CDIO Projects in DTU’s B.Eng. in IT Study Program

Since the fall 2008 all B.Eng. study programs at the Technical University of Denmark have been based on the CDIO concept. The adoption of the CDIO standards and principles resulted in new or significantly revised study programs. As part of this effort design-build projects have been introduced on each of the first 4 semesters, and each semester-project spans several courses. The aim of this paper is to describe the four CDIO semester projects in the B.Eng. in IT study, and – along with similar papers describing the other six B.Eng. programs – to provide documentation to accompany an exposition with stands providing additional information and with students demonstrating their projects. The paper is narrowly focused on the IT-study program. At the time of writing this paper the students enrolled in 2008 have completed all four semesters in the new CDIO-based study plan, and the students enrolled in 2009 are currently in the process of finishing the 4 th semester. Consequently, the paper is reporting on curriculum development which has been implemented, and for which experiences have gained

Combined analyses of 20 common obesity susceptibility variants

OBJECTIVE: Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes. RESEARCH DESIGN AND METHODS: In this study we investigate the combined effect of these variants and their ability to discriminate between normal weight and overweight/obese individuals. We applied receiver operating characteristics (ROC) curves, and estimated the area under the ROC curve (AUC) as a measure of the discriminatory ability. The analyses were performed cross-sectionally in the population-based Inter99 cohort where 1,725 normal weight, 1,519 overweight, and 681 obese individuals were successfully genotyped for all 20 variants. RESULTS: When combining all variants, the 10% of the study participants who carried more than 22 risk-alleles showed a significant increase in probability of being both overweight with an odds ratio of 2.00 (1.47–2.72), P = 4.0 × 10(−5), and obese with an OR of 2.62 (1.76–3.92), P = 6.4 × 10(−7), compared with the 10% of the study participants who carried less than 14 risk-alleles. Discrimination ability for overweight and obesity, using the 20 single nucleotide polymorphisms (SNPs), was determined to AUCs of 0.53 and 0.58, respectively. When combining SNP data with conventional nongenetic risk factors of obesity, the discrimination ability increased to 0.64 for overweight and 0.69 for obesity. The latter is significantly higher (P < 0.001) than for the nongenetic factors alone (AUC = 0.67). CONCLUSIONS: The discriminative value of the 20 validated common obesity variants is at present time sparse and too weak for clinical utility, however, they add to increase the discrimination ability of conventional nongenetic risk factors

The effect of FOXA2 rs1209523 on glucose-related phenotypes and risk of type 2 diabetes in Danish individuals

<p>Abstract</p> <p>Background</p> <p>Variations within the <it>FOXA </it>family have been studied for a putative contribution to the risk of type 2 diabetes (T2D), and recently the minor T-allele of <it>FOXA2 </it>rs1209523 was reported to associate with decreased fasting plasma glucose levels in a study using a weighted false discovery rate control procedure to enhance the statistical power of genome wide association studies in detecting associations between low-frequency variants and a given trait.</p> <p>Thus, the primary aim of this study was to investigate whether the minor T-allele of rs1205923 in <it>FOXA2 </it>associated with 1) decreased fasting plasma glucose and 2) a lower risk of developing T2D. Secondly, we investigated whether rs1205923 in <it>FOXA2 </it>associated with other glucose-related phenotypes.</p> <p>Methods</p> <p>The variant was genotyped in Danish individuals from four different study populations using KASPar^®PCR SNP genotyping system. We examined for associations of the <it>FOXA2 </it>genotype with fasting plasma glucose and estimates of insulin release and insulin sensitivity following an oral glucose tolerance test in 6,162 Danish individuals from the population-based Inter99 study while association with T2D risk was assessed in 10,196 Danish individuals including four different study populations.</p> <p>Results</p> <p>The <it>FOXA2 </it>rs1209523 was not associated with fasting plasma glucose (effect size (β) = -0.03 mmol/l (95%CI: -0.07; 0.01), <it>p </it>= 0.2) in glucose-tolerant individuals from the general Danish population. Furthermore, when employing a case-control setting the variant showed no association with T2D (odds ratio (OR) = 0.82 (95%CI: 0.62-1.07), <it>p </it>= 0.1) among Danish individuals. However, when we performed the analysis in a subset of 6,022 non-obese individuals (BMI < 30 kg/m²) an association with T2D was observed (OR = 0.68 (95%CI: 0.49-0.94), <it>p </it>= 0.02). Also, several indices of insulin release and β-cell function were associated with the minor T-allele of <it>FOXA2 </it>rs1209523 in non-obese individuals.</p> <p>Conclusions</p> <p>We failed to replicate association of the minor T-allele of <it>FOXA2 </it>rs1209523 with fasting plasma glucose in a population based sample of glucose tolerant individuals. More extensive studies are needed in order to fully elucidate the potential role of <it>FOXA2 </it>in glucose homeostasis.</p

Physiologic Characterization of Type 2 Diabetes–Related Loci

For the past two decades, genetics has been widely explored as a tool for unraveling the pathogenesis of diabetes. Many risk alleles for type 2 diabetes and hyperglycemia have been detected in recent years through massive genome-wide association studies and evidence exists that most of these variants influence pancreatic β-cell function. However, risk alleles in five loci seem to have a primary impact on insulin sensitivity. Investigations of more detailed physiologic phenotypes, such as the insulin response to intravenous glucose or the incretion hormones, are now emerging and give indications of more specific pathologic mechanisms for diabetes-related risk variants. Such studies have shed light on the function of some loci but also underlined the complex nature of disease mechanism. In the future, sequencing-based discovery of low-frequency variants with higher impact on intermediate diabetes-related traits is a likely scenario and identification of new pathways involved in type 2 diabetes predisposition will offer opportunities for the development of novel therapeutic and preventative approaches

G-allele of Intronic rs10830963 in MTNR1B Confers Increased Risk of Impaired Fasting Glycemia and Type 2 Diabetes Through an Impaired Glucose-Stimulated Insulin Release: Studies Involving 19,605 Europeans

OBJECTIVE Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity. RESEARCH DESIGN AND METHODS We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461). RESULTS The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 × 10−31) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 × 10−11) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017). CONCLUSIONS The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of β-cell dysfunction and hepatic insulin resistance

Bioinformatics-Driven Identification and Examination of Candidate Genes for Non-Alcoholic Fatty Liver Disease

ObjectiveCandidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes.Research Design and MethodsBy integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS).Results273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P&lt;0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations.ConclusionsUsing a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Funding Information: This research has been conducted using the UK Biobank Resource. This research has been conducted using the Danish National Biobank resource. The authors are grateful to the Raine Study participants and their families, and to the Raine Study research staff for cohort co-ordination and data collection. QIMR is grateful to the twins and their families for their generous participation in these studies. We would like to thank staff at the Queensland Institute of Medical Research: Anjali Henders, Dixie Statham, Lisa Bowdler, Ann Eldridge, and Marlene Grace for sample collection, processing and genotyping, Scott Gordon, Brian McEvoy, Belinda Cornes and Beben Benyamin for data QC and preparation, and David Smyth and Harry Beeby for IT support. HBCS Acknowledgements: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. Finrisk study is grateful for the THL DNA laboratory for its skillful work to produce the DNA samples used in this study and thanks the Sanger Institute and FIMM genotyping facilities for genotyping the samples. We thank the MOLGENIS team and Genomics Coordination Center of the University Medical Center Groningen for software development and data management, in particular Marieke Bijlsma and Edith Adriaanse. This work was supported by the Leenards Foundation (to Z.K.), the Swiss National Science Foundation (31003A_169929 to Z.K., Sinergia grant CRSII33-133044 to AR), Simons Foundation (SFARI274424 to AR) and SystemsX.ch (51RTP0_151019 to Z.K.). A.R.W., H.Y. and T.M.F. are supported by the European Research Council grant: 323195:SZ-245. M.A.T., M.N.W. and An.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). For full funding information of all participating cohorts see Supplementary Note 2. Publisher Copyright: © 2017 The Author(s).There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (> 2.4 cm), weight ( 5 kg), and body mass index (BMI) (> 3.5 kg/m(2)). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 x 10(-10), 6.0 x 10(-5), and 2.9 x 10(-3)). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Peer reviewe

Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes

Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes