| 31. |
- Renström, Frida, et al.
(author)
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Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis : the GLACIER Study
- 2015
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 58:5, s. 997-1005
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Journal article (peer-reviewed)abstract
- Aims/hypothesis The association of single nucleotide polymorphisms (SNPs) proximal to CRY2 and MTNR1B with fasting glucose is well established. CRY1/2 and MTNR1B encode proteins that regulate circadian rhythmicity and influence energy metabolism. Here we tested whether season modified the relationship of these loci with blood glucose concentration. Methods SNPs rs8192440 (CRY1), rs11605924 (CRY2) and rs10830963 (MTNR1B) were genotyped in a prospective cohort study from northern Sweden (n = 16,499). The number of hours of daylight exposure during the year ranged from 4.5 to 22 h daily. Owing to the non-linear distribution of daylight throughout the year, season was dichotomised based on the vernal and autumnal equinoxes. Effect modification was assessed using linear regression models fitted with a SNP x season interaction term, marginal effect terms and putative confounding variables, with fasting or 2 h glucose concentrations as outcomes. Results The rs8192440 (CRY1) variant was only associated with fasting glucose among participants (n = 2,318) examined during the light season (beta = -0.04 mmol/l per A allele, 95% CI -0.08, -0.01, p = 0.02, p (interaction) = 0.01). In addition to the established association with fasting glucose, the rs11605924 (CRY2) and rs10830963 (MTNR1B) loci were associated with 2 h glucose concentrations (beta = 0.07 mmol/l per A allele, 95% CI 0.03, 0.12, p = 0.0008, n = 9,605, and beta = -0.11 mmol/l per G allele, 95% CI -0.15, -0.06, p < 0.0001, n = 9,517, respectively), but only in participants examined during the dark season (p (interaction) = 0.006 and 0.04, respectively). Repeated measures analyses including data collected 10 years after baseline (n = 3,500) confirmed the results for the CRY1 locus (p (interaction) = 0.01). Conclusions/interpretation In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis.
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| 32. |
- Scott, Robert A., et al.
(author)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
-
In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
-
Journal article (peer-reviewed)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 33. |
- Shungin, Dmitry, et al.
(author)
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Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions
- 2017
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In: PLOS Genetics. - : Public Library Science. - 1553-7390 .- 1553-7404. ; 13:6
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Journal article (peer-reviewed)abstract
- Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P-v), GxE interaction effects (with smoking and physical activity), and marginal genetic effects (P-m). Correlations between P-v and P-m were stronger for SNPs with established marginal effects (Spearman's rho = 0.401 for triglycerides, and rho = 0.236 for BMI) compared to all SNPs. When P-v and P-m were compared for all pruned SNPs, only BMI was statistically significant (Spearman's rho = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P-v distribution (P-binomial < 0.05). SNPs from the top 1% of the P-m distribution for BMI had more significant P-v values (Pmann-Whitney = 1.46x10(-5)), and the odds ratio of SNPs with nominally significant (< 0.05) P-m and P-v was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 8.63x10(-9) and 8.52x10(-7) for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.
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| 34. |
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| 35. |
- Stijnen, Pieter, et al.
(author)
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The Association of Common Variants in PCSK1 With Obesity: A HuGE Review and Meta-Analysis
- 2014
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In: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 180:11, s. 1051-1065
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Research review (peer-reviewed)abstract
- Congenital deficiency of the proprotein convertase subtilisine/kexin type 1 gene (PCSK1), which encodes proprotein convertase 1/3, causes a severe multihormonal disorder marked by early-onset obesity. The single nucleotide polymorphisms (SNPs) rs6232 and rs6234-rs6235 in PCSK1 have been associated with obesity. However, case-control studies carried out in populations of different ethnicities have only partly replicated this association. Moreover, these SNPs have only weakly been associated with body mass index (weight (kg)/height (m)(2)) at a genome-wide level of significance. To investigate this discrepancy, we conducted a systematic search for studies published before December 2013 and extracted relevant data. Pooled estimates were calculated for overall and subgroup analyses. This meta-analysis confirmed the association of PCSK1 SNPs with obesity and provides the first evidence that the association between PCSK1 rs6232 and obesity is stronger for childhood obesity than for adult obesity. Moreover, we identified weak associations with body mass index and significantly stronger associations with waist circumference for rs6234-rs6235. No difference was found in the association with different obesity grades, and no association of PCSK1 rs6234-rs6235 with obesity was identified in Asian populations. This systematic Human Genome Epidemiology (HuGE) review showed convincingly that the SNPs rs6232, rs6234, and rs6235 in PCSK1 are associated with obesity in Caucasians.
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| 36. |
- Stitziel, Nathan O., et al.
(author)
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
- 2016
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In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
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Journal article (peer-reviewed)abstract
- BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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| 37. |
- V Varga, Tibor
(author)
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Genetic Determinants of Dyslipidemia
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- Dyslipidemia is a chronic deviation from normal blood lipid levels that can lead to atherosclerosis and other cardiovascular diseases; dyslipidemia and its sequelae are caused by the complex interplay of genetic and environmental factors. Although circulating concentrations of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (LDL-C) have a strong genetic underpinning, not much is known about the genetic factors that affect long-term deteriorations in lipid concentrations. Through the work described in this thesis I sought to identify novel genetic loci associated with long-term lipid level changes and identify gene × environment interactions influencing blood lipid and lipoprotein concentrations.In Papers I and II, large European prospective cohort studies with long-term follow-up were analyzed. The Gene–Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk (GLACIER) Study (N=3,495) was analyzed in the discovery phase of these studies. The MDC, PIVUS, ULSAM and MRC Ely studies (Nmax=8,263) were utilized as replication cohorts. In Paper III, Scandinavian adults from the GLACIER, MDC, Inter99 and Health 2006 Studies were meta-analyzed (Nmax=18,190). In Paper IV, analyses were conducted in the Diabetes Prevention Program (DPP) (N=2,993) multi-ethnic randomized clinical trial. Participants from the GLACIER Study and DPP, the two discovery studies intensively used in this thesis, were genotyped with the Illumina CardioMetaboChip array.In Paper I, TC- and TG-specific genetic risk scores (GRSs) were robustly associated with TC- and TG level changes, respectively. Three genomic loci, APOE, TRIB1 and APOA1 were associated with either TC- or TG changes and were replicated in subsequent analyses. In Paper II, in addition to the findings of Paper I, seven further loci were associated with TC- or TG changes. Of these, variants at CAPN3, HPR and SIX5 showed suggestive evidence for association with coronary artery disease. In Paper III, a robust sex-heterogeneous interaction between the TG-related GRS and body mass index was observed for circulating blood TG levels. In Paper IV, an interaction between the large HDL particle-associated GRS and the lifestyle intervention for large HDL particle concentrations was observed.In conclusion, this thesis work shows genetic associations for long-term lipid changes and demonstrates examples of gene × environment interactions that influence blood lipid concentrations.
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| 38. |
- V Varga, Tibor, et al.
(author)
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Genetic Determinants of Long-Term Changes in Blood Lipid Concentrations: 10-Year Follow-Up of the GLACIER Study.
- 2014
-
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:6
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Journal article (peer-reviewed)abstract
- Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0×10-11 for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0×10-5 for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0×10-5), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1×10-4) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4×10-8), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P≤0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.
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| 39. |
- V Varga, Tibor, et al.
(author)
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Smoking Status, Snus Use, and Variation at the CHRNA5-CHRNA3-CHRNB4 Locus in Relation to Obesity: The GLACIER Study
- 2013
-
In: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 178:1, s. 31-37
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Journal article (peer-reviewed)abstract
- A genetic variant within the CHRNA5-CHRNA3-CHRNB4 region (rs1051730), previously associated with smoking quantity, was recently shown to interact with smoking on obesity predisposition. We attempted to replicate this finding in the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk (GLACIER) Study, a prospective cohort study of adults from northern Sweden (n = 16,426). We also investigated whether a similar interaction is apparent between rs1051730 and snus, a type of moist oral tobacco, to determine whether this interaction is driven by factors that cigarettes and snus have in common, such as nicotine. Main effects of smoking, snus, and the rs1051730 variant and pairwise interaction terms (smoking x rs1051730 and snus x rs1051730) were tested in relation to body mass index (BMI; calculated as weight (kg)/height (m)(2)) through the use of multivariate linear models adjusted for age and sex. Smoking status and BMI were inversely related (beta = -0.46 kg/m(2), standard error (SE) = 0.08; P < 0.0001). Snus use and BMI were positively related (beta = 0.35 kg/m(2), SE = 0.12; P = 0.003). The rs1051730 variant was not significantly associated with smoking status or snus use (P > 0.05); the T allele was associated with lower BMI in the overall cohort (beta = -0.10 kg/m(2), SE = 0.05; P = 0.03) and with smoking quantity in those in whom this was measured (n = 5,304) (beta = 0.08, SE = 0.01; P < 0.0001). Neither smoking status (P-interaction = 0.29) nor snus use (P-interaction = 0.89) modified the association between the rs1051730 variant and BMI.
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| 40. |
- Varga, Tibor V, et al.
(author)
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Acute and Long-Term Changes in Blood-Borne Biomarkers in Response to Dynamic Standing in Nonambulant Children With Cerebral Palsy
- 2024
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In: Pediatric Exercise Science. - Champaign, IL : Human Kinetics. - 0899-8493 .- 1543-2920. ; 36:1, s. 15-22
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Journal article (peer-reviewed)abstract
- Purpose: To investigate acute and long-term changes in hormonal and inflammatory biomarkers in nonambulant children with cerebral palsy in response to dynamic standing exercise.Methods: Fourteen children with severe cerebral palsy were recruited. Anthropometrics and body composition measures were obtained. Physical activity levels before the study were assessed using hip-worn accelerometry. All children underwent a 30-minute dynamic standing exercise using the Innowalk standing aid. Respiratory data during exercise were collected using indirect calorimetry. Blood samples were collected before and after exercise. Blood samples were also obtained after two 16-week exercise protocols, in a resting state. Hormonal and inflammatory metabolites were measured from blood serum/plasma, and acute and long-term changes in biomarker levels were assessed using Wilcoxon signed-rank tests.Results: Of the 14 children at baseline, all had slightly/moderately/severely elevated C-reactive protein and cortisol levels. C-reactive protein levels were decreased following a 30-minute bout of dynamic standing (before exercise: 53 mg/L [interquartile range: 40-201]; after exercise: 39 mg/L [interquartile range: 20-107]; P = .04).Conclusions: We show that several hormonal and inflammatory biomarkers are dysregulated in children with cerebral palsy. Our preliminary results from a small, but deep-phenotyped prospective cohort indicate acute and long-term alterations of several biomarkers in response to exercise. ©2023 The Authors.
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