| 1. |
- Kettunen, Petronella, et al.
(författare)
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Genetic Variants of GSK3B are Associated with Biomarkers for Alzheimer's Disease and Cognitive Function
- 2015
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Ingår i: Journal of Alzheimers Disease. - 1387-2877. ; 44:4, s. 1313-1322
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood.Objective: To evaluate possible associations between gene variants of GSK3B and risk of AD. Methods: Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau (P-tau(181)), and amyloid-beta (A beta(42)).Results: After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (p(c) = 0.04). Next, rs1154597 showed association with reducedA beta(42) levels (pc = 0.007). Lastly, rs3107669was associated with lower MMSE scores (p(c) = 0.03). In addition, one more SNP was nominally significantly associated with reduced A beta(42) levels and another was associated with reduced MMSE.Conclusion: We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and A beta(42). To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (A beta(42)). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis.
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| 2. |
- Lövkvist, Håkan, et al.
(författare)
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Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke?
- 2013
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 20:9, s. 1284-1291
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. Methods: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. Results: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. Conclusions: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants.
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| 3. |
- Fava, Cristiano, et al.
(författare)
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A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case-control study
- 2015
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other ‘traditional risk factors’, also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case–control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029–1.147) per SD increase in the GRS P=0.003) with similar trends in all three samples: LSR (1.050 (0.967–1.140); P=0.25), MDC (1.168 (1.060–1.288); P=0.002) and SAHLSIS (1.124 (0.997–1.267); P=0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case–control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension.
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| 4. |
- Gidlöf, Olof, et al.
(författare)
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A Common Missense Variant in the ATP Receptor P2X7 Is Associated with Reduced Risk of Cardiovascular Events
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Extracellular adenosine triphosphate (ATP) regulates inflammatory cells by activation of the P2X(7) receptor. We hypothesized that polymorphisms in P2RX7 influence the risk of ischemic heart disease (IHD), ischemic stroke (IS) and cardiovascular risk factors and tested this hypothesis using genetic association studies. Methods: Two loss-of-function SNPs in P2RX7 were genotyped in 1244 IHD cases and 2488 controls as well as 5969 individuals with cardiovascular risk factors. Eleven SNPs in a 250 kb region on chromosome 12 spanning P2RX7 as well as neighboring genes OASL, P2RX4 and CAMKK2 were genotyped in 4138 individuals with IS and 2528 controls. Association was examined using linear and logistic regression models with an additive genetic model. Results: The common loss-of-function variant rs3751143 was significantly associated with a decreased risk of IHD in smokers (P = 0.03) as well as decreased risk of IS (OR 0.89; 95% CI = 0.81-0.97; P = 0.012). In addition, an intronic SNP in CAMKK2, rs2686342, were associated with a decreased risk of IS (OR 0.89; 95% CI = 0.82-0.97; P = 0.011). In subgroup analyses, both SNPs were associated with decreased risk of IS in individuals with hypertension (P = 0.045 and 0.015, respectively). Conclusions: A common loss-of-function missense variant in the gene encoding the P2X7 receptor is associated with reduced risk of IS and with IHD in smokers. These findings might implicate a role of purinergic signaling in atherogenesis or atherothrombosis.
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| 5. |
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| 6. |
- Olsson, Sandra, 1976, et al.
(författare)
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Association between genetic variation on chromosome 9p21 and aneurysmal subarachnoid haemorrhage.
- 2011
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 82:4, s. 384-8
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors play a role in susceptibility to subarachnoid haemorrhage, but little is known about which genes are involved. Recently, genome wide association studies have identified the 9p21 region as a risk locus for intracranial aneurysms (IA). The aim of the present study was to examine the possible association between 9p21 and ruptured IA--that is, aneurysmal subarachnoid haemorrhage (aSAH)--in a Swedish population. There is one study showing an association between 9p21 and arterial stiffness, and arterial stiffness plays a role in the development of hypertension. Therefore, a second aim was to investigate whether a putative association is independent of hypertension.
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| 7. |
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| 8. |
- Olsson, Sandra, 1976, et al.
(författare)
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Genetic Variant on Chromosome 12p13 Does Not Show Association to Ischemic Stroke in 3 Swedish Case-Control Studies
- 2011
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Ingår i: STROKE. - 0039-2499. ; 42:1, s. 214-216
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: In a genome-wide association study and subsequent case-control studies, the single-nucleotide polymorphism rs12425791 on chromosome 12p13 was reported to be associated with ischemic stroke, but this could not be validated in a recent well-powered study. We therefore investigated whether an association between ischemic stroke and rs12425791 could be detected in 3 different case-control studies from the southwest of Sweden. Methods: We examined 3606 patients with ischemic stroke and 2528 controls from 3 independent case-controls studies. Results: No significant association between ischemic stroke and the single-nucleotide polymorphism rs12425791 was detected in any of the 3 case-control samples or in the samples combined. The odds ratio for ischemic stroke for the minor allele in the combined sample was 1.02 (95% CI, 0.93 to 1.13). Conclusions: The single-nucleotide polymorphism rs12425791 does not confer a substantial risk for ischemic stroke in our population. Our results support a recent large study including other European populations.
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| 9. |
- Olsson, Sandra, 1976, et al.
(författare)
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Genetic variation in complement component C3 shows association with ischaemic stroke.
- 2011
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Ingår i: European journal of neurology : the official journal of the European Federation of Neurological Societies. - : Wiley. - 1468-1331. ; 42, s. 214-16
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: The aim of this study was to investigate whether genetic variation at the third complement component (C3) locus is associated with ischaemic stroke (IS). Methods: The Sahlgrenska Academy Study on Ischaemic Stroke comprises 844 patients with IS, and 668 healthy controls. Sixteen SNPs were analyzed. Results: Two SNPs, rs2277984 and rs3745565, showed a significant association with overall IS. The SNP rs2277984 also showed association with the IS subtype cryptogenic stroke. These associations were independent of hypertension, diabetes, and smoking. The independent association between rs3745565 and overall IS withstands correction for multiple testing. Conclusion: In this sample of patients with IS, genetic variation in C3 is associated with IS.
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| 10. |
- Olsson, Sandra, 1976, et al.
(författare)
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Genetic variation in the receptor for advanced glycation end-products (RAGE) gene and ischaemic stroke
- 2013
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 20:6, s. 991-993
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose The multi-ligand receptor for advanced glycation end-products (RAGE, alias AGER) is suggested to contribute to the pathogenesis of vascular disease, but its potential role in stroke is unclear. The aim of this study was to investigate whether genetic variation in RAGE gene is associated with ischaemic stroke (IS). Methods The Sahlgrenska Academy Study on Ischaemic Stroke comprises 844 Caucasian patients with first ever (n = 732) and recurrent (n = 112) IS, and 668 Caucasian controls. Three tagSNPs were selected to capture genetic variation in the RAGE gene. IS subtypes were determined using TOAST criteria. Results One SNP, rs1035798, showed significant association with the subtype of small-vessel disease (SVD) after correction for multiple testing (OR 1.56, 95% CI 1.16–2.09), adjusted P-value < 0.05). This association was independent of hypertension, diabetes and smoking. None of the SNPs was associated with overall IS. Conclusion In this sample of patients with IS, genetic variation in RAGE is associated with the IS subtype SVD, but not overall IS.
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