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Entries in genetics (23)

Wednesday
Aug232017

Journal club: The effect of gender (not sex!) on the genome

One of my pet peeves is when scientists use "gender" (i.e., identity) when they actually mean "sex" (i.e., anatomy). It is typically done to avoid embarrassment, but it is imprecise, and the difference can be important. The short-cut for gender vs sex is usually "sex is biological, gender is cultural", but this short-cut is also wrong, since culture can impact on biology.

Take this Nature Genetics paper, from the Gibson lab. They looked at eQTLs in human blood, which is basically the effect of genetic variation on gene expression. The study was performed on Berbers in Morocco, in both a modern urban setting and a traditional rural setting:

 

When looking at gene expression changes in men and women from urban areas (green and blue, below), there is basically complete overlap between men and women. However when you look at the rural traditional areas, with strict cultural separation of men and women (red, below), there is almost complete separation between the men and the women at the transcription level.


In short, men and women are biologically different only because of the gender roles imposed in the rural setting! The social construct of gender can actually substantially change our biology. A good reminder that whenever we see an effect in humans that we think is due to sex, we need to remember that it could actually be an impact of imposed culture.

Read the full paper: Idaghdour et al, "Geographical genomics of human leukocyte gene expression variation in southern Morocco", Nature Genetics 2010. 42(1):62-7

Thursday
Jun082017

MutaMouse is open!

MutaMouse, our new genome engineering Core Facility, is now open! Come talk to us about making KO or KI mice for you!

Tuesday
May092017

MutaMouse Core Facility

Visit our website and found out what we can do for you!

Friday
Sep162016

Understanding variation in the human immune system

My talk from the recent Eppendorf Young Investigator Award ceremony on variation in the human immune system.

Tuesday
Aug302016

Journal club: Genetics breaks the relationship between obesity and diabetes

Samoans tend to be physically large people, with a very strong build in addition to being at high risk for obesity. More than 50% of Samoans are obese, one of the highest rates in the world. A recent paper in Nature Genetics mapped this susceptibility to obesity to a mutation in CREBRF (p.Arg475Gln), which is common in Samoans and very rare in the rest of the world. This gene is extremely potent, the strongest obesity-causing polymorphism yet found.
Samoans also have one of the highest rates of type 2 diabetes in the world, so it is very easy to point a finger and assume that CREBRF causes both obesity and diabetes. Intruigingly, this is wrong - CREBRF (p.Arg475Gln) drives obesity but actually protects against diabetes! 

Increasingly, the theoretical correlation between BMI and diabetes seems to be breaking down. China is having both an obesity and diabetes epidemic, with the transition to a Western diet, but in China there is essentially no correlation between BMI and diabetes. It is starting to look as if diet drives these two phenomenons independently, and diabetes is not simply a consequence of obesity.

Read the article: Minster, R.L. et al. 'A thrifty variant in CREBRF strongly influences body mass index in Samoans'. Nature Genetics 4810491054 (2016).
Tuesday
Jul122016

The Genetic Components of Rare Diseases

Last fall, the conclusion of the 1000 Genomes Project revealed 88 million variants in the human genome. What most of them mean for human health is unclear. Of the known associations between a genetic variant and disease, many are still tenuous at best. How can scientists determine which genes or genetic variants are truly detrimental?

Patients with rare diseases are often caught in the crosshairs of this uncertainty. By the time they have their genome, or portions of it, sequenced, they’ve endured countless physician visits and tests. Sequencing provides some hope for an answer, but the process of uncovering causal variants on which to build a treatment plan is still one of painstaking detective work with many false leads. Even variants that are known to be harmful show no effects in some individuals who harbor them, says Adrian Liston, a translational immunologist at the University of Leuven in Belgium who works on disease gene discovery.

...

Read more in The Scientist

Monday
Apr042016

Nature research highlight

Thursday
Mar312016

Decennia-oude, mysterieuze ziekte ge├»dentificeerd en mogelijke behandeling gevonden

Een mysterieuze ontstekingsziekte teistert al drie generaties lang een Vlaamse familie met ernstige huidletsels, koorts, pijn en uitputting. De ziekte, waarvoor men tot nu toe geen oorzaak of behandeling had gevonden, is nu geïdentificeerd als pyrine-geassocieerde auto-inflammatie met neutrofiele dermatose (Pyrin Associated Autoinflammation with Neutrophilic Dermatosis, afgekort PAAND), en werd ook vastgesteld bij families in Engeland en Frankrijk. In een nieuw onderzoek hebben Adrian Liston (VIB/KU Leuven) en Carine Wouters (UZ Leuven/KU Leuven) de genetische mutatie ontdekt die de ziekte veroorzaakt, en ook een doeltreffende behandeling gevonden. Hun onderzoek werd gepubliceerd in het internationale wetenschappelijke tijdschrift Science Translational Medicine.

Al decennia lang kampen families in België, Engeland en Frankrijk met een mysterieuze ziekte die huidletsels, koorts, pijn en uitputting veroorzaakt. Elke generatie krijgt de helft van de kinderen van personen die de ziekte hebben, dezelfde symptomen. Artsen waren er niet in geslaagd de ziekte te identificeren of een doeltreffende behandeling te vinden. Nu is de identificatie eindelijk een feit en is dankzij een internationaal onderzoeksteam ook een behandeling gevonden. 

Prof. Adrian Liston (VIB/KU Leuven, hoofd van het wetenschappelijk onderzoeksteam): “Dankzij het nauwgezette werk van de artsen weten we nu dat we te maken hebben met een erfelijke aandoening. Dankzij de vooruitgang in de DNA-sequentietechnologie konden we het genoom van deze patiënten bepalen en de mutatie opsporen die de ziekte veroorzaakt.”

Het gaat om een mutatie in het MEFV-gen. Mensen die van hun beide ouders een MEFV-gen met een mutatie overgeërfd hebben, lijden aan de ontstekingsziekte familiaire mediterrane koorts (FMF), een ontstekingsziekte. Bij PAAND-patiënten gaat het echter om een andere mutatie in het MEFV-gen én is één enkele kopie van de mutatie voldoende om de ziekte door te geven. Dit betekent dat de helft van de kinderen van de patiënten de ziekte overerven, in tegenstelling tot de mutaties die FMF veroorzaken (die vaak een generatie overslaan). De PAAND-mutatie zorgt ervoor dat het lichaam reageert alsof er een bacteriële huidinfectie plaatsvindt. Daardoor gaat de huid het ontstekingseiwit interleukin-1β produceren, dat huidletsels, koorts en pijn veroorzaakt. 

Een behandeling voor de nieuwe ziekte?
Dankzij het opsporen van de biologische oorzaak van deze ziekte kon men ook een nieuwe behandeling bepalen. De onderzoekers hergebruikten anakinra (Kineret ®), een middel tegen artritis dat zich richt tegen interleukin-1β, dat ook bij PAAND een belangrijke rol speelt. De resultaten bij een eerste patiënt, uit een Engels gezin, waren opvallend positief. De huidletsels verdwenen snel en de patiënt herstelde helemaal van de koorts en de pijn. Op dit moment wordt een uitgebreidere test uitgevoerd bij Vlaamse patiënten, om te zien of deze gerichte behandeling tot een volledige genezing kan leiden.

Prof. Carine Wouters (KU Leuven/UZ Leuven, hoofd van het klinische onderzoeksteam): “Dit is het resultaat van een intense samenwerking tussen artsen en wetenschappers die al bijna tien jaar de ziekte trachten te begrijpen. Ik ben verheugd vast te stellen dat we deze zeldzame mutatie nu beter begrijpen en dat we voor deze patiënten de weg hebben geopend naar een doeltreffende therapie.”

Citaat van een patiënt: “We zijn blij en heel dankbaar dat de artsen en wetenschappers hun zoektocht naar de oorzaak van de ziekte die onze familie al zo lang treft, nooit hebben gestaakt. We hopen dat de nieuwe behandeling gunstig zal zijn voor onze familie. En we beseffen ook dat de bevindingen andere patiënten zullen helpen om een correcte diagnose en behandeling te krijgen.”

Prof. Adrian Liston (VIB/KU Leuven, hoofd van het wetenschappelijk onderzoeksteam): “Dit is een uitzonderlijke periode voor het onderzoek rond erfelijke aandoeningen. We helderen elke maand klinische gevallen op die enkele jaren geleden nog niet op te lossen waren. We ontdekken nieuwe mutaties en beschrijven nieuwe ziektebeelden en ziektemechanismen waarvoor ook nieuwe werkzame geneesmiddelen kunnen worden voorgeschreven. Patiënten komen daardoor soms in moeilijke situaties terecht, waarbij de wetenschap een oplossing kan bieden, maar de ziekteverzekeringen de kosten voor geavanceerde diagnosetests of nieuwe behandelingen nog niet kunnen terugbetalen. Dit vormt dan ook een uitdaging voor zowel de farmaceutische industrie als de overheid. Zowel nieuwe medicijnen als bestaande medicijnen voor nieuwe indicaties dienen ter beschikking worden gesteld van patiënten die – op basis van genetische testen – zeer goed kunnen gedefinieerd worden. 

Prof. Carine Wouters en prof. Adrian Liston hebben het Leuven Universiteitsfonds Ped IMID (Pediatrische Immuun-inflammatoire aandoeningen) opgericht, een waarmee ze middelen willen werven om onderzoek, diagnose en behandeling mogelijk te maken voor personen die lijden aan zeldzame immuunziekten die momenteel niet door de ziekteverzekeringen worden gedekt.

 

Ook gelezen: De Staandard, Het Laatste NieuwsHet Nieuwsblad, De Morgan

Wednesday
Mar302016

Decades-old mystery disease identified and potential cure found

A mysterious inflammatory disease has been afflicting a Flemish family for three generations, causing severe skin lesions, fevers, pain and exhaustion. This disease, which previously had no known cause or cure, has now been identified as Pyrin Associated Autoinflammation with Neutrophilic Dermatosis (PAAND), and has also been found in families in England and France. New research by Adrian Liston (VIB/University of Leuven, Belgium), Seth Masters (Walter and Elisa Hall Institute, Australia), Carine Wouters (University of Leuven, Belgium) has found the genetic mutation causing the disease and also identified an effective treatment. This research was published in the international scientific journal Science Translational Medicine.

For decades, families in Belgium, England, and France have been living with a mysterious disease that results in skin lesions, fevers, pain and exhaustion. Every generation, half of the children of the people with this disease develop the same symptoms. Doctors had been previously unable to identify the disease or find any effective treatment. For the first time, this disease has been identified and a treatment found due to an international research team.

Professor Adrian Liston (VIB/University Leuven): “Detailed work by clinicians told us that we were dealing with a genetic disease. Thanks to advances in DNA sequencing technology we were able to sequence the genome of these patients and find the mutation causing the disease”.

The mutation is in the gene called MEFV. This gene was known to cause an inflammatory disease called Familial Mediterranean Fever (FMF) in patients who inherit mutated copies from both mother and father. However, the mutation found in the PAAND patients is different. Only a single copy of the mutation is needed to cause disease, meaning it affects half the children of patients, unlike the mutations that cause FMF, which often skip generations.

Professor Seth Masters (Walter and Elisa Hall Institute): “The PAAND mutation causes the body to as if there is a bacterial skin infection. This leads to the skin making the inflammatory protein interleukin-1β, which causes skin lesions, fevers and pain”.

A cure for the new disease?

Understanding the biological basis for this new disease allowed the rational selection of a new treatment. The researchers repurposed an anti-arthritis drug, anakinra, which targets the same protein that causes PAAND, interleukin-1β. The results in the first volunteer, from an English family, were striking, with a rapid clearance of skin lesions and a complete recovery from fevers and pain. A larger trial is now beginning in the Flemish patients to see if this targeted treatment will act as a complete cure.

Professor Carine Wouters (KU Leuven/UZ Leuven, lead clinical researcher): “This is the synthesis of an intense collaboration between clinicians and scientists trying to understand this disease for almost 10 years.  I am delighted to see how it has increased our understanding of rare mutations, and especially has opened a therapeutic perspective for these patients.”

Quote from one of the patients: “We are happy and very grateful to the doctors and scientists who never gave up their search to understand the disease that affected members of our family for so many years. We are very hopeful that the new treatment will be beneficial to our family. Also we realize that the findings will help other patients to get a correct diagnosis and therapy.”

Professor Adrian Liston (VIB/KU Leuven, lead scientific researcher): “This is an amazing time to be working on genetic diseases. Every month we are solving clinical cases that would have been too hard to work out just a few years ago. Actually, to be honest the research is moving much faster than the healthcare system – we are finding new mutations, new diseases and trialling new treatments faster than the healthcare system is adapting. It creates a difficult situation for patients where the science is in, but the health insurance funds are not ready to reimburse the costs of the advanced diagnostic tests we use or novel treatments that we discover. This is a challenge, but also an opportunity – medical improvements could be rolled out quite quickly with political will.”

Professors Carine Wouters and Adrian Liston have established the charity Ped IMID to seek funding for research, diagnosis, and treatment of people living with rare immune disorders not currently covered by the health insurance funds. 

To read more, go to our article in Science Translational Medicine:

Masters, Lagou, Jéru, Baker, Van Eyck, Parry, Lawless, De Nardo, Garcia-Perez, Dagley, Holley, Dooley, Moghaddas, Pasciuto, Jeandel, Sciot, Lyras, Webb, Nicholson, De Somer, van Nieuwenhove, Ruuth-Praz, Copin, Cochet, Medlej-Hashim, Megarbane, Schroder, Savic, Goris, Amselem, Wouters* and Liston*. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Science Translational Medicine. 2016 in press.

Sunday
Mar272016

Yes, diabetes is a genetic disease

With the publicity of our recent Nature Genetics paper, I have been discussing diabetes with many journalists. Almost without exception they seem surprised that I call diabetes a genetic disease - and they are not alone - even among the medical community it is standard to (incorrectly) call diabetes a lifestype disease.

The genetic basis for diabetes has been long established. It really is a shame that diabetes is so often called a "lifestyle disease". It isn't. 50% of the susceptibility to type 1 diabetes is genetic, and 70% of the susceptibility to type 2 diabetes is genetic.

Most of the remainder of the susceptibility is environmental. For example, certain types of dietary fat, such as palmitate, increase the fragility of beta cells. It is quite plausible that much of the increase in diabetes incidence in the past decades is due to changes in diet that make our beta cells more fragile. But even when we are talking about dietary factors, I think it is important to recognise that much of the effect is environmental rather than lifestyle. "Lifestyle" is easy to dismiss by blaming the patient for their own choices. Calling diabetes a lifestyle disease is one of the reasons that research and medical advances in diabetes are lagging behind, and the stigma contributes to the ill effects of diabetes (e.g., increased risk of depression, more antagonistic relationships between patients and clinicians). Recognising diet as an environmental factor takes away this stigma, is more accurate and allows us to tackle the problem using public health approaches. For example, some of the highest rates of diabetes are in the poorest neighbourhoods of America. In these areas, junk food is cheap and available everywhere, while good food is simply not practical - it is rare, expensive and takes more time to prepare than many poor families have. Likewise, the neighbourhoods may not provide the physical infrastructure that allows for a mobile lifestyle (parks for kids, urban design that promotes walking, etc). It is not a "lifestyle choice" to live in these diabetogenic environments, but it is a public policy choice to allow these environments to exist.

To really tackle the diabetes epidemic we need to recognise that the root cause is not in personal choices made by individuals. The root cause is in the social structure that we have created, in the urban design of cities, the changes in food culture, the demands placed on our time. We have made unhealthy lives the easiest to live. We can either ask individuals to make heroic efforts to overcome these obstacles to a healthy lifestyle, or we can use public policy to make our food environment and urban environment more healthy. Some of these policy changes would be immediate and easy (e.g., changing the tax structure to make good foods cheaper and junk food more expensive, or regulating the removal of the most toxic components of junk food). Other policy changes will take generations - even if we require urban planning to take into account healthy lifestyle promotion, the turnover in infrastructure is so slow that it will take a long time to occur. We certainly need major medical advances, which hopefully our study will aid, because the social changes needed will take decades to fully implement. But that is no reason not to start the public policy debate now, and even the small first steps will save the lives of millions (as well as saving billions from health care budgets).