Novo Nordisk Foundation Symposium: Jacobæus award and lecture

Novo Nordisk Foundation

Symposium: Jacobæus award and lecture

Genomics of diabetes–What’s next?

The head of the KG Jebsen Center for Diabetes Research, Prof. Pål R. Njølstad inaugurated the symposium by awarding the Jacobæus award to Prof. Mark McCarthy. The prize is given annually by the Novo Nordisk Foundation to a distinguished international researcher, and is worth DKK 100,000. McCarthy was recognized for his exceptional scientific contribution to the field of Genomics of Diabetes, his profound insights, efforts in knowledge sharing and outstanding leadership of international research consortia, such as ENGAGE, DIAGRAM, T2DGENES, GoT2D, MAGIC, GIANT and EGG.

Mark McCarthy, University of Oxford

The prize winner first introduced the dramatic figures of the diabetes epidemic, as well as the high variety of associated genomics profiles, highlighting the need for global variant studies. His review of ambitious genome-wide association studies (GWAS) analyses showed the discovery of around 100 loci associated with T2D, mostly common variants where the allelic effect is small and a strong transethnic concordance is observed. He underlined that our understanding of the mechanisms inducing T2D in relationship with these variants is limited. McCarthy therefore encouraged the field to move towards functional analyses, and take full advantage of in vivo physiology and iPS-cell models as well as multiple omics characterization techniques. Finally, he insisted on the complexity of the pathology, and especially stressed the importance of co-occurring diseases, hinting at the conjugation of multiple intricate mechanisms. The prize winner envisions that such complexity can only be captured by global population wide studies accounting for the dynamics of the disease over life. He consequently invites the members of the scientific community to coordinate their forces in the worldwide, and especially open, share, and reuse their data freely.

Valeriya Lyssenko, Steno Diabetes Center

T2D is accelerating among children and adolescents from 3 % of childhood diabetes in 2004 to 45 % in 2014. Many of these children have relatives with T2D. Prof. Valeriya Lyssenko gave an exciting talk on the meta-analysis of prospective cohorts and the following increase in susceptibility loci has improved the genetic prediction of T2D. However, she demonstrated that genetic predictors still lack separation power. Thus there is a need for better stratification and categorization of patients. Several studies also indicate that the disease outcome depends on which parent the risk factor is inherited from. Lyssenko also discussed studies where malnutrition in pregnant women gave rise to increased risk for T2D and complications. Some protective variants are also involved in the etiology of diabetes. In a Scandinavian investigation, results show that some individuals in the T1D cohort sustain a better lipid profile and have fewer complications such as early retinopathy and nephropathy. The further study of these cohorts could lead to the identification of protective genes against complications and thereby help in prognosis and treatment.

Camilla Stoltenberg, Norwegian Institute for Public Health

Camilla Stoltenberg, director of the Norwegian Institute of Public Health, discussed the unique resources available from Norwegian and Scandinavian extensive registries in her presentation entitled «When the whole country is a cohort – Scientific opportunities in Norwegian registries, cohorts and biobanks». Norway has 16 mandatory nation-wide registries and over 50 clinical registries, healthcare registries in addition to social, demographic, economic, etc. registries – some of which populated since 1951 – that can be linked via a unique personal identifier: the social security number. Several longitudinal studies are ongoing: HUSK, HUNT, HUBRO, Tromsø-studien, Conor and MoBa. In the latter, biological samples and questionnaires from over 500,000 participants (10% of the Norwegian population) were gathered from 1999 to 2009. Stoltenberg also presented the program Health&Care21, which is a national process aiming at developing a national research and innovation strategy on healthcare for the 21^st century in Norway. The Health&Care21 strategy process was launched by the Ministry of Health and Care Services in 2013. She highlighted the challenges in accessing data from these repositories and raised the need for better sharing and dissemination procedures. She also pointed out that the uniqueness of the Scandinavian registries makes it challenging to replicate findings and confront them with data from other countries. Thus, she encourages international cooperation and coordination. Among the other challenges faced, she mentioned the data fragmentation between institutions as well as the time and money costs induced by permission requests and other administrative duties. National efforts in streamlining data handling will alleviate these problems and harmonization within Scandinavia already enables pioneer international collaboration.

Matthias Blüher, University of Leipzig

Blüher gave an overview of his group's research on pathogenesis related to obesity and body fat distribution. He presented three overarching research questions: 1) Why do many people easily develop a positive energy balance? 2) How does a calorie know where to deposit itself? 3) How does increased fat mass cause organ dysfunction. Blüher and his group have established a large biobank including persons with a body-mass index (BMI) between 13 and 129 (!) and BMI-matched insulin sensitive and insulin resistant obese. An important finding is that obese people who are insulin sensitive show lower maximal and mean adipocyte size in visceral adipose tissue, and are almost entirely protected against inflammation. Blüher also discussed cytokines and other circulating factors that correlate strongly with visceral fat accumulation and inflammation, including RBP4, vaspin, proranulin and chemerin.

Torben Hansen, University of Copenhagen

Type 2 diabetes rates are alarmingly high among the Inuit people. Following a long tradition of Scandinavian exploration, Danish researcher Torben Hansen and his team ventured into the Artic, seeking out a genetic cause for the rising rates. Their efforts lead to the discovery of a variant in the gene TBC1D4, common only among the Inuit people. Further studies have shown that the protein variant alters insulin stimulation via intracellular interaction with GLUT4 vesicles, providing critical insights on the mechanism of type 2 diabetes. Hansen’s team is now exploring the evolutionary significance of common Inuit variants in respect to human migration and adaptation.

Rachel Freathy, University of Exeter Medical School

There is an established association between low birth weight and later risk of Type 2 Diabetes, but through what mechanisms is not properly understood. Both programming due to poor intrauterine conditions and the early effects of genes influencing insulin secretion have been proposed as explanations. The latter is supported by an association between paternal diabetes and birth weight data from UK Biobank data and by a recent study observing that maternal height and fetal growth measures are mainly defined by fetal genetics. By investigating the transmitted vs. untransmitted alleles from mother to offspring, Freathy and her research group seeks to identify parent-of-origin effects for previously identified SNPs for several complex traits including Type 2 Diabetes.

Øyvind Helgeland, KG Jebsen Center for Diabetes Research

The Norwegian Mother Child Cohort study (MoBa) is a daunting longitudinal study collecting data from an original recruitment of 90,000 mothers. One of the biggest challenges of the study is proper data collection. Bioinformatician Øyvind Helgeland gave a fascinating talk about the risks and rewards of working with such large data sets. Helgeland is particularly interested in the over 11,000 trios (mother, father, and child) submitted for GWAS and the insights to be gained from analyzing this data. Preliminary results show that more than 250,000 rare and common variants were found among the trios. Helgeland is looking for trends among variants associated with early growth, childhood obesity and type 2 diabetes and has begun to look at fat mass and obesity-associated protein (FTO) gene variants and changes in child BMI. It will be exciting to see where the analysis takes him!

Ingvild Aukrust, KG Jebsen Center for Diabetes Research

Variants in HNF1A encoding the transcription factor hepatocyte nuclear factor-1A are associated with maturity-onset diabetes of the young (MODY3) and type 2 diabetes. Recently, the spectrum of rare coding variants in 7 of the most common MODY genes was investigated in well-phenotyped samples from the general population. While 0.5-1.5% of randomly selected individuals carried rare variants that are interpreted as causal for MODY in the Human Gene Mutation Database (HGMD) or fulfill bioinformatics criteria for pathogenicity, the majority of these carriers were euglycemic through middle age. A subset of these rare variants may predispose to type 2 diabetes. Senior researcher Ingvild Aukrust presented data showing that these variants could be better distinguished from neutral variants using functional investigations compared to the bioinformatic variant prediction tools commonly used in biomedical research. Using transactivation luciferase and nuclear localization assays, she showed that 11 HNF1A variants of the total 27 variants investigated, had impaired function with a 6-fold association with type 2 diabetes. Functional investigations of HNF1A can therefore identify risk variants for type 2 diabetes.

Anna Gloyn, University of Oxford

The last speaker of this year ‘Jacobæus award & lecture’ symposium was prof. Anna Gloyn from the University of Oxford gave an interesting talk about how genetics/genomics can be used to identify novel mechanisms for diabetes. Her research is focused on the characterization of type 2 diabetes (T2D) risk variants identified through GWAS which are then used to understand the mechanisms of the disease. The majority of these T2D risk variants identified by GWAS, assumed to have regulatory roles, are found at non-coding regions of the genome, leading therefore to uncertainty and difficulties of understanding the biology of the disease. However, prof. Gloyn explained briefly how her research group has so far combined successfully    genetic data (from genotyping, chromatin state, Exon eQTL analysis etc) with expression profiles from human islets to identify effective transcripts for the potential T2D risk variants. Those findings were based on her ongoing studies on some of the identified variants such as in CDKN2A and PAM gene, as well as the effect of the ZMZ1 enzyme on the islet biology and function. 

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