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  1. From this new article from the BBC: "Across mammals alone, expected lifespan can vary 100-fold, from shrews that live for no longer than 1.5 years to the bowhead whales that can live for more than 200. It is as if, for various reasons, natural selection has somehow pushed certain creatures to evolve their own elixir of life." The writer goes on to talk to scientists studying genes and gene expression in whales, bats and naked mole rats, in hopes of discovering how they live so long, and in particular avoid cancer. The article talks about the possibility of using gene therapy to replicate some of the longevity-promoting genetic changes observed in these long-lived animals in people someday. One of the researchers talks about a study I'd sign up for - comparing bowhead whale gene expression to the gene expression of people practicing CR! It reminds me of the study [1] Luigi Fontana did on our muscle tissue - namely comparing our gene expression to that of CRed rats. Note: This is yet another example of a post that would be fit better on a "Science of Health & Longevity" forum, rather than here on the "CR Science & Theory" forum. How about it Brian/Tim? --Dean ---------------------------- [1] Mercken, E. M., Crosby, S. D., Lamming, D. W., JeBailey, L., Krzysik-Walker, S., Villareal, D. T., Capri, M., Franceschi, C., Zhang, Y., Becker, K., Sabatini, D. M., de Cabo, R. and Fontana, L. (2013), Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell, 12: 645–651. doi: 10.1111/acel.12088. Full Text: http://onlinelibrary.wiley.com/doi/10.1111/acel.12088/full
  2. All, I'm usually reluctant to post studies that try to associate single nucleotide polymorphisms (SNPs) with health or longevity outcomes. There are several reasons to be skeptical of such gene studies, including: They often fail to replicate across different populations The effects of individual SNP variations are often quite small - since there are usually many genes and polymorphisms that contribute to any important health/longevity outcome Often it's not even clear from the study what the specific allele variation(s) the authors are evaluating You often can't even find out what variant of an allele you have - since only some of us have our own genetic data and even that is only partial coverage through 23andMe. There is nothing you can do about it anyway - your genes are your genes. These polymorphisms and their effects often have nothing to do with CR. But this new meta-analysis [1] posted by Al Pater (thanks Al!) seems to suffer from none of these shortcomings. It focuses on a SNP in the FoxO3 gene (rs2802292) which has been previously associated with longevity - is it overrepresented in centenarians [2], as discussed here, and summarized as: [T]he odds ratio for reaching 100 years of age for rs2802292(G;G) vs (T;T) carriers was 2.75 (p = 0.00009; adjusted p = 0.00135). One's odds of living to 100 with one copy of 'G' for rs2802292 (i.e. G:T), appears to be about 1.5-2 times greater than people with T:T. Those results were encouraging, but didn't address causality, and was limited to a homogeneous population of men. Plus it only seemed relevant for people without other 'gotchas' (genetic or otherwise) that might kill them off long before reaching 100. What about the rest of us mortals, who may not be destined to live that long? Does having copies of the 'G' allele for rs2802292 do the rest of us any good on the way to extreme longevity? Apparently - Yes! Study [1] followed three pretty large groups of Americans with Japanese (N ≈ 3600), Caucasian (N ≈ 1600), or African (N ≈ 1000) ancestory for 17 years to assess the association between SNP rs2802292 status and mortality. Interestingly, the frequency of being a lucky 'G' Allele Carrier (GAC) for this SNP varied between the three populations - 47% of Japanese, 58% of Caucasian and 92% of African ancestry folks were GACs. Across all three populations, being a GAC was associated with a 10% reduction in all-cause mortality over the 17 year follow-up, with virtually all of the benefit resulting from a 26% reduction in heart disease mortality. Here is the most important figure from the free full text: As you can see the effect was quite consistent across the three populations. The difference in the confidence interval for the three groups was a result of the different population sizes. The cool thing is that those of us with 23andMe data can find out our status for SNP rs2802292. Simply log in to 23andMe and follow this link. I'm fortunate to be in the ~60% of caucasian people who is a 'G' carrier for this allele (I've got one copy). But for anyone who isn't lucky enough to be a GAC for this allele, there is still hope. Why? Because FoxO3 gene activity is something we know quite a bit about, including ways of boosting its activity, like the G allele for rs2802292 apparently does. Curiously, cider vinegar appears to upregulate DAF-16, the C. Elegans equivalent of FoxO3, which in turn resulted in the worms living 25% longer, as discussed here. So maybe cider vinegar is worth including in one's diet. I do. But even more relevant, we know that both CR and cold exposure increase FoxO3 gene expression largely by upregulating SIRT1, as discussed recently here. So everybody wins! --Dean ------------------ [1] The FoxO3 gene and cause-specific mortality. Willcox BJ, Tranah GJ, Chen R, Morris BJ, Masaki KH, He Q, Willcox DC, Allsopp RC, Moisyadi S, Poon LW, Rodriguez B, Newman AB, Harris TB, Cummings SR, Liu Y, Parimi N, Evans DS, Davy P, Gerschenson M, Donlon TA. Aging Cell. 2016 Apr 13. doi: 10.1111/acel.12452. [Epub ahead of print] Free Article http://onlinelibrary.wiley.com/doi/10.1111/acel.12452/full http://onlinelibrary.wiley.com/doi/10.1111/acel.12452/pdf Abstract The G allele of the FOXO3 single nucleotide polymorphism (SNP) rs2802292 exhibits a consistently replicated genetic association with longevity in multiple populations worldwide. The aims of this study were to quantify the mortality risk for the longevity-associated genotype and to discover the particular cause(s) of death associated with this allele in older Americans of diverse ancestry. It involved a 17-year prospective cohort study of 3584 older American men of Japanese ancestry from the Honolulu Heart Program cohort, followed by a 17-year prospective replication study of 1595 white and 1056 black elderly individuals from the Health Aging and Body Composition cohort. The relation between FOXO3 genotype and cause-specific mortality was ascertained for major causes of death including coronary heart disease (CHD), cancer, and stroke. Age-adjusted and multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) for all-cause and cause-specific mortality. We found G allele carriers had a combined (Japanese, white, and black populations) risk reduction of 10% for total (all-cause) mortality (HR = 0.90; 95% CI, 0.84-0.95; P = 0.001). This effect size was consistent across populations and mostly contributed by 26% lower risk for CHD death (HR = 0.74; 95% CI, 0.64-0.86; P = 0.00004). No other causes of death made a significant contribution to the survival advantage for G allele carriers. In conclusion, at older age, there is a large risk reduction in mortality for G allele carriers, mostly due to lower CHD mortality. The findings support further research on FOXO3 and FoxO3 protein as potential targets for therapeutic intervention in aging-related diseases, particularly cardiovascular disease. KEYWORDS: FOXO3; heart disease; longevity; mortality PMID: 27071935 -------------- [2] Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92. doi: 10.1073/pnas.0801030105. Epub 2008 Sep 2. FOXO3A genotype is strongly associated with human longevity. Willcox BJ(1), Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. Author information: (1)Pacific Health Research Institute, 846 South Hotel Street, Honolulu, HI 96813, USA. bjwillcox@phrihawaii.org Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations. PMCID: PMC2544566 PMID: 18765803
  3. I haven't come anywhere near digesting the article fully, but it had enough interesting details about the changes in transcription brought about by endurance exercise that I thought it worth posting. It's from a study at Karolinska Institutet. The article is in the latest issue of PLOS Genetics, and is entitled (full text available at the linked article): The Impact of Endurance Training on Human Skeletal Muscle Memory, Global Isoform Expression and Novel Transcripts Here's the author's summary: Here's the abstract:
  4. Sthira

    On pursuing Biogerontology

    Your thoughts, if, say, hypothetically you were thinking of entering the fray. I copy and paste from: http://www.senescence.info/biogerontology_career.html How to Become a Biogerontologist senescence.info logo Biogerontologists study the biological process of aging at different levels and using different techniques and models. If you would like to do research on the biology of aging and/or you are a student thinking about pursuing a career in biogerontology then this brief essay is for you. Keywords: age-related diseases, gerontology, gerontologists, jobs By and large, biogerontologists work at research institutions, typically universities and laboratories, though some also work in the biotechnology industry--and a few companies research aging. The vast majority of biogerontologists have a PhD (or sometimes an MD or both), so if you want to become a biogerontologist you should be prepared to go to graduate and/or medical school. While it is possible to study aging in a private company or as a staff member of a research institution, the majority of influential biogerontologists have their own research group, like mine, at a research institution. Again, you can certainly contribute to research on aging in a variety of ways and even without making of it your main job, yet if you are serious about becoming a biogerontologist and doing independent research at the highest level then this usually implies developing an academic career. If you have an entrepreneurial spirit you could create, or help build up, a biotech company with some focus on aging. You could then do research, usually with translation to humans as a shorter-term aim than in academia, that has commercial value. Although there are a few people working on aging who followed this path, they are a minority and I know very little about entrepreneurship so cannot offer much advice on this--but wish you good luck. As such, this essay focuses on academia. How to develop a career in science is the subject of another essay of mine. Briefly, an academic career is highly competitive and usually entails having good grades in high school (in particular in science classes), getting a bachelor's degree with honors and later a doctoral degree (and maybe a master's degree in between, though I normally do not recommend it as top students can often enter a doctoral program without a masters), obtaining strong recommendation letters from advisors, and eventually developing a publication record, securing grants, and doing some teaching. If you are a student, you should have a counselor at your institution that can guide you through the process and there are also many resources on pursuing an academic career on the Internet. One major doubt of students is which topics they should study to prepare themselves for a career in biogerontology. Because aging is a biological process I would suggest that you include biology courses in your education. With the sequencing of the human genome and recent progress in the genetics of aging and longevity, I would also recommend some knowledge of genetics. Nevertheless, do not overestimate the importance of choosing the right courses and university. It does not make such a big difference because many different techniques and skills can be employed to study aging. There are physicists, physicians, engineers, biologists, geneticists, computer scientists, mathematicians, and many other different professionals studying aging right now. Therefore, my advice is for you to learn different skills, understand the science of aging, and focus on the area you find more exciting or more adequate to your personal situation. (As a side note, I would also recommend you develop good communication skills, both written and oral, as these are crucial not only in academia but in many other careers as well.) In the end, remember that who you are is more important than what you learn. To quote Einstein: "Creativity is more important than knowledge." Even though my opinion might be biased, I definitely think my essays on the biology of aging are an excellent introduction to anyone wishing to pursue a career in biogerontology. A briefer overview of gerontology is available as one of my papers (de Magalhaes, 2011). Nonetheless, I also suggest you take a look at my book recommendations since there may be other sources that better fit your personal taste. Lastly, there are occasional intensive courses on the biology of aging, such as the Molecular Biology of Aging course in Woods Hole, MA, USA. As an undergraduate, I would recommend you gain some research experience. This might also help you decide whether doing research is the career for you. For example, you can do an internship in a research group, like ours, and often your mentor or counselor will help you arrange this. I should note that I am always glad to help students aspiring to develop a career in aging research so if you wish to visit our lab or even spend some time here to see what we do just let me know. Once you become more familiar with research in general you will need to start reading academic papers. The main bibliographical database in the biomedical sciences is PubMed and you will need to become familiar with it at some point in your career, possibly in high school or the latest in college. At some point before going to graduate school, I would advise students to start identifying those researchers in the field whose work they most admire and sub-fields of particular interest. This can be done through publications, though often it is difficult for beginners to make sense of the massive archive of publications. Therefore, I would also advise you to look at the list I maintain of researchers working on aging, which includes links to the researchers' websites (if available) and links to PubMed that allow you to more quickly find relevant publications by each of the researchers. Similar to the point made above about how there is no right topic to study, there is no right school or even degree. Assuming your priority is research on aging then having a PhD has advantages over having an MD since it is difficult to balance research and clinical work, but more often than not this is a personal choice and many people enjoy clinical work. Regarding the choice of countries, this is certainly influenced by the mobility of each individual but a few points may be worth considering. The US and European systems are different in regard to graduate and medical schools. For example, graduate students in the US usually take longer to receive their PhDs. Mostly because of this, and please have in mind that I am an European, I normally would not recommend for an European to get his/her PhD in the US, but like many other suggestions in this essay this is often a personal decision. It is also possible to get a PhD from an European institution but do part or even most of the work in the US. Likewise, many people carry out most of their doctoral work in Europe or in the US but then receive their PhDs from institutions in other countries, often their native countries. Overall, working on aging has its challenges, such as the lack of adequate models of human aging and a lack of funding when compared to other biomedical disciplines. Salary-wise, in fact, working in academia is not the best career choice. Scientists usually do research because they love it, not because they want to become millionaires, though some scientists are also associated with industry which brings in extra income. Working in academia does have its advantages, such as schedule flexibility and creative freedom. Besides, since the field of aging is still largely mysterious with many unanswered questions, bright young minds have an extraordinary opportunity to make important contributions to science by studying aging. I hope you will be one of those minds. Please feel free to contact me if you have questions not covered in this essay or need any advice. Up to the Visitor's Resources Back to senescence.info Thank you for visiting my website. Please feel free to contact me if you have any questions, ideas, comments or suggestions. Copyright © 2007, 2008, 2012 by João Pedro de Magalhães. All rights reserved.
  5. All, Here is an interesting new study [1] (popular press story) that I appreciated as much for its data as its conclusions. In it, researchers identified a group of ~1400 "Wellderly" individuals - which they defined as: ndividuals who are >80 years old with no chronic diseases and who are not taking chronic medications. As you might imagine, these folks are pretty rare, and so they wanted to compare their genomes with those of an average population of elderly people. But first, they did an interesting thing - they compared the longevity of the siblings of the Wellderly cohort (who share a lot of genetics, and probably some lifestyle factors too, with the Wellderly folks) to see how their lifespan compares with the average US population. Here are the "survival curves" for the Wellderly siblings (red) vs. average folks (blue): As you can see, the Wellderly siblings had a more square mortality curve, but their survival curve wasn't shifted right - i.e. their "maximum lifespan" wasn't any longer than the average folks. Instead, both curves hit (near) zero around 100 years. Like the Wellderly themselves, their siblings appear to avoid / postpone the diseases of aging, and so do better in the "middle years" of elderliness (65-85), but beyond that have a mortality rate similar to the population as a whole. They then looked at the Wellderly folks' genetics. Interestingly, they didn't find their genomes to be particularly enriched with so-called "longevity genes" - those that have been identified as more common in centenarians or other very long-lived people. In other words, these folks are healthy agers, but don't seem to be blessed with genes for extreme longevity, which I thought was interesting. It suggests that at least to some degree healthy aging and extreme longevity are distinct, based both on the (sibling) survival curve data and their own genetics. Here is how the authors summarized this part of their findings: [O]ur results suggest that healthy aging is a genetically overlapping but divergent phenotype from exceptional longevity and that the healthy aging phenotype is potentially enriched for heritable components of both reduced risk of age-associated disease and resistance to age-associated disease. I'm curious what Michael would say, but it seems like this apparent distinction between disease avoidance and extreme longevity might undermine to some degree the SENS hypothesis - that aging simple is the accumulation of damage from the diseases of aging. Note: that is my potentially inaccurate summary of the SENS hypothesis... But what I found personally most interesting and helpful from this paper were two of their tables, listing the various genetic markers they tested for both longevity and Alzheimer's disease (AD). They quite explicitly listed the SNPs and which alleles of those SNPs are associated with longevity or AD. I've reproduced the two tables below, and added my own data, a friend's 23andMe data I have access to, and links to 23andMe so that any other 23andMe customers can check their own status for the corresponding SNPs. I've even added a tally at the bottom of each table with a genetic "score" - basically the number of "good" alleles one carries minus (in the case of the AD table) the number of "bad" alleles one carries. Although in the case of AD, it was the evil APOE4 allele that dominated - i.e. the biggest difference between the genes of the "Wellderly" folks and the average population was that the Wellderly were a lot less likely to carry APOE4 alleles. Anyway, here are the tables. First, the table with the SNPs and alleles previously identified (via other studies) to be associated with increased longevity. The "Longevity Allele" column shows that variant of the SNP that has been shown to be associated with increased longevity. The second column shows the gene the SNP is part of - as you can see many familiar names, including FOXO3, SIRT1, IL-6, IGF1, AKT (all of which I note have been associated with both CR and Cold Exposure in one way or another). The green letters show when I or "Person X" are carriers for the "good" longevity allele: Here are "live" links to the 23andMe page for each SNP so 23andMe customers can check their own results on these SNPs: https://www.23andme.com/you/explorer/snp/?snp_name=rs2802292 https://www.23andme.com/you/explorer/snp/?snp_name=rs1935949 https://www.23andme.com/you/explorer/snp/?snp_name=rs3758391 https://www.23andme.com/you/explorer/snp/?snp_name=rs5882 https://www.23andme.com/you/explorer/snp/?snp_name=rs1042522 https://www.23andme.com/you/explorer/snp/?snp_name=rs1800795 https://www.23andme.com/you/explorer/snp/?snp_name=rs2811712 https://www.23andme.com/you/explorer/snp/?snp_name=rs34516635 https://www.23andme.com/you/explorer/snp/?snp_name=rs2542052 https://www.23andme.com/you/explorer/snp/?snp_name=rs3803304 Here is the same sort of table, but this time for SNPs and Alleles associated with Alzheimer's disease and/or cognitive decline. Note, the last SNP in the table is the dreaded APOE4. As you can see from the p-value column, the APOE4 allele was far and away the most significant predictor of AD/cognitive decline, and the Wellderly had it less frequently that the general population (the column labelled "ITMI A2 Freq"). Also not that unlike the longevity SNPs, 23andMe didn't have data for many of the AD-related SNPs. Once again, the green letters show when I or "Person X" are carriers for the "good" allele (for avoiding AD) or and red letters show where one of us is a carrier for the "bad" allele (increasing risk of AD): Here are the direct links to 23andMe for the subset of SNPs from the table that were available (at least for me): https://www.23andme.com/you/explorer/snp/?snp_name=rs190982 https://www.23andme.com/you/explorer/snp/?snp_name=rs2718058 https://www.23andme.com/you/explorer/snp/?snp_name=rs1476679 https://www.23andme.com/you/explorer/snp/?snp_name=rs11771145 https://www.23andme.com/you/explorer/snp/?snp_name=rs11218343 https://www.23andme.com/you/explorer/snp/?snp_name=rs17125944 https://www.23andme.com/you/explorer/snp/?snp_name=rs10498633 https://www.23andme.com/you/explorer/snp/?snp_name=rs2075650 As you can see, for both the longevity SNPs and the AD SNPs, my score is a bit better than the score for my friend, "Person X" - so I got that goin' for me. And they are an unfortunate carrier of one APOE4 allele. ☹ To wrap up, the researchers also also found that a few of the Wellderly folks were enriched with an ultra-rare variants of a gene that seems to be especially protective against AD, called COL25A1 but I couldn't figure out what SNPs or alleles they were talking about. As always, these genetic marker studies need to be taken with a grain of salt. But it was fun to see where I and "Person X" stand regarding all these variants. I'd be curious if anyone else would be willing to share their data, or at least their "scores". --Dean ------- [1] Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.03.022 Whole-Genome Sequencing of a Healthy Aging Cohort Galina A. Erikson5, Dale L. Bodian5, Manuel Rueda, Bhuvan Molparia, Erick R. Scott, Ashley A. Scott-Van Zeeland, Sarah E. Topol, Nathan E. Wineinger, John E. Niederhuber, Eric J. Topol6, Ali Torkamani6 Free full text: http://www.cell.com/cell/pdf/S0092-8674(16)30278-1.pdf Summary Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype—healthy aging—to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. PMID: Unavailable
  6. Dean Pomerleau

    Epigenetics and "Intelligent Design"

    [Note: I really hate to put this post on the "Chit-Chat" forum, since it is science heavy. It would fit much better on a (longed-for) "Non-CR Health and Longevity" forum. But its too far from CR to justify posting it to "CR Science", so here goes...] I'm reading philosopher Thomas Nagel's most recent book, Mind and Cosmos in which he argues that the "neo-Darwinian conception of nature is almost certainly false" - in fact, that is the subtitle of the book. Key to his argument is that it doesn't appear that the cornerstone of neo-Darwinism, namely random mutation to genes that turn out to be fitness enhancing, could ever come up with the vast variety of large scale variations in body morphology and physiological systems we see in the world, many of which are argued to be "irreducibly complex" (i.e. all-or-nothing from an evolutionary fitness perspective). The architecture of the eye, and the molecular motor that powers flagellum in bacteria are examples of these complex biological structures that would seem (to some) impossible to evolve through simple random mutation. Nagel, and others (and not just intelligent design (ID) folks, some of whom think God orchestrates evolution) see the need for some more directed form of evolution to explain the diversity and complexity of life on our planet. Nagel seems to think mind / consciousness, and not God in the traditional conception of the term, might fit the bill. But to me that seems rather extreme, and goes against "reductive materialism / naturalism" that has been so successful at explaining how the world works over the last few hundred years. One wonders if a less drastic solution that tweaks the mechanism of neo-Darwinian evolution, might be invoked to save the day for materialism / naturalism. As discussed elsewhere (see this post for details), I've recently been studying epigenetics, where gene expression can be modulated by methylation (among other mechanisms). In methylation, a methyl groups can attach to a particular DNA base pair, causing the gene to "wrap up" around a histone, preventing it from being transcribed into RNA, thereby suppressing expression of the protein that the gene codes for. This methylation can be driven by environmental factors, is quite localized, specific, and repeatable, and can occur not only in somatic cells, but also in germ-line cells (eggs and sperm), and thereby get passed down to several subsequent generations. While the epigenetic changes can be adaptive both for the organism in which they first occur, as well as their progeny, they aren't permanent changes to the base-pair sequence of genes, so they aren't heritable variations over thousands or millions of years, like we see across species in the world. So they are "Lamarkian" to a point, but not in the true sense of the world - giraffe necks could get longer for a generation or two after (hypothetical) epigenetic changes occurred as a result of a giraffe stretching to reach the high leaves on a tree, but eventually the epigenetic changes would "wear off" and subsequent generations would go back to having short necks. But what if epigenetic changes via methylation not only silences genes, but also made those silenced genes more prone to mutation? The methylation would not only be a signal that "this gene isn't worth expressing in the current environment", it would also be signaling "this gene is not very useful in is current form in the current environment, so target it for mutation". With an elevated mutation rate specific to maladaptive genes lasting several generations, new variations should more readily arise in subsequent generations, accelerating experimentation with parts of the genome where changes would be mostly likely to be beneficial in a rapidly changing environment. This sort of elevated mutation rate in parts of genes that have been methylated (silenced) is exactly what this study [1] found. To quote the abstract: Our results ... provid[e] the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data. It's not clear that this targeting of random mutations to specific maladaptive genes could result in the type of big changes Nagel and others point to when criticizing neo-Darwinian evolution. But it seems like a way to facilitate a sort of "semi-Intelligent Design", without an explicit designer, by focusing "random tinkering" with the genome in places where genetic changes could do the most good in the current environment. Anyway, while not (directly) related to CR, I thought it was interesting nonetheless. Comments appreciated. --Dean ---------- [1] Full text: http://www.biomedcentral.com/1471-2164/13/S8/S7 BMC Genomics. 2012;13 Suppl 8:S7. doi: 10.1186/1471-2164-13-S8-S7. Epub 2012 Dec 17.Investigating the relationship of DNA methylation with mutation rate and allele frequency in the human genome. Xia J1, Han L, Zhao Z. Author information AbstractBACKGROUND:DNA methylation, which mainly occurs at CpG dinucleotides, is a dynamic epigenetic regulation mechanism in most eukaryotic genomes. It is already known that methylated CpG dinucleotides can lead to a high rate of C to T mutation at these sites. However, less is known about whether and how the methylation level causes a different mutation rate, especially at the single-base resolution. RESULTS:In this study, we used genome-wide single-base resolution methylation data to perform a comprehensive analysis of the mutation rate of methylated cytosines from human embryonic stem cell. Through the analysis of the density of single nucleotide polymorphisms, we first confirmed that the mutation rate in methylated CpG sites is greater than that in unmethylated CpG sites. Then, we showed that among methylated CpG sites, the mutation rate is markedly increased in low-intermediately (20-40% methylation level) to intermediately methylated CpG sites (40-60% methylation level) of the human genome. This mutation pattern was observed regardless of DNA strand direction and the sequence coverage over the site on which the methylation level was calculated. Moreover, this highly non-random mutation pattern was found more apparent in intergenic and intronic regions than in promoter regions and CpG islands. Our investigation suggested this pattern appears primarily in autosomes rather than sex chromosomes. Further analysis based on human-chimpanzee divergence confirmed these observations. Finally, we observed a significant correlation between the methylation level and cytosine allele frequency. CONCLUSIONS:Our results showed a high mutation rate in low-intermediately to intermediately methylated CpG sites at different scales, from the categorized genomic region, whole chromosome, to the whole genome level, thereby providing the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data. PMID: 23281708
  7. It's not surprising that people who are overweight and obese benefit from reducing their Calorie intake to shed the excess fat tissue. By contrast, it's more than a little counterintuitive that Calorie restriction is also beneficial to animals (and possibly humans) who are already lean to begin with. In animal studies, CR is one of only a very small number of interventions that actually slow down the degenerative aging process, and its "anti-aging" benefits kick in exactly starting from the point at which the animals' Calorie intake is reduced below the level required to sustain their "normal" weight, and continue to become more powerful as Calories are cut further and further — right up to the limits of starvation. Even more surprisingly, there's also evidence that animals whose metabolism does a better job of "defending" their fat tissue as their Calories are cut actually benefit more from CR than animals who shed the weight easily. In a recent thread in the CR Society Forum, we discuss some of the latest evidence on this phenomenon.
  8. Dean Pomerleau

    Genetics of Obesity

    There is an new study on the link between genetics and obesity reported on in this popular press article: http://www.huffingtonpost.com/entry/obesity-gene-discovery-could-forever-change-weight-loss_55d4f994e4b0ab468d9fc0f4 Study [1] is the (rather technical) abstract for the paper associated with the story. I'll do my best to summarize the background and the findings of this study, which I found really interesting. First a little background. It has been known for a while that a particular gene on chromosome 16 named FTO has many (over 200) SNPs (single nucleotide polymorphisms - i.e. common variations in particular base pairs along this gene), several of which appear to be associated with obesity. Here are two older studies [2][3] that address this linkage. Study [2] focused on SNP rs9939609. It found that people who carry one (or especially two) copies of the 'obese' allele ('A') for this SNP were significantly more likely to be obese than those who carry the 'lean' variant ('T'). Study [3] found the same thing for three other FTO SNPs, rs1421085, rs17817449 and rs8043757. It found that people with the 'obese' variants for these three SNPs ('C', 'G' and 'T', respectively) were about 2.5 times more likely to be obese than those who had the lean variants for these three SNPs ('T', 'T', 'A', respectively). The newest study [1], focused on the first of the three SNPs from [3], namely SNP rs1421085, and did something really cool and cutting edge. They took fat cells from mice and humans and used the recently-developed CRISPR gene editing technique to change this particular SNP from the 'obese' variant ('C') to the 'lean' variant ('T'), and then observed what happened to the cells. What they found was that the fat cells converted from being thermogenically active, 'beige' fat cells (i.e. like brown fat cells) to 'white' fat cells that are much more efficient at storing fat, rather than burning it. This can be spun as a nice mechanistic story to explain why at least this SNP is associated with obesity. People who have 'C' for rs1421085 produce more white fat cells, making them more efficient at storing fat - i.e. they have a more 'thrifty' genotype and will therefore (presumably) store more fat for a given calorie intake. Now comes the interesting citizen science part. Data on all four of obesity-related SNPs mentioned above are available to subscribers of 23andMe. Simply log in, then go to this page: https://www.23andme.com/you/explorer/gene/?gene_name=FTO to get a list of all 200+ SNPs from the FTO gene that 23andMe sequences, and search on the page for these four SNPs. Here are my results: rs9939609 TT (lean variant = T) rs1421085 TT (lean variant = T) rs17817449 TT (lean variant = T) rs8043757 AA (lean variant = A) As you can see, I've inherited two copies (one from each of my parents) of the 'lean' allele for each of these four SNPs. So it is no wonder that unintended weight gain has never been an problem for me - at least according to these SNPs I have the antithesis of the 'thrifty genotype'. I'm curious what other CRONies who are also subscribers to 23andMe have for these SNPs, and whether they consider themselves to have a 'thrifty genotype' (easily gain weight) or not. I also wonder whether long-term success on a CR lifestyle is in any way correlated with the values for these SNPs. There is some indication [4] that some of the FTO SNPs (including rs9939609) have an effect on energy intake and preference for energy dense (i.e. high fat) foods, and from [2] we saw that people with the 'obese' allele for rs9939609 and who eat a high-fat, low-carb diet have a higher BMI, which could discourage people trying to practice CR in order to lose weight. Conversely, having a 'thrifty genotype' might make it easier to maintain a low calorie intake without becoming terribly skinny, which can sometimes result in social pressure to eat more to avoid looking like a concentration camp victim. :) Anyway, I've probably grossly oversimplified the science, but I found it fascinating and would be interested to hear what other 23andMe subscribers have for these alleles. --Dean ------------------------------- [1] N Engl J Med. 2015 Aug 19. [Epub ahead of print] FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. Claussnitzer M(1), Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C, Glunk V, Sousa IS, Beaudry JL, Puviindran V, Abdennur NA, Liu J, Svensson PA, Hsu YH, Drucker DJ, Mellgren G, Hui CC, Hauner H, Kellis M. Background Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. Methods We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. Results Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. Conclusions Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.). PMID: 26287746 --------------- [2] Br J Nutr. 2012 Nov 28;108(10):1859-65. doi: 10.1017/S0007114511007410. Epub 2012 Jan 23. Association of the fat mass and obesity-associated (FTO) gene variant (rs9939609) with dietary intake in the Finnish Diabetes Prevention Study. Lappalainen T(1), Lindström J, Paananen J, Eriksson JG, Karhunen L, Tuomilehto J, Uusitupa M. A cluster of variants in the fat mass and obesity-associated (FTO) gene are associated with the common form of obesity. Well-documented dietary data are required for identifying how the genetic risk can be modified by dietary factors. The objective of the present study was to investigate the associations between the FTO risk allele (rs9939609) and dietary intake, and to evaluate how dietary intake affects the association between FTO and BMI in the Finnish Diabetes Prevention Study during a mean follow-up of 3·2 years. A total of 479 (BMI >25 kg/m2) men and women were genotyped for rs9939609. The participants completed a 3 d food record at baseline and before every annual study visit. The average intakes at baseline and during the years 1, 2 and 3 were calculated. At baseline, the FTO variant rs9939609 was not associated with the mean values of total energy intake, macronutrients or fibre. At baseline, a higher BMI by the FTO risk genotype was detected especially in those who reported a diet high in fat with mean BMI of 30·6 (sd 4·1), 31·3 (sd 4·6) and 34·5 (sd 6·2) kg/m2 for TT, TA and AA carriers, respectively (P =0·005). Higher BMI was also observed in those who had a diet low in carbohydrates (P =0·028) and fibre (P =0·015). However, in the analyses adjusted for total energy intake, age and sex, significant interactions between FTO and dietary intakes were not found. These findings suggest that the association between the FTO genotype and obesity is influenced by the components of dietary intake, and the current dietary recommendations are particularly beneficial for those who are genetically susceptible for obesity. PMID: 22265018 ----------------------- [3] Gene. 2015 Mar 1;558(1):75-81. doi: 10.1016/j.gene.2014.12.050. Epub 2014 Dec 24. Common variations in the FTO gene and obesity in Thais: a family-based study. Chuenta W(1), Phonrat B(2), Tungtrongchitr A(3), Limwongse C(4), Chongviriyaphan N(5), Santiprabhob J(6), Tungtrongchitr R(7). Several studies have revealed the association between single nucleotide polymorphisms (SNPs) in the first intron of fat mass and obesity-associated (FTO) gene and obesity. To date, more than 100 SNPs in the FTO gene have been identified in various populations. Nevertheless, this association has not yet been confirmed in Thai populations. The aim of this study was to investigate whether FTO variants are associated with obesity in Thais. We analyzed ten variants in the FTO gene (rs9939609, rs9926289, rs8050136, rs9930501, rs9930506, rs9940646, rs9940128, rs1421085, rs17817449, and rs8043757) in 12 families (83 persons); composed of 12 proband cases and 71 associated family members. All participants were genotyped using polymerase chain reaction (PCR) method and DNA sequencing assay. We found significant associations between three SNPs located in the first intron of FTO gene (rs1421085, rs17817449, and rs8043757) and obesity. The odds ratios were 2.82 (95% CI, 1.16-6.90, p=0.02) for rs1421085 and rs17817449, and 3.15 (95% CI, 1.28-7.76, p=0.01) for rs8043757. Strong linkage disequilibrium among ten SNPs was observed (D'>0.8). Haplotype analysis (combination of rs1421085 (T/C), rs17817449 (T/G), and rs8043757 (A/T)) showed that the CGT haplotype is associated with an increased risk of obesity (OR, 2.42; 95% CI, 1.18-4.97; p=0.018) when compared to the reference haplotype (TTA). The SNPs rs1421085, rs17817449 and rs8043757 in the first intron of the FTO gene are associated with increasing risk of obesity in Thais. Copyright © 2014 Elsevier B.V. All rights reserved. PMID: 25542809 [PubMed - indexed for MEDLINE] ------------------ [4] N Engl J Med. 2008 Dec 11;359(24):2558-66. doi: 10.1056/NEJMoa0803839. An obesity-associated FTO gene variant and increased energy intake in children. Cecil JE(1), Tavendale R, Watt P, Hetherington MM, Palmer CN. Author information: (1)Bute Medical School, University of St Andrews, St Andrews, United Kingdom. Comment in N Engl J Med. 2009 Apr 9;360(15):1571-2; author reply 1572. N Engl J Med. 2008 Dec 11;359(24):2603-4. BACKGROUND: Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. METHODS: We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. RESULTS: In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). CONCLUSIONS: The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods. 2008 Massachusetts Medical Society PMID: 19073975
  9. All, One of the initial motivations for studying the possible benefits of the Omega-3s PUFAs DHA & EPA came from observations that the Inuits of Greenland, whose diet contains a very high proportion of polyunsaturated fat from cold-water fish and marine mammals, suffer from relatively low rates of cardiovascular disease. But randomized control trials of the benefits of DHA / EPA supplements for (primary or secondary) prevention of cardiovascular disease have generally been disappointing (e.g. [1]). This new study [2] in Science, might suggest at least part of the explanation for this apparent paradox. That paper used population-genetic analysis of Greenland Inuits to discover regions of two chromosomes that seem to have experienced strong selection in the recent past. Those regions also happen to contain genes involved in fatty acid metabolism; and the variants of the genes that have increased in frequency in Inuits are also associated with small stature and lower weight. From the abstract: By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs. In an accompanying commentary, there is a fascinating map of relatively recent human genetic variations and where they occur around the world (click to enlarge): The one that isn't shown that I find very interesting is the salivary amylase gene (AMY1) for digesting starch. Several studies (e.g. [3]) have found that the number of duplicates of the AMY1 a person has can vary from 2 to about 15 from one individual to the next. The more AMY1 copies you have, the better you are at digesting starch / carbohydrates, and the less prone you are to obesity [3]. Study [4] looked at how the number of AMY1 copies varied between people of different ethnic groups and found a striking correlation between the amount of starch in their ancestral diet and the number of AMY1 copies their genome contained. Here is that result illustrated on a map (click to enlarge): In short, it appears that in cultures whose ancestral diet contained a large fraction of carbohydrates, more copies of the AMY1 gene were selected for since it helped them better process carbs. The bottom line appears to be that there is no "one size fits all" diet that is right for everyone. To some extent at least, the best diet for an individual depends on his/her genes. --Dean -------------------------------- [1] Arch Intern Med. 2012 May 14;172(9):686-94. doi: 10.1001/archinternmed.2012.262. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Kwak SM(1), Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group. Collaborators: Myung SK, Ju W, Oh SW, Bae JH, Kim YK, Park CH, Jeon YJ, Lee EH, Chang YJ, Park SM, Eom CS, Lee YJ, Jung HS, Kwak SM. BACKGROUND: Although previous randomized, double-blind, placebo-controlled trials reported the efficacy of omega-3 fatty acid supplements in the secondary prevention of cardiovascular disease (CVD), the evidence remains inconclusive. Using a meta-analysis, we investigated the efficacy of eicosapentaenoic acid and docosahexaenoic acid in the secondary prevention of CVD. METHODS: We searched PubMed, EMBASE, and the Cochrane Library in April 2011. Two of us independently reviewed and selected eligible randomized controlled trials. RESULTS: Of 1007 articles retrieved, 14 randomized, double-blind, placebo-controlled trials (involving 20 485 patients with a history of CVD) were included in the final analyses. Supplementation with omega-3 fatty acids did not reduce the risk of overall cardiovascular events (relative risk, 0.99; 95% CI, 0.89-1.09), all-cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke. There was a small reduction in cardiovascular death (relative risk, 0.91; 95% CI, 0.84-0.99), which disappeared when we excluded a study with major methodological problems. Furthermore, no significant preventive effect was observed in subgroup analyses by the following: country location, inland or coastal geographic area, history of CVD, concomitant medication use, type of placebo material in the trial, methodological quality of the trial, duration of treatment, dosage of eicosapentaenoic acid or docosahexaenoic acid, or use of fish oil supplementation only as treatment. CONCLUSION: Our meta-analysis showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease. PMID: 22493407 ----------------- [2] Science. 2015 Sep 18;349(6254):1343-1347. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Fumagalli M(1), Moltke I(2), Grarup N(3), Racimo F(4), Bjerregaard P(5), Jørgensen ME(6), Korneliussen TS(7), Gerbault P(8), Skotte L(2), Linneberg A(9), Christensen C(10), Brandslund I(11), Jørgensen T(12), Huerta-Sánchez E(13), Schmidt EB(14), Pedersen O(3), Hansen T(15), Albrechtsen A(16), Nielsen R(17). The indigenous people of Greenland, the Inuit, have lived for a long time in the extreme conditions of the Arctic, including low annual temperatures, and with a specialized diet rich in protein and fatty acids, particularly omega-3 polyunsaturated fatty acids (PUFAs). A scan of Inuit genomes for signatures of adaptation revealed signals at several loci, with the strongest signal located in a cluster of fatty acid desaturases that determine PUFA levels. The selected alleles are associated with multiple metabolic and anthropometric phenotypes and have large effect sizes for weight and height, with the effect on height replicated in Europeans. By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs. Copyright © 2015, American Association for the Advancement of Science. PMID: 26383953 ----------------- [3] Nat Genet. 2014 May;46(5):492-7. doi: 10.1038/ng.2939. Epub 2014 Mar 30. Low copy number of the salivary amylase gene predisposes to obesity. Falchi M(1), El-Sayed Moustafa JS(2), Takousis P(3), Pesce F(4), Bonnefond A(5), Andersson-Assarsson JC(6), Sudmant PH(7), Dorajoo R(8), Al-Shafai MN(9), Bottolo L(10), Ozdemir E(3), So HC(11), Davies RW(12), Patrice A(13), Dent R(14), Mangino M(15), Hysi PG(15), Dechaume A(16), Huyvaert M(16), Skinner J(17), Pigeyre M(18), Caiazzo R(18), Raverdy V(13), Vaillant E(16), Field S(19), Balkau B(20), Marre M(21), Visvikis-Siest S(22), Weill J(23), Poulain-Godefroy O(16), Jacobson P(24), Sjostrom L(24), Hammond CJ(15), Deloukas P(25), Sham PC(11), McPherson R(26), Lee J(27), Tai ES(28), Sladek R(29), Carlsson LM(24), Walley A(30), Eichler EE(31), Pattou F(18), Spector TD(32), Froguel P(33). Comment in Nat Rev Endocrinol. 2014 Jun;10(6):312. Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. PMID: 24686848 ------------------------- [4] Perry, G. H., Dominy, N. J., Claw, K. G., Lee, A. S., Fiegler, H., Redon, R., et al. (2007). Diet and the evolution of human amylase gene copy number variation. [10.1038/ng2123]. Nat Genet, 39(10), 1256-1260.
  10. In my exploration of nutrigenomics, I came across this interesting recent study [1] that looked at the interaction between a particular gene polymorphism (rs4977574 - available on 23andMe) and cardiovascular disease (CVD), as mediated by consumption of either vegetables or wine. The researchers followed 24,000 people for 15 years, during which time about 3000 of them developed cardiovascular disease. So it was a pretty big cohort, with lots of people experiencing the outcome in question - cardiovascular disease. Across the entire population, eating more veggies and drinking more wine resulted in less CVD - not too surprising given previous research on the health benefits of these foods. Things got more interesting when the researchers looked at polymorphisms of SNP rs4977574. Having one or two of the risk alleles (G worse than A) for this SNP on chromosome 9 has been previously shown to be associated with an increased risk of CVD [2]. For example, study [3] found for every G allele one carries, one has about a 13% increased risk of CVD. Study [2] was similar - in the 20-25% of the population that carry two G alleles for this SNP, risk of CVD was increased 30-40% relative to people with AA for rs4977574. This new study [1] found something very similar - for each additional G allele at rs4977574, people were 16% more likely to develop CVD. And these polymorphisms are quite common, ~30% of the study population were AA for rs4977574, 50% were AG, and 20% were GG. But things got really interesting when they looked at how vegetable and wine consumption influenced with the link between this polymorphism and CVD. For people with two 'normal' alleles for rs4977574 (AA), increasing vegetable intake was associated with lower CVD, just like in the population as a whole - no surprise. But for people with either one or two G's for rs4977574, higher vegetable intake didn't help! In other words, compared with high consumers of vegetables who carried two A's for rs4977574 (the reference group), people with AG for rs4977574 were 20-30% more likely to develop CVD, and people with GG for rs4977574 were 40-50% more likely to develop CVD, regardless of how many vegetables they ate! The opposite was true for wine. Wine didn't help reduce risk of CVD in AA carriers for rs4977574, but it did reduce risk in AG and GG carriers, by ~30% and ~40% respectively! In fact, drinking wine appeared to nearly entirely counteract the baseline increased risk of CVD in AG and GG carriers, relative to AA carriers. Here is the relevant table of results from the paper for those interested in the precise details: In summary, this study suggests that if you have one or (especially) two G alleles for rs4977574, you are at higher risk for cardiovascular disease, and that consuming wine, but not vegetables, can help lower your risk. FYI, 23andMe shows I've got one G allele for rs4977574 - which is a bummer since I love veggies and don't drink alcohol. :( Of course its only one study, and one gene locus, so the results should be taken with a grain of salt. I don't plan to eat fewer veggies or take up drinking as a result of this study, particularly since alcoholism runs in my family. I figure my good cholesterol numbers and healthy diet/lifestyle make it unlikely I'll die of CVD anyway. But it seems like another interesting example how genes and diet/lifestyle can interact to influence health in significant and sometimes surprising ways. --Dean ------------------------------------------- [1] BMC Med Genet. 2014 Dec 31;15(1):1220. [Epub ahead of print] The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease: a population based cohort study. Hindy G, Ericson U, Hamrefors V, Drake I, Wirfält E, Melander O, Orho-Melander M. Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331503/pdf/12881_2014_Article_138.pdf AbstractBackgroundChromosome 9p21 variants are associated with cardiovascular disease (CVD) but not with any of its known risk markers. However, recent studies have suggested that the risk associated with 9p21 variation is modified by a prudent dietary pattern and smoking. We tested if the increased risk of CVD by the 9p21 single nucleotide polymorphism rs4977574 is modified by intakes of vegetables, fruits, alcohol, or wine, and if rs4977574 interacts with environmental factors on known CVD risk markers.MethodsMultivariable Cox regression analyses were performed in 23,949 individuals from the population-based prospective Malmö Diet and Cancer Study (MDCS), of whom 3,164 developed CVD during 15 years of follow-up. The rs4977574 variant (major allele: A; minor allele: G) was genotyped using TaqMan® Assay Design probes. Dietary data were collected at baseline using a modified diet history method. Cross-sectional analyses were performed in 4,828 MDCS participants with fasting blood levels of circulating risk factors measured at baseline.ResultsEach rs4977574 G allele was associated with a 16% increased incidence of CVD (95% confidence interval (CI), 1.10¿1.22). Higher vegetable intake (hazard ratio (HR), 0.95 [CI: 0.91¿0.996]), wine intake (HR, 0.91 [CI: 0.86¿0.96]), and total alcohol consumption (HR, 0.92 [CI: 0.86¿0.98]) were associated with lower CVD incidence. The increased CVD incidence by the G allele was restricted to individuals with medium or high vegetable intake (Pinteraction¿=¿0.043), and to non- and low consumers of wine (Pinteraction¿=¿0.029). Although rs4977574 did not associate with any known risk markers, stratification by vegetable intake and smoking suggested an interaction with rs4977574 on glycated hemoglobin and high-density lipoprotein cholesterol (Pinteraction¿=¿0.015 and 0.049, respectively).ConclusionsOur results indicate that rs4977574 interacts with vegetable and wine intake to affect the incidence of CVD, and suggest that an interaction may exist between environmental risk factors and rs4977574 on known risk markers of CVD. PMID: 25551366 --------------------- [2] Science. 2007 Jun 8;316(5830):1488-91. Epub 2007 May 3. A common allele on chromosome 9 associated with coronary heart disease. McPherson R1, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E, Hobbs HH, Cohen JC. Author information AbstractCoronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD. PMID: 17478681 --------------------------------- [3] J Intern Med. 2013 Sep;274(3):233-40. doi: 10.1111/joim.12063. Epub 2013 Mar 25. Chromosome 9p21 genetic variation explains 13% of cardiovascular disease incidence but does not improve risk prediction. Gränsbo K1, Almgren P, Sjögren M, Smith JG, Engström G, Hedblad B, Melander O. Author information AbstractOBJECTIVES:To evaluate the proportion of cardiovascular disease (CVD) incidence that is explained by genetic variation at chromosome 9p21 and to test whether such variation adds incremental information with regard to CVD prediction, beyond traditional risk factors. DESIGN, SETTING AND PARTICIPANTS:rs4977574 on chromosome 9p21 was genotyped in 24 777 subjects from the Malmö Diet and Cancer study who were free from CVD prior to the baseline examination. Association between genotype and incident CVD (n = 2668) during a median follow-up of 11.7 years was evaluated in multivariate Cox proportional hazard models. Analyses were performed in quartiles of baseline age, and linear trends in effect size across age groups were estimated in logistic regression models. RESULTS:In additive models, chromosome 9p21 significantly predicted CVD in the entire population (hazard ratio 1.17 per G allele, 95% confidence interval 1.11-1.23, P < 0.001). Effect estimates increased from the highest (Q4) to the lowest quartile (Q1) of baseline age, but this trend was not significant. The overall population attributable risk conferred by chromosome 9p21 in fully adjusted models was 13%, ranging from 17% in Q1 to 11% in Q4. Addition of chromosome 9p21 to traditional risk factors only marginally improved predictive accuracy. CONCLUSION:The high population attributable risk conferred by chromosome 9p21 suggests that future interventions interfering with downstream mechanisms of the genetic variation may affect CVD incidence over a broad range of ages. However, variation of chromosome 9p21 alone does not add clinically meaningful information in terms of CVD prediction beyond traditional risk factors at any age.
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