Genetics of diabetes and obesity
In this lecture, Professor of Epidemiology, Director of the Center for Epidemiology Cambridge University's Nick Warham talks about the genetic prerequisites of diabetes.
Type 2 diabetes and obesity are two related health conditions. The question is what connects them. One hypothesis is that they may be related by a single genetic predisposition. It has long been known that obesity, which we characterize as excess fat and measure by the presence of excess body weight (the ratio of weight divided by height squared; body mass index greater than 30), and type 2 diabetes mellitus are disorders associated with chronic hypoglycemia. It is known that both of these conditions are more common among members of the same family. We also know from studies of twins that the heritability of both diseases is about 50%. The question is what is the molecular basis of this phenomenon.
Progress in unraveling the molecular basis consisted in the study of extreme phenotypes – monogenic conditions that have more autosomal dominant inheritance patterns. In the case of diabetes, the main focus was on forms of diabetes that looked like type 2 diabetes, but manifested in early adulthood and had autosomal dominant inheritance patterns in the family. This led to the emergence of the concept of MODY-diabetes (adult-type diabetes mellitus in young people). Modern genetics has divided these ailments into several subtypes. The importance is not only that it gives people the opportunity to make a diagnosis, but also that it helps to unravel the pathogenesis pathways. But most importantly, it allows us to personalize the treatment. In some forms of MODY diabetes, patients got better from certain types of glucose-lowering treatment.
In the case of obesity, the determination of monogenic forms of obesity was slower. My colleagues from the Institute of Metabolism Research in Cambridge were looking for families with children with very early and severe forms of obesity. The first gene that was found was the leptin gene. Leptin is a key hormone that is involved in the mechanisms of satiety and hunger suppression. Children who had leptin gene mutations had uncontrolled appetite and severe early obesity. And this is as important as MODY-diabetes, because it allowed not only to make a diagnosis, but also to come up with a therapy for the treatment of these children. The replacement of leptin made it possible to overcome the problem of overeating and obesity. The children who participated in this study had a much more normal physique. The key question here is whether we can apply the results of studies of such monogenic diseases to human metabolism in general and its diseases, whether they can find application to the majority of people who do not have such rare forms of diabetes and obesity. This is an important task facing science, and it has become a scientific practice only with the development of appropriate technologies. We have the opportunity to characterize variations in the genome thanks to developments in genotyping and global collaboration of consortia around the world, as well as by obtaining the results of several very large-scale population studies of people with obesity and diabetes. It was this combination of technology and global collaboration that made it possible to understand the disease.
About a hundred genes associated with diabetes are now known. It all started with the TCF7L2 gene, which affects insulin secretion. This gene was identified by positional cloning, and not by that form of mass genotyping, which we call the search for genomic associations. This was followed by the identification of a number of other genes. Progress in obesity research has been achieved differently. The first gene that was found was the FTO gene. It was found by British scientists by a genome-wide association search. Then other obesity genes were found. The second gene was MC4R. My colleagues from Cambridge found out that it is associated with obesity. As for diabetes, there are now about a hundred genes that are associated with obesity.
Both with obesity and diabetes, the question arises: how did understanding genetics help us? I think it helped us in several ways. This fueled other studies that led scientists to think about how genetic associations are related to pathogenesis and disease. In the case of FTO and obesity, it was a difficult scientific journey. We still haven't figured out what the biological link is between FTO and obesity.
As for diabetes and hypoglycemia, we have learned a lot from studies of genetic associations. For example, we learned that the melatonin receptor gene is associated with hypoglycemia during fasting. Then new studies began, during which we tried to find links between melatonin, circadian rhythms and blood glucose control. But, in addition to simply transferring information from genetic associations to biology, understanding these things has helped science in other directions. First of all, it helped to set precise goals. In the case of diabetes, we found a set of drugs that affect the GLP1R receptor. There is a therapy for diabetes that affects both diabetes and obesity. But before it was not known whether it carries any complications, including on the heart. Genetic changes in the GLP1R receptor are associated with a decrease in blood glucose levels, and it can also be proved that they are associated with a lower risk of heart disease. This form of genetic epidemiology can help the pharmaceutical industry find the right targets for medical intervention and identify possible long-term complications. This is important because the cost of drug development and late detection of side effects is too high.
Another area in which genetics can help is the search for cause-and-effect relationships. In epidemiology, many factors are associated with any consequences, but it is impossible to say for sure whether they are causes or they are only indirectly related to the consequences. This is a problem that is inherent in population research, and it is impossible to approach it from the point of view of analysis, however, genetic changes can be used to simulate randomized controlled trials in a process called Mendeleev randomization. If you can find a genetic variant that is associated with an intermediate trait, it is unlikely to be an indirect factor, because this trait is present from birth and throughout life the body interacts with this biomarker. You can use genetics to try to find the causes of diabetes. This may sound very technical, but it is very important because it can help us focus on the pathways of diabetes that are more likely to be the causes, and it can also help us avoid wasting time developing interventions in the pathways of diabetes that are not causal.
Another question is whether ideas about genetics can help us in the framework of personalized prevention and treatment? At the very beginning, I said that the monogenic effects of diabetes and obesity led to personalized treatment. At the moment, there is no evidence that understanding common genetic variants will lead to improved therapy, stratification, or personalized prevention. This is not to say that this is not possible in the future. It's just that the level of our understanding does not imply that people can be divided into certain subgroups, which are characterized by the presence of certain genes for obesity and diabetes. The data set that exists now suggests that all people should try not to gain weight, lead an active lifestyle and eat right. And these are not just preventive measures that are necessary for certain genetic subgroups.
The scale of research that is needed to find the genetic basis of diabetes and obesity is really huge. In one of the papers we wrote on this topic in 2003, we compared 500 people with diabetes, 500 people without diabetes, focusing on 73 single-nucleotide polymorphisms. The studies that we are conducting now are considering hundreds of thousands of people, and now we are not considering 73 single-nucleotide polymorphisms, but about half a million, and then we will consider 10 million. These are studies that will last for the next 10-15 years. Therefore, the scale of the efforts and research carried out, as well as the depth of genetic information, have grown exponentially.
Type 2 diabetes is spread unevenly around the world. One of the main questions is whether our understanding of genetic changes is a tool with which to understand global differences in the prevalence of conditions? The short answer is no, because the general variance, which we most often study when looking for genomic associations, is natural for all populations. There are traditional, old genes that may have appeared before the exodus from Africa. Genetic differences between populations and probably differences in diabetes risk are explained by recent genetic changes. They are rarer and may be inherent in certain populations. This is quite a difficult task. Now there is progress among research groups studying isolated populations. They were able to find rare genetic changes that cause disease in populations. For example, in the population of Greenland there is a gene that affects the two-hour blood glucose level and the glucose level during fasting. But this variant of the gene was actually found only in the Greenland population. This has contributed to biology, but in terms of explaining the diversity of the disease in different populations, we are still only at the beginning of the path.
About the author: Nick Wareham – Professor of Epidemiology, Director of the MRC Epidemiology Unit and co-Director of the Institute of Metabolic Science, University of Cambridge.
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16.12.2016