| 1. |
- Njølstad, Pål Rasmus, et al.
(author)
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Roadmap for a precision-medicine initiative in the Nordic region
- 2019
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718.
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Journal article (peer-reviewed)abstract
- The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.
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| 2. |
- Shungin, Dmitry, 1982-
(author)
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Interplay between genetics and environment in obesity
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Background. Being one of the largest current global health problems, obesity is a result of interplay between genetic and environmental factors. In this thesis we studied the genetic underpinning of adipose tissue distribution; investigated causality between obesity and periodontitis using instrumental variable analyses in genetic epidemiology settings; studied interactions between obesity-associated loci and physical activity on obesity; and checked if loci identified in genome-wide association studies are good candidates for gene-environment interactions using heterogeneity of variance analyses.Methods. In Paper 1 we performed a meta-analysis of large-scale genetic association studies for waist traits in 224,459 participants followed by a variety of statistical and bioinformatics methods to obtain insights into the biology of the underlying adipose distributions. In Paper 2 we used genetic variants associated with body mass index (BMI) as instruments within a Mendelian randomization framework to study causality between obesity and periodontitis in 49,066 participants. In Paper 3 we studied the interaction between an FTO single nucleotide polymorphism (SNP) rs9939609 and physical activity in obesity outcomes through meta-analysis of 237,434 participants. In Paper 4 we evaluated if SNPs established through main-effects meta-analysis of genome-wide association studies represent strong or weak candidates for gene-environment interactions, inferred by the degree of phenotypic heterogeneity across genotypes at a given SNP locus.Results. In Paper 1 we identified 49 loci (33 novel) associated with waist-to-hip ratio adjusted for BMI (P<5×10-8), 20 of which displayed significant sexual dimorphism, of which 19 displayed a stronger effect in women than in men. We also detected 19 additional loci newly associated with related waist and hip circumference measures. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insights into potential pathophysiological mechanisms. In Paper 2 we confirmed observational associations between BMI and periodontitis with a pooled odds ratio (OR) of 1.13 per standard deviation increase in BMI (95%CI:1.03, 1.24) in all participants and 1.25 (95%CI:1.10, 1.42) in participants with clinical data. The instrumental variable meta-analysis yielded an OR of 1.05 (95%CI:0.80, 1.38) per BMI standard deviation, and 0.90 (95%CI:0.56, 1.46) in participants with clinical data. In Paper 3 we showed that physical activity attenuates the influence of FTO variation in rs9939609 on obesity (Pinteraction=0.001) with the A allele of rs9939609 increasing the odds of obesity less in the physically active group, with a per-allele OR of 1.22 (95%CI:1.19, 1.25), than in the inactive group, with a per-allele OR of 1.30 (95%CI:1.24, 1.36). In Paper 4 we show that rank-ordered distributions of P-values between marginal effects genome-wide association studies (GWAS) and heterogeneity of variance analyses for all SNPs for BMI and lipid traits have very weak correlations for most traits (Spearman rho of 0.0034 for total cholesterol and 0.0044 for BMI for the squared phenotype residuals regression method) indicating that variants with strong marginal effects are in general poor candidates for gene-environment interactions based on heterogeneity of variance analyses, although a small number of variants convey strong marginal and variance effects, such as those at the FTO locus, meaning that they are likely to convey both marginal and interaction effects.Conclusion. The work outlined in this thesis sheds light on the complexity of genetic and environmental factors in obesity. We have identified novel loci associated with waist traits and described pathways implicated in adipose distribution. We have shown that based on Mendelian randomization analyses the association between periodontitis and obesity is unlikely to be causal. We have confirmed interactions between a bona-fide obesity locus (FTO) and physical activity on obesity and have shown that, in contrast to FTO, the majority of genetic variants identified through GWAS are unlikely to be good candidates for gene-environment interactions based on heterogeneity of variance analyses.
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| 3. |
- Späth, Florentin, et al.
(author)
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Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants : a nested case-control study
- 2016
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In: Tumor Biology. - : Springer Science and Business Media LLC. - 1010-4283 .- 1423-0380. ; 37:8, s. 11065-11072
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Journal article (peer-reviewed)abstract
- Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00-1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2.
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| 4. |
- Wibom, Carl, et al.
(author)
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Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case-Control Study
- 2015
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In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 24:5, s. 810-816
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Journal article (peer-reviewed)abstract
- Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology.
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