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- Broadaway, K Alaine, et al.
(author)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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In: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Journal article (peer-reviewed)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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| 2. |
- Huvinen, Emilia, et al.
(author)
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Genetic risk of type 2 diabetes modifies the effects of a lifestyle intervention aimed at the prevention of gestational and postpartum diabetes
- 2022
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 65:8, s. 1291-1301
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: The aim of this study was to assess the interaction between genetic risk and lifestyle intervention on the occurrence of gestational diabetes mellitus (GDM) and postpartum diabetes. Methods: The RADIEL study is an RCT aimed at prevention of GDM and postpartum diabetes through lifestyle intervention. Participants with a BMI ≥30 kg/m2 and/or prior GDM were allocated to intervention and control groups before pregnancy or in early pregnancy. The study visits took place every 3 months before pregnancy, once in each trimester, and at 6 weeks and 6 and 12 months postpartum. We calculated a polygenic risk score (PRS) based on 50 risk variants for type 2 diabetes. Results: Altogether, 516 participants provided genetic and GDM data. The PRS was associated with higher glycaemic levels (fasting glucose and/or HbA1c) and a lower insulin secretion index in the second and third trimesters and at 12 months postpartum, as well as with a higher occurrence of GDM and glycaemic abnormalities at 12 months postpartum (n = 356). There was an interaction between the PRS and lifestyle intervention (p=0.016 during pregnancy and p=0.024 postpartum) when analysing participants who did not have GDM at the first study visit during pregnancy (n = 386). When analysing women in tertiles according to the PRS, the intervention was effective in reducing the age-adjusted occurrence of GDM only among those with the highest genetic risk (OR 0.37; 95% CI 0.17, 0.82). The risk of glycaemic abnormalities at 12 months postpartum was reduced in the same group after adjusting additionally for BMI, parity, smoking and education (OR 0.35; 95% CI 0.13, 0.97). Conclusions/interpretation: Genetic predisposition to diabetes modifies the response to a lifestyle intervention aimed at prevention of GDM and postpartum diabetes. This suggests that lifestyle intervention may benefit from being tailored according to genetic risk. Clinical trial registration: ClinicalTrials.gov identifier: NCT01698385 Graphical abstract: [Figure not available: see fulltext.]
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| 3. |
- Merid, Simon Kebede, et al.
(author)
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Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
- 2020
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In: Genome Medicine. - Stockholm : Karolinska Institutet, Dept of Clinical Science and Education, Södersjukhuset. - 1756-994X.
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Journal article (peer-reviewed)abstract
- Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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| 4. |
- Pervjakova, Natalia, et al.
(author)
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Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes
- 2022
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 31:19, s. 3377-3391
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Journal article (peer-reviewed)abstract
- Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy (GenDIP) Consortium assembled genome-wide association studies (GWAS) of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (p < 5x10-8) with GDM, mapping to/near MTNR1B (p = 4.3x10-54), TCF7L2 (p = 4.0x10-16), CDKAL1 (p = 1.6 × 10-14), CDKN2A-CDKN2B (p = 4.1x10-9) and HKDC1 (p = 2.9x10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D; and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomisation analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.
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| 5. |
- van de Vegte, Yordi, et al.
(author)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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