertility. The correlation between lower testosterone and infertility may partially explain the higher rate of cardiovascular death observed in childless men.
Eisenberg and Pletcher did not take into account the fertility of the women in these families (male infertility accounts for about half of infertility cases in couples) nor did they take into account the many fertile couples who did not wish to have children. Fatherhood is, therefore, far from a perfect proxy for male fertility.  Furthermore, the theory that testosterone deficiency underlies both infertility and heart disease just a theory, and some older research suggested that very high testosterone levels also increase a man’s risk for heart disease.  Another biological or social factor may, in actuality, be the underlying source of the correlation.  More research is needed to better understand the link between heart health and fatherhood.
So, Dads, next time you’re on diaper duty, don’t think of the sacrifices you are making for your children; think instead of the great health benefits you may be reaping for yourself. Let your children bring joy to your heart.

Ah, Fatherhood — Dirty Diapers, Skinned Knees … and Healthier Hearts?

<img loading="lazy" decoding="async" class="aligncenter size-full wp-image-11702" title="haplogroup-I" src="https://blog-api.23andme.com/wp-content/uploads/2012/03/haplogroup-I.png" alt="" width="514" height="268" srcset="https://blogcms.23andme.com/wp-content/uploads/2012/03/haplogroup-I.png 514w, https://blogcms.23andme.com/wp-content/uploads/2012/03/haplogroup-I-300x156.png 300w" sizes="auto, (max-width: 514px) 100vw, 514px" />
<a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61453-0/abstract" target="_blank" rel="noopener noreferrer">A recent study in The Lancet</a> reported that variation on the Y chromosome &#8212; haplogroup I, tagged by the SNP rs2032597 &#8212; is associated with coronary artery disease (CAD) in British men, with an odds ratio of 1.56. This finding stands out for several reasons. For one thing, the effect is substantially larger than any other reported genetic associations with CAD. Furthermore, it is rare to hear about functional effects of Y chromosome variation &#8212; at least partly because the Y chromosome is small and contains very few genes. The finding also invites special attention for some of the same reasons that make the Y chromosome interesting for population genetics. Here, we discuss the special properties of the Y chromosome and their implications for association studies, our concerns about the evidence the authors use to support their finding, and observations from the 23andMe database for haplogroup I and heart disease.
<h6>Why the Y is problematic</h6>
Most of the Y chromosome is not subject to recombination (the shuffling of maternal and paternal DNA that creates the unique genetic material passed down through sperm and egg) and is inherited intact from father to son. A consequence of this is that genetic variation on the Y chromosome is strongly associated with genetic ancestry. That doesn&#8217;t necessarily mean that genetic variation on the Y can&#8217;t also be functional, but it complicates functional analyses because it can be especially difficult to distinguish between ancestry effects and effects that are directly due to a particular Y chromosome variant. The lack of recombination also means that variants that are very far apart on the Y chromosome can still be strongly correlated, so it is also very difficult to use an association on the Y chromosome to identify a particular region as functionally important: the causal variant could be almost anywhere on the chromosome.
<h6>How strong is the evidence?</h6>
In The Lancet study, the authors carefully checked for alternative explanations for the association between haplogroup I and CAD. They looked for differences in conventional cardiovascular disease risk factors &#8212; both clinical biomarkers like blood pressure, BMI, and HDL, and lifestyle factors like smoking, alcohol consumption, and education &#8212; between haplogroup I and other haplogroups. None of these explained the association between haplogroup I and coronary artery disease. The authors also showed that the presence of haplogroup I did not correlate with the most significant dimensions of genetic ancestry within the study participants. This is a little surprising because haplogroup I is differentially distributed across Europe on a larger scale: it has a higher prevalence in Scandinavia and a lower prevalence in Southern Europe. Of course, it is possible that this gradient is not present in the smaller population of British men.
The trouble with candidate gene studies Candidate gene association studies (studies looking at one or a few genes as opposed to studies looking at variation across the entire genome) have a long and somewhat sordid history, largely because we tend to misjudge our ability to choose hypotheses that have a good likelihood of being true. If we choose a SNP at random and hypothesize that it might be associated with CAD, it would probably be better to use the genome-wide threshold for statistical significance (p-value &lt; 5 x 10-8) to evaluate the results, rather than, say, P &lt; 0.05 based on the fact that we have done just a single statistical test. If we&#8217;ve used a lot of prior knowledge to choose this one SNP, then maybe we could argue for using a more lenient standard. But it is very hard to decide how much prior knowledge is &#8220;worth&#8221; in this context.
What about the statistical evidence in favor of the haplogroup I association? In the target population of British men, more than 90% of individuals have either haplogroup I or another paternal haplogroup, R1b1b2. One could thus argue that the authors are effectively performing just a single statistical test comparing these two groups. On that basis, their statistical results (p-values of 0.004 in their initial study set, 0.012 in their replication set, and 0.0002 overall), seem convincing. However, it could be argued that the odds were stacked against their initial hypothesis that Y chromosome variation might be associated with CAD. The reported result would not meet criteria for significance in a genome wide association study (typically, p-values &lt; 5 x 10-8), so a lot depends on the credibility of this initial hypothesis.
The authors suggest that their hypothesis was motivated by the observation that CAD is more common in men than women but this fact is not convincing by itself. Physical differences between men and women are largely determined by the presence or absence of the Y chromosome, but that does not necessarily mean that specific variations on the Y chromosome affect traits or risk for disease among men. (It is much more likely that variations in many other parts of the genome that are functionally involved in those traits account for those differences.) The authors also cite work on animal models, as well as a few studies in humans suggesting that Y chromosome variants may affect cardiovascular phenotypes. However, the authors did not test the specific variants or phenotypes implicated in those studies.
<h6>Findings in the 23andMe community</h6>
We investigated whether the tag SNP for haplogroup I &#8212; the C version of rs2032597 &#8212; was associated with cardiovascular phenotypes in men with European ancestry from the 23andMe community using four traits: self-reported coronary artery disease, heart attack, high blood pressure, and high cholesterol. The following table shows results of association tests for these phenotypes. We see no significant association between rs2032597 and any cardiovascular phenotype, and can easily exclude values as large as the odds ratio of 1.56 reported by the authors of the Lancet study.
<div style="border: 1px solid #ccc; padding: 10px; margin-top: 10px; margin-bottom: 10px;">
Table 1. Association results for rs2032597 and heart disease phenotypes
<table style="font-family: 'Courier New'; font-size: 13px;" cellspacing="10">
<tbody>
<tr>
<td></td>
<td># cases</td>
<td># controls</td>
<td>p-value</td>
<td>Effect</td>
<td>95% CI</td>
</tr>
<tr>
<td>Coronary artery disease</td>
<td>1014</td>
<td>20120</td>
<td>0.92</td>
<td>1.009</td>
<td>[0.845,1.206]</td>
</tr>
<tr>
<td>Heart attack</td>
<td>486</td>
<td>22498</td>
<td>0.31</td>
<td>0.881</td>
<td>[0.687,1.130]</td>
</tr>
<tr>
<td>High blood pressure</td>
<td>5230</td>
<td>15797</td>
<td>0.34</td>
<td>0.958</td>
<td>[0.878,1.046]</td>
</tr>
<tr>
<td>High cholesterol</td>
<td>7970</td>
<td>15030</td>
<td>0.84</td>
<td>1.008</td>
<td>[0.932,1.090]</td>
</tr>
</tbody>
</table>
</div>
In contrast, we replicate the association for rs4977574, which is the variant (located on chromosome 9) most strongly associated with CAD in a recent <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119261/" target="_blank" rel="noopener noreferrer">large-scale meta-analysis</a>. In this case, results from the 23andMe database match the reported odds ratio of 1.3, suggesting that self-reported data from 23andMe members is sufficient for detecting true associations.
<div style="border: 1px solid #ccc; padding: 10px; margin-top: 10px; margin-bottom: 10px;">
Table 2. Association between rs4977574 and heart disease phenotypes
<table style="font-family: 'Courier New'; font-size: 13px;" cellspacing="10">
<tbody>
<tr>
<td></td>
<td># cases</td>
<td># controls</td>
<td>p-value</td>
<td>Effect</td>
<td>95% CI</td>
</tr>
<tr>
<td>Coronary artery disease</td>
<td>1014</td>
<td>20120</td>
<td>2.7E-08</td>
<td>1.312</td>
<td>[1.192,1.444]</td>
</tr>
<tr>
<td>Heart attack</td>
<td>486</td>
<td>22498</td>
<td>3.9E-05</td>
<td>1.318</td>
<td>[1.155,1.503]</td>
</tr>
<tr>
<td>High blood pressure</td>
<td>5230</td>
<td>15797</td>
<td>0.0091</td>
<td>1.065</td>
<td>[1.016,1.117]</td>
</tr>
<tr>
<td>High cholesterol</td>
<td>7970</td>
<td>15030</td>
<td>0.18</td>
<td>1.029</td>
<td>[0.987,1.073]</td>
</tr>
</tbody>
</table>
</div>
<h6>Concluding thoughts</h6>
What might explain the failure to replicate The Lancet finding in the 23andMe cohort? One possibility is that it is simply a false positive, and the apparent replication in the original study was just luck. Another possibility is that the association is real but restricted to the original study population of British men. That is, it might replicate in a new study of British men, but might not generalize well. Distinguishing between these possibilities will probably require additional studies, since it is very difficult to &#8220;prove a negative&#8221; and establish that a hypothetical association does not exist. The authors suggest that their study is the first to evaluate association between Y chromosome haplogroups and CAD. However, rs2032597 is present on recent Illumina SNP arrays used for GWAS, so data for this variant should exist in other large studies of CAD. Thus, it should be possible to quickly test many cohorts for this association, even if the Y chromosome data has not been previously analyzed.

Haplogroup I Likely Not Linked to Heart Disease

<img loading="lazy" decoding="async" class="alignright wp-image-2176 size-full" src="http://35.88.189.111/wp-content/uploads/2008/12/cholesterol.jpg" alt="" width="350" height="233" srcset="https://blogcms.23andme.com/wp-content/uploads/2008/12/cholesterol.jpg 350w, https://blogcms.23andme.com/wp-content/uploads/2008/12/cholesterol-300x200.jpg 300w" sizes="auto, (max-width: 350px) 100vw, 350px" />
By Bethann Hromatka, Ph.D. 

HLDL is the “bad” cholesterol that clogs arteries and is linked to coronary heart disease. Although people can do a lot to lower LDL levels and prevent heart disease – eating healthy, exercising, and taking certain medications – it’s also likely that genetics influences the relationship between LDL and heart disease.
For instance, some studies suggest that a particular version of the KIF6 gene called 719Arg may be linked to both heart disease and response to statins, a class of drugs used to lower LDL. The involvement of this SNP in the complex interplay between LDL cholesterol and heart disease, however, is proving to be controversial.
The KIF6 variant came to the attention of researchers when it was suggestively <a href="https://www.ncbi.nlm.nih.gov/pubmed?term=Five%20common%20gene%20variants%20identify%20elevated%20genetic%20risk%20for%20coronary%20heart%20disease.%20" target="_blank" rel="noopener noreferrer">linked to coronary heart disease</a> in 2007. Weak evidence for the association was also reported in a number of <a href="https://www.sciencedirect.com/science/article/pii/S0735109707034481" target="_blank" rel="noopener noreferrer">prospective studies</a> – people with at least one copy of the KIF6 variant, also called “carriers”, seemed to develop heart disease more than people without this version of the gene (non-carriers). Additional <a href="http://content.onlinejacc.org/cgi/content/short/51/4/449" target="_blank" rel="noopener noreferrer">studies</a> suggested that carriers receive greater benefit from statin therapy (pravastatin or atorvastatin) than non-carriers, but overall, none of these reports provided definitive statistical evidence for an association between the KIF6 variant and heart disease. 
 
Based on these initial reports, Celera, a biotechnology company that was involved in many of these studies, developed a <a href="http://kif6genotype.com/" target="_blank" rel="noopener noreferrer">genetic test</a> that determines whether a person has the KIF6 variant. This test was devised with the hope that it could pinpoint individuals who would derive the most benefit from statin therapy. Since as much as 60% of people with European ancestry carry at least one copy of this version of the KIF6 gene, millions of Americans with high LDL could potentially benefit from such a test. Although this version of the gene is also fairly common in African Americans and Asians, most of the research on KIF6 has been performed in people of European ancestry.
Although Celera filed for FDA clearance to market the test in early 2011, the application was <a href="http://www.genomeweb.com/dxpgx/fda-tells-celera-kif6-test-unapprovable-without-changes" target="_blank" rel="noopener noreferrer">rejected</a> because there wasn’t enough data to support its safety and effectiveness. This is in part because data surfaced in 2010 that contradicted the original reports. A large <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084526/?tool=pubmed" target="_blank" rel="noopener noreferrer">study</a> with 56,000 participants showed that people with the KIF6 variant do not suffer cardiac events more than non-carriers and another <a href="https://www.ncbi.nlm.nih.gov/pubmed/21458191">report</a> suggested that statin therapy had the same effect on carriers and non-carriers.
But like many research stories, there is now another twist. New findings published in <a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0028834" target="_blank" rel="noopener noreferrer">PLoS One</a> by lead author Brian Ference confirmed that, on average, the KIF6 variant is not associated with heart disease risk, but then offered novel findings suggesting that people with the KIF6 variant are more vulnerable to the harmful effects of LDL and therefore may be at increased risk for heart disease. This study is the largest meta-analysis of KIF6 to date with 144,931 participants.
In Ference’s study, KIF6 carriers with very high LDL suffered more cardiac events than non-carriers with similar LDL levels and, conversely, carriers who lowered their LDL experienced greater protection from cardiac events compared to non-carriers who lowered their LDL to a similar degree. In addition, people with KIF6 variant benefited more from statin therapies than non-carriers. Carriers on statin therapy experienced a 27% reduction in heart disease risk per mmol/L decrease in LDL, while non-carriers on statin therapy experienced a 17% reduction per mmol/L decrease in LDL.
<img decoding="async" class="alignright size-full wp-image-11001" title="heart disease vs LDL" src="https://blog-api.23andme.com/wp-content/uploads/2012/02/heart-disease-vs-LDL.png" alt="" width="350" srcset="https://blogcms.23andme.com/wp-content/uploads/2012/02/heart-disease-vs-LDL.png 613w, https://blogcms.23andme.com/wp-content/uploads/2012/02/heart-disease-vs-LDL-300x230.png 300w" sizes="(max-width: 613px) 100vw, 613px" />This figure shows a theoretical effect of a genetic variant on heart disease risk dependent on LDL levels. In the case of KIF6, the red line would correspond to carriers and the blue line to non-carriers. KIF6 carriers would exhibit increased heart disease risk than non-carriers at high LDL levels, but would also see a larger reduction in risk from lowering their LDL compared to non-carriers. (Figure adapted from Ference et al (2011).
These new findings add complexity to the story. They suggest that KIF6 carriers are more susceptible to heart disease risk conferred by high LDL levels but conversely derive greater benefit from lowering their LDL. These LDL-specific effects may help to explain why some of the early, small studies observed a possible link between the KIF6 variant and heart disease when the large study from 2010 – in people with a range of LDL levels – did not. Future studies may add even more clarity.
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KIF6 Tangos with LDL Cholesterol and Coronary Heart Disease

By Arnab Chowdry, Senior Scientific Software Engineer at 23andMe
Having been young and healthy for the majority of my life, I haven’t had many opportunities to interact with our health care system.   Not too long ago I was a sedentary, slightly-overweight, South Asian man entering my thirties.  I had some ambiguous family history of diabetes but, like everyone I know, I felt that the less I saw my doctor, the better.  Most importantly, by medical standards, I had no reason to consider myself predisposed to heart disease.
<img loading="lazy" decoding="async" class="alignright size-medium wp-image-10962" title="Arnab1" src="https://blog-api.23andme.com/wp-content/uploads/2012/01/Arnab1-300x199.jpg" alt="" width="300" height="199" srcset="https://blogcms.23andme.com/wp-content/uploads/2012/01/Arnab1-300x199.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2012/01/Arnab1-768x511.jpg 768w, https://blogcms.23andme.com/wp-content/uploads/2012/01/Arnab1-1024x681.jpg 1024w, https://blogcms.23andme.com/wp-content/uploads/2012/01/Arnab1-880x585.jpg 880w, https://blogcms.23andme.com/wp-content/uploads/2012/01/Arnab1-1180x785.jpg 1180w" sizes="auto, (max-width: 300px) 100vw, 300px" />
Then, not long ago, my 23andMe data and a paper in Nature Genetics changed my story.  Ironically, I work for 23andMe as a scientist and engineer; I analyze genetic data for a living, but until then my work had been abstract.  I knew we were helping people but never expected any particularly life-altering information to come out of my personal genetics.
It turns out that I carry a mutation in the MYBPC3 gene that is associated with familial hypertrophic cardiomyopathy (HCM). South Asians that carry this mutation are at greatly increased risk for HCM.   Well that’s strange&#8211;if I’m a carrier, then one of my parents has to be a carrier, and one of their parents (and so on).  But if it is such a significant modifier of risk, shouldn’t I have heard of HCM running in my family, before?
With some research, I learned that HCM is not commonly screened for, in the United States or India, but is a leading cause of sudden cardiac death in <a title="“Dying to Play”" href="https://www.slate.com/articles/health_and_science/medical_examiner/2009/02/dying_to_play.html" target="_blank" rel="noopener noreferrer">athletes</a>.  So it’s reasonable that I may not have heard of HCM in my family, because it may never have been diagnosed.  But I called my mother anyway and started asking questions: do we have any heart disease in our family?
I was surprised to learn that the answer was an emphatic: yes.  Though we had never discussed it, my mother was similarly surprised that I didn’t know that the majority of deaths in my family were related to heart disease.  My grandmother, who I thought had died of diabetes, actually suffered from angina and died of heart failure.  My grandfather on my father’s side had early-onset heart attacks and died from a blood clot.  Their brothers and sisters?  Cardiac arrest.  I even had a middle-aged cousin I never met who died the month before due to sudden cardiac death.  And all this time, at the doctor’s office, I never checked any box related to heart disease in my family history.  This information wasn’t recorded, anywhere, except the notepad I was using.
Given the surprising prevalence of heart issues on both sides of my family, it was hard to pin down which of my parents was likely to carry my mutation, so I got them both genotyped by 23andMe.  From there, it was easy to determine that the mutation came from my father’s side, which had more of the early-onset heart attacks.  I explained the research paper and its caveats to him and told him to talk to his doctor, then hung up the phone and realized: “Wait, shouldn’t I talk to my doctor?”
How do I even bring it up?  I’m a member of an HMO (Kaiser), and I like my primary care physician.  He’s always taken me seriously and referred me to the appropriate specialists, but he’s not a geneticist and I’m sure he’s never heard of this mutation, this gene, or this paper.  I was afraid he would laugh at me if I tried to explain that I bought a test online and found a mutation that suggests I should be screened for HCM.  But that’s what I did, in a nutshell, and to my surprise, he called up cardiology right away.
The cardiologist had never heard of this mutation, either, and went so far as to claim that there aren’t any such dominant mutations in MYBPC3.  All right, the paper came out in 2009 and, living in North America, I didn’t expect a South Asian variant to be well-known, but I didn’t expect the cardiologist to speak so authoritatively on something he was clearly wrong about.  My physician, to his credit, referred me to the genetics department and sent me home.
The geneticist who called me back was surprisingly informed and began the conversation by apologizing for the misinformation the cardiologist gave me.  She was particularly disappointed because she had recently given a talk about mutations in MYBPC3 to that department.  She also hadn’t heard of this mutation, but asked me to forward her the relevant papers and spent a week reading them.  She said that this would be considered a “variant of unknown significance,” but because of the deletion being in MYBPC3, I should be screened for HCM anyway.
I was referred back to cardiology for testing.  I took a resting and stress test EKG that indicated a worrying drop in blood pressure after exercise and an unusually long recovery time (consistent with my experiences attempting to work out).  I got an echocardiogram which didn’t detect HCM but found abnormal wall motion in my heart.  I spoke to another cardiologist who told me: “you aren’t 40 yet, so you aren’t at risk.”  The results were forwarded back to my physician, who summarized them as “normal” and sent me home.
I’m a scientist and I’ve worked professionally with clinicians in the past.  I know how the population statistics work and why they sent me home.  It doesn’t make economic sense for an HMO to spend any more money on me, when they can’t treat the condition, anyway.  But as an individual, this was unsatisfying.  What could I do to empower myself?
A lot of things.  I started dieting and losing weight.  I increased my activity level with more standing and walking, did more yard work and less video gaming.  I cut out a number of stressful activities in my life.  Today, I’m still South Asian, I still have this mutation, and I’m not getting any younger. But I’m back to a healthy BMI. I have an active lifestyle, I e-mail my doctor regularly to keep in touch, and I have a well-documented family history of heart disease.  Most importantly, I’ll be regularly screened for HCM from here on out and that’s one disease that won’t catch me by surprise.
Results will vary due to unique differences in each individual’s DNA. On average users receive at least one or two results that may be relevant to proactively managing health. 23andMe&#8217;s service does not diagnose disease. 23andMe is not a substitute for professional medical or diagnostic advice.

Arnab Chowdry

My Heart, My Family, and MYBPC3

<img loading="lazy" decoding="async" class="alignnone size-medium wp-image-10396" src="https://blog-api.23andme.com/wp-content/uploads/2011/11/foodchoicesna-300x220.jpg" alt="" width="300" height="220" srcset="https://blogcms.23andme.com/wp-content/uploads/2011/11/foodchoicesna-300x220.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2011/11/foodchoicesna.jpg 350w" sizes="auto, (max-width: 300px) 100vw, 300px" />
For some, eating a <a href="http://www.livestrong.com/article/86638-nutrition-information-donuts/" target="_blank" rel="noopener noreferrer">doughnut</a> every morning is a recipe for heart attack. For others, the doughnut doesn’t seem to matter–it’s almost as if certain individuals can’t get heart disease even if they try.
 The flip side is that people who are predisposed to heart disease can make lifestyle changes, in this example by cutting down on saturated fats and cholesterol, to decrease their odds of actually experiencing a heart attack. This is because heart disease is caused by a combination of genetic and lifestyle factors like diet and exercise. 
<h6>Genetics and Lifestyle</h6>
As a new paper published last month in <a href="https://www.google.com/url?q=http%3A%2F%2Fwww.plosmedicine.org%2Farticle%2Finfo%253Adoi%252F10.1371%252Fjournal.pmed.1001106&amp;sa=D&amp;sntz=1&amp;usg=AFQjCNG9EjWWh8juy6M7I8g_EpUd-zuN2A" target="_blank" rel="noopener noreferrer">PLoS Medicine</a> illustrates, lifestyle choices can have an even greater impact on heart disease risk depending on a person’s genetics. The study’s findings suggest that diet influences the association between SNPs in the 9p21 region of the genome and risk for heart attack and cardiovascular disease. 
The 9p21 region is one of the most established genetic associations for heart disease, but until now its interactions with environmental factors had not been thoroughly investigated. The current study, conducted by Ron Do of McGill University and the INTERHEART consortium, was carried out with DNA from over 27,000 people of different ethnicities.
A number of <a href="http://www.sciencemag.org/content/316/5830/1491.short" target="_blank" rel="noopener noreferrer">studies</a> have shown that one variants puts you at 1.5 higher odds of having a heart attack. In the current study, people with this variant who occasionally ate raw vegetables and fruit had a two-fold higher risk of heart attack compared to controls with a different variant who ate a similar diet. The surprising finding is that people the higher risk variant who frequently ate raw vegetables and fruit did not experience heart attacks more than controls.
<h6>Ethnicity Matters Too</h6>
The effect of diet on the association between SNPs in the 9p21 region and heart attack risk was strongest for people of South Asian ancestry. The evidence for this effect was suggestive but weaker in the European, Latin American, and Chinese populations studied. Although the researchers also looked to see if smoking and exercise modified the relationship between 9p21 SNPs and heart attack risk, they didn’t find evidence of a connection. 
These findings suggest that people with a predisposition for coronary heart disease, at least based on their genotype at 9p21, can eat a <a href="http://www.mayoclinic.com/health/heart-healthy-diet/NU00196" target="_blank" rel="noopener noreferrer">heart-healthy diet</a> to decrease their chances of actually experiencing a heart attack. Thus, having two risky versions of these SNPs isn’t necessarily a recipe for heart attack. We already know that diet strongly impacts health–indeed there is a reason why your parents told you to eat your vegetables–and this study suggests that diet may actually override genetic risk in some cases.

Heart Disease — Page 2