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- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 2. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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| 7. |
- Ahlqvist, E., et al.
(författare)
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Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables
- 2018
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Ingår i: Lancet Diabetes & Endocrinology. - : Elsevier BV. - 2213-8587. ; 6:5, s. 361-369
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Tidskriftsartikel (refereegranskat)abstract
- Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. Methods We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA(1c), and homoeostatic model assessment 2 estimates of beta-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. Findings We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. Interpretation We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.
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| 9. |
- Arora, G. P., et al.
(författare)
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Insulin secretion and action in North Indian women during pregnancy
- 2017
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Ingår i: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 34:10, s. 1477-1482
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab.METHODS: Insulin secretion (HOMA2-B) and insulin action (HOMA2-IR) were assessed in 4665 Indian women with or without gestational diabetes defined by the GDM1999 or adapted GDM2013 criteria.RESULTS: Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women with normal glucose tolerance, and furthermore displayed lower insulin secretion than GDM1999 women. Urban habitat, illiteracy, high age and low BMI were independently associated with reduced insulin secretion, whereas Sikh religion, increasing age and BMI, as well as a family history of diabetes were independently associated with increased insulin resistance.CONCLUSIONS: Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more severe impairments of insulin secretion and action.
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| 10. |
- Tagetti, A., et al.
(författare)
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A genetic risk score for hypertension is associated with risk of thoracic aortic aneurysm
- 2019
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Ingår i: Journal of Human Hypertension. - : Springer Science and Business Media LLC. - 0950-9240 .- 1476-5527. ; 33:9, s. 658-663
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Tidskriftsartikel (refereegranskat)abstract
- A genetic risk score (GRS) based on 29 single nucleotide polymorpysms (SNPs) associated with high blood pressure (BP) was prospectively associated with development of hypertension, stroke and cardiovascular events. The aim of the present study was to evaluate the impact of this GRS on the incidence of aortic disease, including aortic dissection (AD), rupture or surgery of a thoracic (TAA) or abdominal (AAA) aortic aneurysm. More than 25,000 people from the Swedish Malmo Diet and Cancer Study had information on at least 24 SNPs and were followed up for a median ≥ 18 years. The number of BP elevating alleles of each SNPs, weighted by their effect size in the discovery studies, was summed into a BP-GRS. In Cox regression models, adjusted for traditional cardiovascular risk factors including hypertension, we found significant associations of the BP-GRS, prospectively, with incident TAA (hazard ratio (HR) 1.64 (95% confidence interval (CI) 1.081–2.475 comparing the third vs. the first tertile; p = 0.020) but not with either AAA or aortic dissection. Calibration, discrimination and reclassification analyses show modest improvement in prediction using the BP-GRS in addition to the model which used only traditional risk factors. A GRS for hypertension associates with TAA suggesting a link between genetic determinants of BP and aortic disease. The effect size is small but the addition of more SNPs to the GRS might improve its discriminatory capability.
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