Shiro Maeda
Laboratory Head, Laboratory for Endocrinology and Metabolism
RIKEN Center for Genomic Medicine
“Although many studies have been conducted for more than 20 years all over the world in search of genes related to susceptibility to diabetes, most of them can be said to have failed. In the last two years, however, the situation has changed dramatically,” says Shiro Maeda, Laboratory Head in the Laboratory for Endocrinology and Metabolism at the Center for Genomic Medicine of the RIKEN Yokohama Institute. This year Maeda and his colleagues discovered a gene that is closely associated with the development of diabetes in East Asians, including Japanese. Now research is progressing rapidly with the aim of conquering diabetes.
One-third of people aged 40 or older will contract diabetes
According to a survey of diabetes by Japan’s Ministry of Health, Labor and Welfare in 2006, the prevalence of diabetes in Japan is estimated at 8.20 million patients, and 10.50 million people are likely to suffer from the disease in the future. Hence, a quarter of Japanese people aged 40 or older are reportedly affected, either currently or potentially, by diabetes. This ratio is increasing rapidly with the aging of the general population; the latest survey results have shown that the ratio is approaching one-third. Focusing on world trends, the prevalence is increasing dramatically: it is estimated that the number of patients with diabetes will be 380 million in 2025, a 1.6-fold increase compared with the 2005 level of 230 million. To conquer diabetes is one of mankind’s great challenges.
Diabetes is a disease characterized by increased glucose levels in the blood (hyperglycemia). Sugars in ingested food are digested to glucose, which in turn enters the blood circulation and is distributed to cells around the whole body. In this process, a hormone, insulin, is secreted from pancreatic β cells, and stimulates the transfer of glucose into cells, which consume the glucose as a source of energy. If insulin secretion decreases or becomes less effective, the glucose is no longer absorbed into the cells, and instead accumulates in the blood. Thus, the blood glucose level remains persistently high. This is the pathologic condition of diabetes.
If the cellular uptake of glucose ceases, the cells become short of energy, resulting in general dullness and emaciation. Additionally, a prolonged hyperglycemic state damages small blood vessels, which in turn often leads to complications affecting the peripheral nerves, the retina, and the kidneys. In Japan, more than 10,000 people have now become dependent on hemodialysis because of renal disease caused by diabetes (diabetic nephropathy) per year. Diabetic nephropathy ranks first among the various conditions that necessitate hemodialysis.
There are several types of diabetes; type 2 occurs mainly in adults, and accounts for more than 80–90% of all patients with diabetes. Described below are the history and present status of research into the genetics of type 2 diabetes.
Nightmarish times prolonged
As we put on weight or age, we become more susceptible to diabetes. It is also known that accumulation of visceral fat results in the release of a hormone that hampers the effect of insulin on the fat cells.
“However, some people contract diabetes and others do not, even when they become obese or get old. This difference has been attributed to hereditary factors for about 30 years, and research was begun to look for genes related to susceptibility to diabetes. Until very recently, however, no one had been successful in identifying the genes,” says Maeda, looking back on the results of past research.
Type 2 diabetes is not a monogenic disorder (one that develops with a probability of nearly 100% if a mutation is present in a single gene). Maeda continues, “It is thought that whether a person contracts diabetes or not depends on environmental factors, such as obesity and aging, which account for 60–70% of cases, and on hereditary factors, which account for the remaining 30–40%.”
Diabetes is thought to develop when these environmental factors are combined with multiple genes related to susceptibility to the disease. This means that having many diabetes-related genes does not always lead to development of the disease. Genes involved in lifestyle-related diseases, such as diabetes, in which daily habits are significantly involved in the pathogenesis, are more difficult to find than causal genes for monogenic hereditary disorders.
“So far, various genes have been proposed as possibly being related to diabetes. However, none of them have reproduced positive results in confirmatory studies by other researchers. Some researchers in other disciplines have said that there are no genes related to lifestyle-related diseases such as diabetes, so that research on this theme was illogical. Some workers in the same field even advised their colleagues against conducting research into genes related to type 2 diabetes because they considered the subject to be a ‘nightmare.’ Dark times like this have continued for a long time.”
Genome-wide association analysis
“But,” continues Maeda, “the situation has changed dramatically in the last two years. Several genes related to diabetes have been discovered and identified one after another.” What happened?
To find a diabetes-related gene, it is necessary to compare genetic information statistically between a population of patients with diabetes and another without diabetes. Essentially, genetic information is written in the way in which the four bases adenine (A), thymine (T), guanine (G), and cytosine (C) are arranged in the DNA (the base sequence). The entire genetic information for human beings (the human genome) consists of sequences of about three billion bases. In 2003, the human genome project finished decoding almost the whole genome, showing that 99.9% of the base sequences of human genes are common to all people, whereas the remaining 0.1% differ from person to person. This personal variation in the base sequence is called polymorphism. Although there is a wide variety of polymorphisms, the most prevalent are single nucleotide polymorphisms (SNPs) involving only one base (Fig. 2). It is estimated that there are about ten million SNPs in the human genome.
“It is thought that only a small percentage of the polymorphisms influence susceptibility to disease, and efficacy or adverse reaction profiles of drugs. Before about 10 years ago, however, it took one month to examine one SNP in a population of several hundred people.”
The unsuccessful attempts to explore diabetes-related genes were due to the small number of polymorphisms examined and the small population size. To find a diabetes-related gene, it is necessary to conduct a ‘genome-wide association analysis’ to compare polymorphisms over the entire genome between a population of several thousand patients with diabetes and another population of those without. “It was only two years ago that this approach became feasible.”
One hour that changed Maeda’s life as a scientist
While working as a clinical physician for about 15 years before joining RIKEN, Maeda was engaged in research to identify the genes involved in diabetes or diabetic nephropathy.
“When I was a staff member in the Department of Internal Medicine at Shiga University of Medical Science in 1999, all faculty staff members in the department, about ten in all, were requested by the professor to attend a lecture by Yusuke Nakamura, who is currently the Director of the RIKEN Center for Genomic Medicine (CGM). I am ashamed to say that I didn’t know RIKEN or the name Nakamura.”
In those days, Nakamura was working on preparations to establish the SNP Research Center (SRC), the predecessor to CGM, in April 2000, to implement the world’s first research project to examine the entire human genome for SNPs in the search for genes related to lifestyle-related diseases. “I think that Nakamura’s lecture lasted for about one hour. I was overwhelmed by the magnitude of the idea he had to identify disease-related genes by examining all the SNPs in the whole genome at a time when it took one month to check the SNPs at only one site. By the end of the lecture, I had decided to resign from my university post and join the SRC project, although my wife could not understand my decision,” says Maeda with a laugh.
The HapMap Project
When the SRC was founded in 2000, the prevalent opinion was that it was impossible to find the genes involved in lifestyle-related diseases by examining SNPs. In the midst of those circumstances, in 2002, SRC researchers discovered a gene related to myocardial infarction by using the SNP approach. This was the first study in which a gene responsible for a lifestyle-related disease was identified as a result of examining the whole genome. Then the SRC announced the successive discovery of genes involved in other diseases, including rheumatoid arthritis.
These achievements by the SRC moved the world. The HapMap Project was instituted with international cooperation in 2003. So far, about six million SNPs have been found in the human genome. With the conventional approach for examining the whole genome, however, it would take too long and be too expensive to find disease-related genes by comparing all six million SNPs in every subject in a population of several thousand people.
In fact, a more efficient method is available. When a number of SNPs are located close together on the genome, they are inherited as a group. Hence, if an SNP occurs in G, for example, C is always present in a nearby SNP; for an SNP in T, another T is always present in a nearby SNP (Fig. 3). If this relationship is maintained to a certain extent, examining only a representative SNP (tag SNP) will enable the acquisition of information on nearly all SNPs. Then an examination of the tag SNPs in the entire genome will give information about almost all SNPs.
Acquisition of such SNP information was pursued within the framework of the HapMap Project, and this goal was accomplished in October 2005. Now it is thought that nearly all SNPs in the entire genome could be identified by examining 0.5–0.6 million tag SNPs.
The research group in the CGM made a significant contribution to the HapMap Project. “However, it was research groups in Europe and the United States that preceded us in finding diabetes-related genes using the information from the project. They started extensive studies on European and American subjects early, and since then more than a dozen related genes have been reported.” In Japan, the Biobank Japan Project on the Implementation of Personalized Medicine (the Personalized Medicine Project) was launched in 2003 by the Ministry of Education, Culture, Sports, Science and Technology, Japan. Samples have been collected from 0.3 million patients with 47 diseases, and the CGM is responsible for SNP analyses for all of them.
Maeda and his colleagues conducted genome-wide association analyses using the data obtained from the national project, and discovered that the KCNQ1 gene is strongly associated with diabetes. About 20% of Japanese patients with diabetes are estimated to be under the influence of this gene (Fig. 4). Maeda continues, “No other genes have been discovered that are more strongly related to diabetes in Japanese. This is the result of an investigation on a population of several thousand people. Even so, I was unable to feel confident that KCNQ1 is a diabetes-related gene.”
Maeda and his colleagues conducted a joint research project with a Singaporean group and a Danish group, and revealed the association of KCNQ1 with diabetes in subjects in these countries. The association was found to be equally strong in Singaporeans and in Japanese, but less so in Danes. “It is thought that different races have different hereditary factors and hence different mechanisms for the pathogenesis of diabetes. KCNQ1 was identified as a gene closely related to diabetes in East Asians, including Japanese. However, even at that time, I was worried that not all people would accept the identity of KCNQ1 that we had uncovered. Luckily, by chance, at about the same time another research group independently discovered that KCNQ1 is a diabetes-related gene. This was the Team for Diabetes in the Millennium Genome Project under the Ministry of Health, Labor and Welfare. This gave me confidence that people would believe our results.”
Toward personalized medicine
“Our goal is not to find diabetes-related genes,” avers Maeda. “We are working to explore the mechanisms behind the involvement of the related genes in diabetes, and to develop new remedies. Ultimately, we are aiming at personalized medicine, in which therapy and medication are optimized according to the genetic information of individual patients, so that people with a defect in a particular gene can be treated with a selected drug, and those with a defect in a different gene can be treated with an alternative drug.”
The functions of the more than a dozen diabetes-related genes that have been discovered so far have been almost completely clarified. However, it remains unclear how they are related to the disease. For example, KCNQ1, a gene related to the transport of potassium ions through the cell membrane (the potassium channel), is known to have a pivotal role in the muscle cells of the heart. However, nothing is yet known about its association with diabetes.
Maeda hypothesizes that KCNQ1 is involved in the regulation of insulin secretion in pancreatic β cells (Fig. 1), and he is planning to verify this hypothesis.
Even once the mechanism behind the association between a related gene and diabetes has been elucidated, considerable research will be required for the development of a new curative drug based on the mechanism. “However, advances in the elucidation of the mechanism for each related gene will make it possible to explain more clearly the etiology of diabetes on the basis of genetic information from affected patients. Thus the best therapies and drugs could be chosen according to the etiologic profile of each patient. Additionally, the physician will have more power to persuade potential patients with multiple related genes to improve their lifestyles. I want to continue my research with the goal of achieving this kind of personalized medicine within five years.”
In the near future, the results of Maeda’s research into genes involved in lifestyle-related disease will totally change clinical practice.
About the researcher
Shiro Maeda was born in 1960 and is currently Laboratory Head at the Laboratory for Endocrinology and Metabolism, RIKEN Center for Genomic Medicine, where his research area is the genetics of diabetic nephropathy and type 2 diabetes. He received his MD and PhD from Shiga University of Medical Science. He worked as a physician at Koka public hospital and Shiga University of Medical Science for the next three years. From 1993 to 1996 he was a research fellow at the Department of Pathology, University of Michigan, where he studied osmotic response elements within the ALR2 gene. For the next two years he undertook a residency at Shiga University of Medical Science in internal medicine, and emergency and critical medicine. In 1999 he was an instructor for the Third Department of Medicine, Shiga University of Medical Science; he joined RIKEN in the following year as a research scientist in the Laboratory for Genotyping, SNP Research Center. He was a Laboratory Head at Laboratory for Diabetic Nephropathy between 2001 and 2008, and has been in his present post since 2008.
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