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| 2. |
- Kilpeläinen, Tuomas O, et al.
(författare)
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Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
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- Persson, Frederik, et al.
(författare)
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Different patterns of second-line treatment in type 2 diabetes after metformin monotherapy in Denmark, Finland, Norway and Sweden (D360 Nordic) : A multinational observational study.
- 2018
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Ingår i: Endocrinology, diabetes & metabolism. - : Wiley. - 2398-9238. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The understanding of second-line use of glucose-lowering drugs (GLDs) in the general population with type 2 diabetes (T2D) treatment is important as recent results have shown cardiovascular benefits with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). Our aim was to describe second-line GLD treatment patterns in four Nordic countries.Methods: All T2D patients treated with GLD between 2006 and 2015 were identified in prescribed drug registries in Denmark, Finland, Norway and Sweden, and linked with National Patient and Cause of Death Registries. Second-line treatment was defined as a prescription of a second GLD class following ≥6 months of metformin monotherapy. Index was the date of first dispense of the second-line drug.Results: A rapid uptake of newer GLDs (GLP-1RA, DPP-4i and SGLT-2i) over the 10-year observation period was seen in Denmark, Finland and Norway, while slower in Sweden. In 2015, 33,880 (3.1%) of 1,078,692 T2D patients initiated second-line treatment, and newer GLDs were more commonly used in Finland (92%), Norway (71%) and Denmark (70%) vs Sweden (44%). In 2015, the use of older GLDs (insulin and sulphonylureas) was 7-fold greater in Sweden compared to Finland (49% vs 7%), and 1.6-fold greater compared with Denmark and Norway (49% vs 30% and 29%, respectively).Conclusions: Despite comparable demography and healthcare systems in four neighbouring countries, surprisingly large differences in second-line use of newer GLDs were found. With recent evidence of potential cardiovascular benefits with newer GLDs, such differences may have an important impact on cardiovascular outcomes.
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- Birkeland, Kare I., et al.
(författare)
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Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic) : A Multinational Observational Analysis
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - New York : Elsevier. - 2213-8587 .- 2213-8595. ; 5:9, s. 709-717
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Tidskriftsartikel (refereegranskat)abstract
- Background In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile. Methods CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0.9 (SD 4.1) years (80 669 patient-years) and mean age of 61 (12.0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0.53 [95% CI 0.40-0.71]), major adverse cardiovascular events (0.78 [0.69-0.87]), and hospital events for heart failure (0.70 [0.61-0.81]; p<0.0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0.76 [0.65-0.90]; p=0.001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0.60 [0.42-0.85] vs 0.55 [0.34-0.90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0.70 (0.59-0.83) versus 0.90 (0.76-1.07) in the group without. Interpretation In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk.
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| 7. |
- Eriksson, Marit
(författare)
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Body size and physical activity : epidemiological studies on children and young adults
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this thesis was to increase the knowledge about different aspects of body size and physical activity among Swedish children and young adults. Specific aims were: (i) to investigate how BMI-distributions (BMI=Body Mass Index) have changed among Swedish children over a 12 year period, (ii) to study effects of pre- and postnatal growth on body size and body composition in adolescence, (iii) to study associations between parents and children s physical activity, and (iv) to investigate genetic contributions to physical activity behavior. The study of changes in BMI-distributions was based on a comparison of two population-based cohorts; one of 3,650 children born in 1973-75 and a one of 2,591 children born in 1985-87 - the COMPASS study. The comparison showed marked differences in the BMI-distributions from 5-6 years of age with higher BMI-values in the younger cohort. No differences were observed for the children at 2-5 years of age. Differences started to appear at the 25th percentile and became increasingly pronounced in the upper parts of the distributions, i.e. the heavy children became heavier over the 12 year period. The COMPASS study was also used for the study of associations of pre- and postnatal growth with body size and body composition at age 15. Prenatal growth, measured with birth weight z-score, was positively associated with BMI, fat free mass, fat mass and waist circumference. For one unit increase in birth weight z-score, fat free mass increased 1.66 kg among boys and 1.05 kg among girls. Further, there was a positive relation between prenatal growth and fat mass as percentage of total body mass among boys, but not among girls. Postnatal growth, measured by change in weight z-score during first year of life, showed strong, positive associations with all measures of body composition in adolescence. For one unit increase in weight z-score during first year of life, fat free mass increased 2.30 kg among boys and 1.64 kg among girls. Postnatal growth had stronger effect than prenatal growth on all measures of body composition. The study of associations between parents and children s physical activity was based on the PITCH study. The study population comprised 1,124 12-year-old children and their parents. Parents physical activity was strongly associated with their children s participation in sport and vigorous activities. With two parents active in sport the odds ratio for their children to participate in sport was 3.9 (95% CI, 2.2; 6.9) (girls) and 8.8 (4.3; 18.0) (boys) compared with having two inactive parents. The Swedish Young Male Twins Study was used to investigate the contribution of genetic factors to physical activity behavior. The study population comprised 2,044 male twins born 1973-1979. There were moderate to high genetic contributions to physical activity. Heritability estimates were in the range of 0.40 to 0.65, depending on physical activity dimension. Only additive genetic and non-shared environmental factors seemed to be of importance for the variation in physical activity in this young adult male population.
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| 8. |
- Eriksson, Marit, et al.
(författare)
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Trends in prevalence of thinness, overweight and obesity among Swedish children and adolescents between 2004 and 2015.
- 2018
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 107:10, s. 1818-1825
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Tidskriftsartikel (refereegranskat)abstract
- AIM: This study explored weight trends among children aged 4, 7, 11, 14 and 17 years in Jönköping County Sweden, from 2004 to 2015.METHODS: The study had a repeated cross-sectional design, and body mass index (BMI) was calculated based on height and weight measurements collected from child health and school health records. The prevalence of thinness, overweight and obesity was estimated with international cut-offs, with linear trends calculated separately for boys and girls.RESULTS: There were 190 965 measurements of BMI and these covered 82-97% of the younger children and 55-69% of the older children during the study period. The prevalence of thinness varied between 0.2% and 2.2% across time and age groups and did not change over the study period. There was a small decrease in overweight among both girls and boys aged four years. There were increasing trends in overweight and obesity in both girls and boys aged 11 and 14 years of age and a sharp increase among 17-year-old boys, with 7.3% obese in 2014/2015 and 3.6% in 2004/2005.CONCLUSION: The prevalence of obesity decreased from 2004 to 2015 or was stable in younger Swedish children, but increased among older children, with a large increase in adolescent boys.
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| 10. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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