83 research outputs found
The functional variant V433M of the CYP4F2 and the metabolic syndrome in Swedes.
No full textBACKGROUND AND AIM: The genetic basis of Metabolic syndrome (MetS) is largely unknown but a link with salt sensitivity is recognized. The cytochrome P450 isoform 4F2 (CYP4F2) is involved in renal production of 20-hydroxyeicosatethraenoic acid (20-HETE), a natriuretic substance associated with salt sensitivity. The same enzyme is implicated in ω-hydroxylation of very long and medium chain fatty acids in the liver suggesting its possible influence on gluco-metabolic components of MetS. The aim of the present study was to evaluate the effect of CYP4F2 V433M, a functional polymorphism previously associated with hypertension via renal salt reabsorption, on the individual components of MetS and MetS itself. METHODS: The polymorphism was genotyped in the cardiovascular cohort of the Malmö Diet and Cancer (MDC-CVA) study and successively in the Malmö Preventive Project (MPP) cohort. Different definitions of the MetS were applied. RESULTS: In the MDC-CVA, male, but not female, CYP4F2 M433 carriers had significantly higher levels of waist, triglycerides, BP and a composite sum of MetS phenotypes (MetS score) beside lower HDL-cholesterol respect to V-homozygotes. MetS, as defined in the ATPIII and the AHA/NHLBI definitions, was more prevalent in M-carriers with respect to V-homozygotes. In the MPP cohort, significant association was detectable only for triglycerides at baseline and for Diastolic BP at reinvestigation in male M-carriers. CONCLUSION: The initial positive association of the CYP4F2 V433M polymorphism with components of MetS and MetS itself, found in MDC-CVA, was partially denied in another large cohort. The first association either could be due to a false positive result or alternatively, different genetic background or population stratification could have hidden the effect of the polymorphism in the replication cohort
High-resolution diffusion-weighted brain MRI under motion
No full textMagnetic resonance imaging is one of the fastest developing medical imaging techniques. It provides excellent soft tissue contrast and has been a leading tool for neuroradiology and neuroscience research over the last decades. One of the possible MR imaging contrasts is the ability to visualize diffusion processes. The method, referred to as diffusion-weighted imaging, is one of the most common clinical contrasts but is prone to artifacts and is challenging to acquire at high resolutions.This thesis aimed to improve the resolution of diffusion weighted imaging, both in a clinical and in a research context. While diffusion-weighted imaging traditionally has been considered a 2D technique the manuscripts and methods presented here explore 3D diffusion acquisitions with isotropic resolution. Acquiring multiple small 3D volumes, or slabs, which are combined into one full volume has been the method of choice in this work.The first paper presented explores a parallel imaging driven multi-echo EPI readout to enable high resolution with reduced geometric distortions. The work performed on diffusion phase correction lead to an understanding that was used for the subsequent multi-slab papers.The second and third papers introduce the diffusion-weighted 3D multi-slab echo-planar imaging technique and explore its advantages and performance. As the method requires a slightly increased acquisition time the need for prospective motion correction became apparent.The forth paper suggests a new motion navigator using the subcutaneous fat surrounding the skull for rigid body head motion estimation, dubbed FatNav. The spatially sparse representation of the fat signal allowed for high parallel imaging acceleration factors, short acquisition times, and reduced geometric distortions of the navigator.The fifth manuscript presents a combination of the high-resolution 3D multi-slab technique and a modified FatNav module. Unlike our first FatNav implementation, using a single sagittal slab, this modified navigator acquired orthogonal projections of the head using the fat signal alone.The combined use of both presented methods provides a promising start for a fully motion corrected high-resolution diffusion acquisition in a clinical setting.List of scientific papersI. Diffusion Weighted Vertical Gradient and Spin Echo. Engström M, Bammer R, Skare S. Magn Reson Med. 68:1755-1763 (2013). https://doi.org/10.1002/mrm.24506 II. Diffusion-Weighted 3D Multi-Slab Echo Planar Imaging for High Signal-to-Noise Ratio Efficiency and Isotropic Image Resolution. Engström M, Skare S. Magn Reson Med. 70:1507-14 (2013). https://doi.org/10.1002/mrm.24594 III. On the Signal-to-Noise Ratio Efficiency and Slab-Banding Artifacts in Three-Dimensional Multi-Slab Diffusion-Weighted Echo Planar Imaging. Engström M, Mårtensson M, Avventi E, Skare S. Magn Reson Med. 2014 Mar 19. https://doi.org/10.1002/mrm.25182 IV. Properties of a 2D Fat Navigator for Prospective Image Domain Correction of Nodding Motion in brain MRI. Skare S, Hartwig A, Mårtensson M, Avventi E, Engström. M Magn Reson Med. 2014 Apr 2014. https://doi.org/10.1002/mrm.25234 V. Collapsed Fat Navigators for Brain 3D Rigid Body Motion. Engström M, Mårtensson M, Avventi E, Norbeck O, Skare S. [Manuscript]</p
Vanin-1 I26T polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedwes.
No full textBACKGROUND AND AIMS:Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of red-ox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events.METHODS AND RESULTS:The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmö Diet and Cancer" (MDC-CVA) study and successively in 17874 participants of the "Malmö Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP. Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females. However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in the MDC-CVA was not significantly different in carriers of different genotypes.CONCLUSIONS:Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events
STK39 is a candidate gene for primary hypertension especially in females: results from two cohort studies in Swedes
No full textBACKGROUND: As recently pinpointed by a genome-wide association study the serine/threonine kinase 39 (STK39) is a candidate gene for hypertension. This kinase is strongly implicated in sodium reabsorption by the kidney through its modulating effect on furosemide-sensitive and thiazide-sensitive channels. The aim of our study was to test the effects of the STK39 rs35929607A>G polymorphism on blood pressure (BP) levels and the prevalence and incidence of hypertension in middle-aged Swedes participating in two urban-based surveys in Malmö (Sweden).
METHODS: The rs35929607A>G polymorphism was genotyped in 5634 participants included in the cardiovascular cohort of the 'Malmö Diet and Cancer-cardiovascular arm' (MDC-CVA) study and successively in 17 894 participants of the 'Malmö Preventive Project' (MPP) both at baseline and at reinvestigation after a mean of 23 years. The effect of the same single nucleotide polymorphism on salt sensitivity was tested in 39 participants of the Salt Reduction to Avoid Hypertension study.
RESULTS: Both before and after adjustment for covariates, the functional rs35929607A>G polymorphism was associated with higher SBP and DBP values in the MDC-CVA, but not in the MPP. In both surveys, the polymorphism was associated with hypertension prevalence; after adjustment using the autosomal-dominant model, the odds ratio for hypertension ranged between 1.077 (MPP at baseline) and 1.151 (MDC-CVA) with P-value less than 0.05. After stratification for sex, the results remained statistically significant in women, but not in men. Carriers of the G-allele displayed an increase in salt sensitivity.
CONCLUSION: Our results from two large cohort studies support previous evidence about the association of the STK39 rs35929607A>G variant with hypertension, especially in women. If further confirmed in successive studies, owing to its pivotal role in sodium reabsorption at the renal tubule level, STK39 might prove to be a suitable target for antihypertensive therapy. The greater effect of the STK39 rs35929607A>G polymorphism in women with respect to men deserves further investigation
Cardiovascular consequences of a polygenetic component of blood pressure in an urban-based longitudinal study: the Malmö Diet and Cancer.
No full textA recently published genome wide association study identified 29 single nucleotide polymorphisms (SNPs) influencing blood pressure (BP). Case-control studies suggest that a genetic risk score (GRS) based on these 29 SNPs affect the risk of cardiovascular disease (CVD), but its role for CVD at population level is unknown. Here, we prospectively evaluate the impact of this polygenetic BP component on CVD morbidity and mortality in a large urban-based middle-aged population
Prediction Of Blood Pressure Changes Over Time And Incidence Of Hypertension By A Genetic Risk Score In Swedes.
No full textRecent Genome Wide Association Studies (GWAS) have pinpointed different single nucleotide polymorphisms (SNPs) consistently associated with blood pressure (BP) and hypertension prevalence. However, little data exist regarding SNPs predicting BP variation over time and hypertension incidence. The aim of this study was to confirm the association of a genetic risk score (GRS), based on 29 independent SNPs, with cross sectional BP and hypertension prevalence and to challenge its prediction of BP change over time and hypertension incidence in more than 17,000 middle-aged Swedes participating in a prospective study, the “Malmö Preventive Project” (MPP), investigated at baseline and over a 23-year average period of follow-up. The GRS was associated with higher systolic and diastolic BP values both at baseline (ß±SEM 0.968±0.102mmHg and 0.585±0.064mmHg; p<1E-19 for both) and at reinvestigation (ß±SEM 1.333±0.161mmHg and 0.724±0.086mmHg; p<1E-15 for both) and with increased hypertension prevalence (OR [95%CI] 1.192 [1.140-1.245] and 1.144 [1.107-1.183]; p<1E-15 for both). The GRS was positively associated with change (Δ) in BP (ß±SEM 0.033±0.008mmHg/year and 0.023±0.004mmHg/year; p<1E-04 for both) and hypertension incidence (OR 95%CI 1.110 (1.065-1.156) p=6.7 E-07), independently from traditional risk factors. The relative weight of the GRS was lower in magnitude than obesity or pre-hypertension, but comparable to diabetes mellitus or a positive family history of hypertension (PFH). A C-statistics analysis does not show any improvement in the prediction of incident hypertension on top of traditional risk factors. Our data from a large cohort study show that a GRS is independently associated with BP increase and incidence of hypertension
The <it>Renalase</it> Asp37Glu polymorphism is not associated with hypertension and cardiovascular events in an urban-based prospective cohort: the Malmö Diet and cancer study
No full textAbstract Background Renalase (gene name RNLS), a recently discovered enzyme with monoamine oxidase activity, is implicated in the degradation of catecholamines. Recent studies delineate a possible role of this enzyme in blood pressure (BP) maintenance and cardiac protection and two single nucleotide polymorphisms, RNLS rs2576178 A > G and rs2296545 C > G have been associated with hypertension. The latter SNP leads to a non synonymous Asp to Glu substitution deleting a flavin adenine dinucleotide (FAD) binding site with possible impaired functionality. We tested the hypothesis that these polymorphisms could affect BP levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. Methods The polymorphisms were genotyped in 5696 participants of the population-based Cardiovascular Cohort of the "Malmö Diet and Cancer" (MDC-CC). The incidence of cardiovascular events (coronary events [n = 408], strokes [n = 330], heart failure [n = 190] and atrial fibrillation/flutter [n = 406]) was monitored for an average of approximately 15 years of follow-up. Results Both before and after adjustment for sex, age and BMI the polymorphisms did not show any effect on BP level and hypertension prevalence. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for cardiac and cerebrovascular events was not significantly different in carriers of different genotypes. A significant interaction was found between the rs2296545 C > G and age with respect to BP/hypertension. Conclusions Our data do not support a major role for these RNLS polymorphisms in determining BP level and incident events at population level. The positive interaction with age suggest that the effect of the rs2296545 C > G polymorphism, if any, could vary between different ages.</p
STK39 is a candidate gene for primary hypertension especially in females: results from two cohort studies in Swedes
No full textBACKGROUND: As recently pinpointed by a genome-wide association study the serine/threonine kinase 39 (STK39) is a candidate gene for hypertension. This kinase is strongly implicated in sodium reabsorption by the kidney through its modulating effect on furosemide-sensitive and thiazide-sensitive channels. The aim of our study was to test the effects of the STK39 rs35929607A>G polymorphism on blood pressure (BP) levels and the prevalence and incidence of hypertension in middle-aged Swedes participating in two urban-based surveys in Malmö (Sweden).
METHODS: The rs35929607A>G polymorphism was genotyped in 5634 participants included in the cardiovascular cohort of the 'Malmö Diet and Cancer-cardiovascular arm' (MDC-CVA) study and successively in 17 894 participants of the 'Malmö Preventive Project' (MPP) both at baseline and at reinvestigation after a mean of 23 years. The effect of the same single nucleotide polymorphism on salt sensitivity was tested in 39 participants of the Salt Reduction to Avoid Hypertension study.
RESULTS: Both before and after adjustment for covariates, the functional rs35929607A>G polymorphism was associated with higher SBP and DBP values in the MDC-CVA, but not in the MPP. In both surveys, the polymorphism was associated with hypertension prevalence; after adjustment using the autosomal-dominant model, the odds ratio for hypertension ranged between 1.077 (MPP at baseline) and 1.151 (MDC-CVA) with P-value less than 0.05. After stratification for sex, the results remained statistically significant in women, but not in men. Carriers of the G-allele displayed an increase in salt sensitivity.
CONCLUSION: Our results from two large cohort studies support previous evidence about the association of the STK39 rs35929607A>G variant with hypertension, especially in women. If further confirmed in successive studies, owing to its pivotal role in sodium reabsorption at the renal tubule level, STK39 might prove to be a suitable target for antihypertensive therapy. The greater effect of the STK39 rs35929607A>G polymorphism in women with respect to men deserves further investigation
A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case-control study.
No full textGenetic 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.European Journal of Human Genetics advance online publication, 8 October 2014; doi:10.1038/ejhg.2014.212
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