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Twelve in one fell swoop – New type 2 diabetes genes

An international team of scientists working on the largest diabetes study to date have found 12 new diabetes genes in around 140,000 Europeans. One of the authors, the endocrinologist Bernhard Böhm from Ulm, considers the findings to be a breakthrough in the research and treatment of type 2 diabetes. The results, which were achieved around a year ago, have now been published in the scientific journal Nature Genetics on the occasion of a congress held by the American Diabetes Society. The new genes bring the total number of genetic regions known to be linked with type 2 diabetes to 38 and Böhm envisages that further genes will soon be identified. Böhm is currently working with colleagues from Oxford to identify subtypes of the disease that lead to early diabetes manifestation.

Dozens of researchers from the USA, Great Britain, Iceland and eight other countries contributed to this elucidation of the genetic causes of type 2 diabetes. The German teams included researchers from Böhm’s group as well as scientists from the Munich-based Helmholtz Centre and the Düsseldorf-based Diabetes Centre. The project was funded through the Baden-Württemberg government (Metabolic Diseases excellence centre) and the USA National Institutes of Health.

Only large numbers provide reliable results

Prof. Bernhard Böhm, diabetes researcher from Ulm © UK Ulm

The newly discovered diabetes genes play a crucial role in the function of insulin-producing beta-cells that regulate the blood glucose level. Moreover, the researchers discovered gene variants that control cell growth. They found that each of the 12 gene variants taken separately had just a minimal effect on diabetes risk. Böhm explained that when combined, the genes' "capacity to predict an individual's personal risk can be considerably increased, especially in people who might develop type 2 diabetes very early."

The newly discovered T2D gene variants are found in the following gene loci: BCL11A (chromosome 2), ZBED3 (chromosome 5), KLF14 (chromosome 7), TP53INP1 (chromosome 8), CHCHD9 (chromosome 9), KCNQ1 (chromosome 10, two signals), CENTD2 (chromosome 11); HGMG2 and HNF1A (both on chromosome 12), ZFAND6 and PRC1 (both on chromosome 15) and DUSP9 (X chromosome).

The large-scale association study included eight diabetes studies. Since diabetes is a polygenic disease, large numbers of patients and data are needed to carry out such a study. Böhm explained that a few thousand data do not provide statistical relevance, but that the large study has provided a "stable statistical basis." Böhm also mentioned that his team will soon have discovered further diabetes gene variants. Böhm's team uses a method known as "deep sequencing" to analyse certain gene regions.

One drug for all – a pharmaceutical dogma has to be revised

Nevertheless, the findings of the "Diagram+" meta analysis have one limitation: they are only valid for Europeans. Böhm highlights that similar investigations in Asia differ from the findings obtained by Böhm and his colleagues in that Asians have different risk profiles from Europeans. This has an effect on medication; it has been found that certain diabetes drugs are ineffective in Asian diabetes sufferers. Böhm believes that individualised therapies that take the situation in the different continents into account would be the correct road to take. However, Böhm also highlights that this finding has not become part of the thinking of the pharmaceutical industry to the degree required as it still continues to develop one drug for all patients. Böhm further explains that genetic doctrines support the notion that food and drugs have different effects in different individuals (interaction between genes and the environment), a finding that is to an increasing extent being taken into account by modern pharmacotherapy.

The researchers were surprised to find a diabetes-associated gene on the X chromosome. This finding might provide initial evidence on the assumed sex-dependent frequency of diabetes. Böhm is quite sure that, depending on X-chromosomal inactivation, the phenomenon represents differently in women. It is known that more men than women suffer from diabetes. English researchers are currently working on the sex-specific differences in the frequency of the disease.

Böhm finds the new gene locus KCNQ1, which was previously known for a very rare diabetes variant, even more remarkable. It seems that something of this rare variant is also present in the general variant, an assumption that, according to Böhm, has sparked a lively discussion as to whether these rare variants may be of much greater importance for the disease as a whole.

It is not only the scientific world that will benefit from these new findings, but patients too. Böhm’s colleagues from the Harvard Medical School and its Department of Epidemiology have developed a model for the predictability of the disease based on the large number of genes that are linked with type 2 diabetes. Böhm explains that for the first time this enables the different effects of diabetes drugs to be predicted to the extent that patients can be spared from associated side effects.

The genes that have been shown to have a link with type 2 diabetes can be divided into different groups: 1) genes that are directly related with the capacity of islet cells, 2) genes that affect the effect of insulin in tissue, and 3) genes that affect cell growth and hence increase an individual’s predisposition to certain tumour diseases.

New understanding of diabetes pathogenesis is breaking the ground

Diagram+ and Böhm’s yet unpublished papers are starting to shake up the traditional understanding of diabetes. “There is growing evidence that the most important thing is the life, survival and function of the insulin-producing cells. This leads to a completely different perception of the disease and the opportunities for treating it in the future.” Previously, therapy focused mainly on increasing the performance of beta cells. Now it is largely assumed that beta cells need to regenerate and develop better fitness through signals such as nutrition and in combination with new medication,” said Böhm.

Off the peg gene analysis?

The twelve newly identified diabetes genes are also associated with other diseases, including cardiovascular and malignant (tumour) diseases. But there is also good news: risk genes for prostate cancer protect people against developing type 2 diabetes. The predisposition to developing type 2 diabetes is inherited, but it must be kept in mind that the pathogenesis of the disease depends on numerous factors. Since genome sequencing is becoming cheaper and cheaper, it might also become as acceptable as in the USA where the majority of people are happy to have their genes analysed and sequenced, without showing any particular interest in qualified genetic counselling.

A breakthrough that actually is a breakthrough

Böhm is not alone in seeing the recently published findings as a breakthrough. Many other researchers and doctors are of the same opinion, which Böhm says can be understood when one considers the background of diabetes genetics. The familiar quotation of the geneticist James Neel (diabetes is a nightmare) is no longer valid. The genetic basis of diabetes is now well known, although this “painful process” (Böhm) only led to success thanks to a discovery by Icelandic researchers a couple of years ago. The Icelandic researchers discovered a transcription factor that could be reproduced by scientists around the world, something that had previously been impossible for any of the diabetes genes. It is also possible to make the therapy more rational due to more accurate subtyping abilities. “This is a breakthrough for a common disease such as diabetes,” said Böhm alluding to another common disease, hypertension, where the situation is the exact opposite.

Voight, B./Scott, L, et. al.: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis, in Nature Genetics
Nature Genetics, Vol. 42, Number 7, July 2010, P. 579ff. (DOI.10.1038/ng.609)

Further information:
Prof. Dr. Bernhard O. Böhm
University Hospital Ulm

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