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Do Genetics Explain Variability in Weight-Loss Response to Liraglutide?

sharma-obesity-dna_molecule9As with any medication (for anything!) not everyone responds the same.

Now a small study by Mojca Jensterle and colleagues from Ljubljana, published in the European Journal of Clinical Pharmacology, reports that genetic variability in the GLP-1 receptor gene may predict the variability to the human GLP-1 analogue liraglutide, now approved for obesity treatment in the US, Canada and Europe.

In their study, Jensterle and colleagues examine the realationship between two common alleles (variants) of the GLP-1 receptor in 57 women with obesity and polycystic ovary syndrome.

All women were treated with liraglutide 1.2 mg QD s.c (well under the 3.0 mg QD dose approved for obesity treatment) for 12 weeks.

Twenty of the participants were classified as strong responders (>5% weight loss), who lost about 7.4 Kg, whereas 37 were considered poor responders losing only 2.2 Kg.

Carriers of at least one rs10305420 allele were about 70% less likely to be a high responder than individuals with two wild-type alleles. Similarly, carriers of at least one rs6923761 allele were about three times as likely to high responders compared to homozygous carriers of the wild type.

Although my previous work in these type of genetic studies have made me highly critical (not to say sceptical) of these types of small studies, the notion that genetic variability in the GLP-1 receptor (the molecular target of liraglutide) may well lead to differences in response is not all that far fetched.

Thus, whether true or not, I have little doubt that indeed much of the variability in pharmacological response to liraglutide (or for that matter any other drug for anything) may well be determined by genetics.

Whether testing people for genetic markers before starting a specific treatment will ever become reality for obesity and whether or not, the genetic variability seen in this study will still be seen when lirglutide is used at the actual dose approved for obesity treatment remains to be seen.

In the meantime, the easiest way to see who responds and who does not is to try it. This why the regulatory approval of liraglutide for obesity comes with a simple stopping rule – if it doesn’t work for you – stop taking it!

@DrSharma
Edmonton, Alberta

Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the maker of liraglutide.

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Childhood Cranial Radiation Therapy May Increase Obesity Risk in Adults

sharma-obesity-cancer-cellsAmong all of the possible factors that may contribute to obesity, one that is seldom discussed (and most people are largely unaware of) is surviving cancer.

While this is increasingly being appreciated in adults, data on childhood cancer survivors is rather sparse.

Thus, a study by Carmen Wilson and colleagues, published in Cancer, which follows the development of obesity in individuals treated for cancer as kids is of particular interest.

The study looks at 1996 cancer survivors who previously received treatment for cancer at a large Children’s Research Hospital, who survived ≥10 years from diagnosis (median age at diagnosis, 7.2 years; median age at follow-up, 32.4 years).

Interestingly, 47% of survivors, who received cranial radiation therapy developed obesity compared to only 30% of those who did not.

This risk was greatest in those who also received glucocorticoids or were the youngest at the time of treatment.

The researchers also found a significant modifying effect of genetic markers, some of which are known to be involved in neural growth, repair and connectivity.

Thus, this study shows that survivors of childhood cancer appear to be prone to developing obesity as adults particularly if they were treated with cranial radiation therapy and/or corticosteroids.

Clinicians should be aware of this increased risk and should consider measures to prevent excess weight gain in individuals with a history of childhood cancer.

@DrSharma
Edmonton, AB

ResearchBlogging.orgWilson CL, Liu W, Yang JJ, Kang G, Ojha RP, Neale GA, Srivastava DK, Gurney JG, Hudson MM, Robison LL, & Ness KK (2015). Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. Cancer PMID: 25963547

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When Identical Twins Are Different

Professor Aila Rissanen, University of Helsinki, Finland

Professor Aila Rissanen, University of Helsinki, Finland

This year’s prestigious Fredrich Wassermann Award of the European Association for the Study of Obesity presented at the 22nd European Congress on Obesity goes to Helsinki’s Aila Rissanen, Europe’s grande dame of obesity research.

I have personally known Aila for as lo as I have been involved in obesity and there is much in her work and approach to obesity that has stimulated my own thoughts on this issue.

In her acceptance address, Aila chose to focus on her work in BMI-discordant twins (among the many topics she has worked on) due to the remarkable insights into the “natre-nurture” discussion that this model offers.

Indeed, it is extremely rare to find genetically identical twins, who differ in body weight (demonstarting just how highly heritable body weight actually is). Thus, body weight in identical twins is remarkably homogeneous not only because of the heritability of weight per se but also due to heritability of weight gain.

Cining the work of her wildly successful trainee Kirsi Pietilainen, Aila described the efforts it took to identify just 30 obesity discordant (weight difference of >10 Kg) identical twins from well over 500 identical twin pairs.

These discordant twin pairs have now been extensively phenotyped with every imaginable laboratory test, measurement and tissue biopsies.

The most consistent difference between the discordant twins appears to be a greater level of physical activity in the leaner twin, which appears to precede the onset of weight gain.  In addition to voluntary physical exertion, there also appears to be a significant difference in fidgeting between the twins.

Compared to their co-twins, the obese twins had greater pro-inflammatory lipid profiles, lower antioxident activity and higher pro-coagulation markers. The reasons for these differences remains unclear.

Finally, Aila provided a brief overview of some of the exciting work that is now going on to further study the differences between these genetically identical but obesity disparate twins – metabolomics, lipidomics, epigenomics and even bacteriomics.

Although any of this has yet to translate to better obesity prevention or management, you never know where these fundamental insights into human biology may lead you.

For know, this is certainly a space I intend to watch.

@DrSharma
Prague, Czech Republic

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Environmental Factors Affect the Heritability of Obesity

sharma-obesity-dna_molecule9To anyone, who understands genetics, this heading is simply common sense.

Unfortunately, most people have rather simplistic views of genetics – either you have a gene for disease X and you get it, or you don’t have the gene for disease X and so you’re safe.

In reality, this is not at all how genetics works (with the few rare exceptions of single-gene disorders – and even there is not at all as straightforward as most people imagine).

In fact, whether or not a gene (or group of genes) actually results in a specific phenotype is highly dependent on the environment.

As a simple example: I could be genetically highly predisposed to salt-sensitivity (i.e. having a blood pressure increase on a high-salt diet) – but unless I am actually exposed to a high-salt diet, I can go my entire life without ever developing high blood pressure.

This is pretty much the case for all complex (and even some single-gene) disorders – it is only when you put the susceptible “disease gene(s)” in the wrong environment, that the gene does what it does. This is why most “nature vs. nurture” debates lead nowhere – it is virtually never one OR the other – it is mostly BOTH!

A good example of how changing environments may be important when studying the genetics of diseases is suggested in a new study by James Niel Rosenquist and colleagues, published in the PNAS.

The researchers examines the association between the FTO gene and BMI using longitudinal data from the Framingham Heart Study collected over 30 y from a geographically relatively localized sample in the US.

What they found was that the well-documented association between the rs993609 variant of the FTO (fat mass and obesity associated) gene and body mass index (BMI) varies substantially across birth cohorts, time period, and the lifecycle, with a apparently increasing impact of this gene for those born after 1942.

As the authors point out,

“Such cohort and period effects integrate many potential environmental factors, and this gene-by-environment analysis examines interactions with both time-varying contemporaneous and historical environmental influences.”

Thus,

“These results suggest genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance.”

In other words, as the environment changes, certain genetic “phenotypes” may become more (or less) common.

It is however important to remember in this context that the term “environment” is rather broad and may include biological drivers that include changes in the epigenome, bacteriome or even virome, all of which will have substantially changed over time (and continue to change as we we speak).

On a more practical level, this is also why genetic testing for complex genetic diseases (and so-called “personalized” medicine) will likely be nothing more than a pipe dream and a money grab, at least for the foreseeable future.

@DrSharma
Edmonton, AB

ResearchBlogging.orgRosenquist JN, Lehrer SF, O’Malley AJ, Zaslavsky AM, Smoller JW, & Christakis NA (2015). Cohort of birth modifies the association between FTO genotype and BMI. Proceedings of the National Academy of Sciences of the United States of America, 112 (2), 354-9 PMID: 25548176

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Social Network Analysis of the Obesity Research Boot Camp

bootcamp_pin_finalRegular readers may recall that for the past nine years, I have had the privilege and pleasure of serving as faculty of the Canadian Obesity Network’s annual Obesity Research Summer Bootcamp.

The camp is open to a select group of graduate and post-graduate trainees from a wide range of disciplines with an interest in obesity research. Over nine days, the trainees are mentored and have a chance to learn about obesity research in areas ranging from basic science to epidemiology and childhood obesity to health policy.

Now, a formal network analysis of bootcamp attendees, published by Jenny Godley and colleagues in the Journal of Interdisciplinary Healthcare, documents the substantial impact that this camp has on the careers of the trainees.

As the analysis of trainees who attended this camp over its first 5 years of operation (2006-2010) shows, camp attendance had a profound positive impact on their career development, particularly in terms of establishing contacts and professional relationships.

Thus, both the quantitative and the qualitative results demonstrate the importance of interdisciplinary training and relationships for career development in obesity researcher (and possibly beyond).

Personally, participation at this camp has been one of the most rewarding experiences of my career and I look forward to continuing this annual exercise for years to come.

To apply for the 2015 Bootcamp, which is also open to international trainees – click here.

@DrSharma
Toronto, ON

ResearchBlogging.orgGodley J, Glenn NM, Sharma AM, & Spence JC (2014). Networks of trainees: examining the effects of attending an interdisciplinary research training camp on the careers of new obesity scholars. Journal of multidisciplinary healthcare, 7, 459-70 PMID: 25336965

 

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