Severe obesity – a hereditary illness

The first genetic map of obesity has been constructed using DNA microarray technology. This result was published in Nature Genetics on 18 January 2009 by a research group led by CNRS senior researcher Philippe Froguel and Inserm researcher David Meyre from the laboratory “Génomique et physiologie moléculaire des maladies métaboliques”, in association with their British colleagues from Imperial College. This study, run in collaboration with French, Finnish, Swiss, Canadian and German researchers, has led to the discovery of three new genes that increase the risk not only of severe obesity but also ordinary weight gain in the population. It underlines that there is no difference between being overweight and other forms of obesity (mild, severe or massive).

Obesity is spreading throughout the world like an epidemic. For the first time in history, obesity-related health problems (like type 2 diabetes, heart disease and cancer) could reduce the lifeexpectancy of today’s children by several years compared with their parents’ generation. Even though the increase in the number of obese people over the two last decades is partially due to social causes (inactivity, junk food, etc.), heredity plays an important part in determining body weight (70% hereditary) and the occurrence of obesity, especially when this is severe and appears early in life.

Froguel’s team has been working for 15 years to better understand the molecular basis of type 2 diabetes and the obesity found in 80% of diabetics. Their work has revealed several genes responsible for monogenic forms of obesity and has demonstrated the essential role these genes play in appetite control. Since a full map was established of human genetic variations, it has been possible to study all the genes implicated in the genetic predisposition to obesity using DNA microarrays. With joint funding from the ANR, Région Nord Pasde- Calais and the British Medical Research Council, French and British researchers have combed through the complete genomes of 2,796 French volunteers, 1,380 of which had severe familial obesity, compared with 1,416 lean subjects. The genetic mutations most likely to cause obesity were then analysed in 14,000 samples from French, Swiss, German and Finnish populations.

The scientists, led by Froguel and Meyre, first confirmed that the genes FTO and MC4R played a major role in susceptibility to common obesity and weight gain in the population as a whole. These two genes work by controlling eating behaviour.

Three new genes associated with obesity and weight gain identified

The researchers also found variations in the DNA close to the genes MAF and PTER, and directly in the coding sequence of the NPC1 gene. These genetic polymorphisms, widespread in European populations, alter the general population’s risk of severe obesity and weight gain throughout their lifetime. The NPC1 gene has more than 200 pathogenic mutations responsible for Niemann-Pick type C disease, a progressive neurodegenerative condition. Mice without NPC1, and which also have neurological disorders, also lose weight and have no appetite. The mutation associated with obesity could therefore directly induce an increase in the function of the NPC1 protein, such that it would work too well if the gene had mutated. As for the MAF gene, it codes for a particular protein involved in the differentiation of adipose tissue (tissue responsible for fat storage) and in the production of a digestive hormone involved in satiety and insulin secretion. The last gene (PRL) is more particularly associated with obesity and weight gain in adults. PRL produces prolactin, a hormone well known for its effect in stimulating lactation in women. Prolactin also plays a role in controlling the amount of food we consume.

Combined with the genetic approaches conducted on the general population, this work reveals that the study of family forms of obesity is particularly useful for understanding the genetic causes of obesity. They demonstrate the fundamental role of eating behaviour in the regulation and evolution of human corpulence and in the incidence of severe childhood obesity. In the long term these results should allow the early identification of children at risk of obesity and the development of personalised preventive and therapeutic medical strategies.

Six new obesity genes active in brain cells

An international team of scientists with German participation through the Helmholtz Zentrum München identified six new obesity genes. Gene expression analyses have shown that all six genes are active in brain cells.

The international GIANT (Genetic Investigation of Anthropometric Parameters) consortium works on the discovery of obesity genes. So far, the scientists have analysed two million DNA variations in 15 genome-wide association studies with a total of more than 32,000 participants. The hereby identified candidate genes were validated in 14 further studies including 59,000 participants. In addition to the FTO and MC4R genes already known, it was now possible for six more obesity genes to be identified: TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, and NEGR1.

Gene expression analyses have shown that all six genes are active in brain cells. Also the previously known two obesity genes, FTO and MC4R, show a similar expression pattern; in case of the MC4R gene, a genotype-dependant influence on the behavior of appetite is already established. Scientists of the German National Genome Research Network (NGFN), Prof. H.- Erich Wichmann and Dr. Iris Heid from the Helmholtz Zentrum München, Institute of Epidemiology, who lead the German participation of this consortium, emphasise: “Definitely, the two main causes for obesity are poor nutrition and lack of physical activity. But the biology of these genes suggests genetic factors underlying the different reaction of people to lifestyle and environmental conditions.”

With the exception of the SH2B1 gene, which plays a role in the leptin signalling and thus in the regulation of appetite, none of the other five genes was hitherto discussed as obesity genes. Iris Heid and her collegue Claudia Lamina from the Ludwigs-Maximilians- Universität München are enthused: “The purely statistical approach of the genomewide association analysis can depict new aspects of the biology of weight regulation, which were previously unanticipated.”

As a next step, the scientists evaluate other anthropometric measures, in order to shed light on different aspects of obesity. In addition, they will expand and include further studies into their analysis as they have realised that the individual studies are all too small, and only by means of collaboration, is it possible to achieve further success here.

● Willer et al.: Six New Loci Associated with Body Mass Index Highlight a Neuronal Influence on Body Weight Regulation. Nature Genetics 2008. (DOI 10.1038/ng.287)

Gene links circadian rhythm and fasting glucose levels

Is there a relationship between sleep-wake rhythm and diabetes? A new gene variant influences fasting glucose levels via the melatonin metabolism.

An international research team with German participation including Helmholtz Zentrum München, among other institutions, has succeeded in identifying a new gene variant which is associated with elevated fasting glucose levels and a high risk for type 2 diabetes.

The gene mediates insulin secretion indirectly via the release of melatonin, which implicates a previously unknown relationship between the sleep-wake rhythm and the fasting glucose level. The finding could open up new possibilities of treatment which go far beyond the primarily symptomatic therapy approaches to diabetes that have been practised until now.

Diabetes mellitus and diabetes-associated late complications are among the most frequent chronic diseases and causes of death worldwide. Besides lifestyle factors such as overweight and lack of exercise, genetic factors play an important role in the pathogenesis of this disease.

The international MAGIC Consortium (MAGIC = Meta- Analyses of Glucose and Insulin-related traits Consortium) combined the data from 13 case-control studies with over 18,000 diabetic and 64,000 nondiabetic study participants and was able to identify a variant of the MTNR1B gene which is associated with both elevated fasting glucose levels as well an elevated risk for type 2 diabetes. The goal of the MAGIC Consortium is to identify gene variants which regulate the fasting glucose levels in healthy individuals.

The study results were published in the January 2009 issue of Nature Genetics.

The MTNR1B gene is expressed in insulin-producing islet cells, among other cells, and encodes one of the two known melatonin receptors. It is assumed that this receptor inhibits the release of insulin via the neural hormone melatonin. The melatonin level in the body is high at night and declines in daylight, whereas the insulin level is higher during the day than in the night. Taken together, these new data implicate an association between the sleep-wake rhythm, the so-called circadian rhythm, and fasting glucose levels, which was not known previously.

Until now an efficient strategy for prevention and for therapies to treat the cause of the disease has been missing in diabetes research. Further studies will show which role melatonin plays in the regulation of insulin secretion, fasting glucose levels and the development of diabetes and whether this finding will lead to new treatment options.

First data on genetic basis of adverse drug events released

The first data offering healthcare professionals a better look into the genetic basis of certain types of adverse drug events has been released by the US FDA and the International Serious Adverse Event Consortium (SAEC). The data are focused on the genetics associated with drug-induced serious skin rashes, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, and helps better predict an individual’s risk of developing these reactions.

Both skin conditions appear as allergic-like skin reactions associated with blistering and peeling, and are considered life-threatening. Medications causing these serious allergic reactions should be discontinued; and if such signs and symptoms are not quickly recognised, these reactions can be fatal.

“The SAEC has fulfilled a key goal of the Critical Path Initiative by providing the research community with public access to new genomic data on adverse drug events,” said Janet Woodcock, MD, director, the FDA’s Center for Drug Evaluation and Research. “This consortium has taken a significant step forward by promoting open sharing of drug safety data. This type of cooperation has the potential to lead to more personalised approaches to medicine that can reduce a patient’s risk for experiencing an adverse drug event.”

The consortium will publish its initial research results later this year.

● For more information on the International Serious Adverse Event Consortium see
● For information on the FDA’s Critical Path Initiative see 

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