| 201. |
- Wang, Yunzhang, et al.
(författare)
-
Epigenetic influences on aging : a longitudinal genome-wide methylation study in old Swedish twins
- 2018
-
Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 13:9, s. 975-987
-
Tidskriftsartikel (refereegranskat)abstract
- Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3x10(-7)) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9x10(-5)), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1x10(-5)) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.
|
|
| 202. |
- Wiklund, Karolin, et al.
(författare)
-
Amino acids predict prognosis in patients with acute dyspnea
- 2021
-
Ingår i: BMC Emergency Medicine. - : Springer Science and Business Media LLC. - 1471-227X. ; 21:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: To identify amino acids that can predict risk of 90-day mortality in patients with acute dyspnea. Method: Plasma levels of nine amino acids were analyzed 663 adult patients admitted to the Emergency Department (ED) with acute dyspnea. Cox proportional hazards models were used to examine the relation between amino acid levels and the risk of 90-day mortality. Result: Eighty patients (12.1%) died within 90 days of admission. An “Amino Acid Mortality Risk Score” (AMRS), summing absolute plasma levels of glycine, phenylalanine and valine, demonstrated that among the patients belonging to quartile 1 (Q1) of the AMRS, only 4 patients died, compared to 44 patients in quartile 4. Using Q1 of the AMRS as reference, each increment of 1 SD in the AMRS was associated with a hazard ratio (HR) of 2.15 for 90-day mortality, and the HR was > 9 times higher in Q4. Conclusion: Glycine, phenylalanine and valine are associated with a risk of 90-day mortality in patients admitted to the ED for acute dyspnea, suggesting that these amino acids may be useful in risk assessments.
|
|
| 203. |
- Winckler, W, et al.
(författare)
-
Association of common variation in the HNF1 alpha gene region with risk of type 2 diabetes
- 2005
-
Ingår i: Diabetes. - 1939-327X. ; 54:8, s. 2336-2342
-
Tidskriftsartikel (refereegranskat)abstract
- It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1 alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1a with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1 alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in > 4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1 alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.
|
|
| 204. |
- Winckler, W, et al.
(författare)
-
Association testing of variants in the hepatocyte nuclear factor 4 alpha gene with risk of type 2 diabetes in 7,883 people
- 2005
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:3, s. 886-892
-
Tidskriftsartikel (refereegranskat)abstract
- Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4alpha (HNF4alpha) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4a coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4alpha. Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
|
|
| 205. |
- Winckler, Wendy, et al.
(författare)
-
Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes
- 2007
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 56:3, s. 685-693
-
Tidskriftsartikel (refereegranskat)abstract
- An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation irk the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, lpf1, Tcf2, and NeuroD1 (MODY2 and MODY4-MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value < 0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values < 0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value < 10(-6) in > 15,000 samples. We combined these results with our previous studies on HNF4 alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.
|
|
| 206. |
- Yaghmur, Anan, et al.
(författare)
-
Self-assembly in monoelaidin aqueous dispersions : direct vesicles to cubosomes transition
- 2008
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:11, s. e3747-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: In the present study, synchrotron small-angle X-ray scattering (SAXS) and Cryo-TEM were used to characterize the temp.-induced structural transitions of monoelaidin (ME) aq. dispersion in the presence of the polymeric stabilizer F127. We prove that the direct transition from vesicles to cubosomes by heating this dispersion is possible. The obtained results were compared with the fully hydrated bulk ME phase. Methodol./Principal Findings: Our results indicate the formation of ME dispersion, which is less stable than that based on the congener monoolein (MO). In addn., the temp.-dependence behavior significantly differs from the fully hydrated bulk phase. SAXS findings indicate a direct Lalpha -V2 internal transition in the dispersion. While the transition temp. is conserved in the dispersion, the formed cubosomes with internal Im3m symmetry clearly contain more water and this ordered interior is retained over a wider temp. range as compared to its fully hydrated bulk system. At 25 DegC, Cryo-TEM observations reveal the formation of most likely closely packed onion-like vesicles. Above the lamellar to non-lamellar phase transition at 65 DegC, flattened cubosomes with an internal nanostructure are obsd. However, they have only arbitrary shapes and thus, their morphol. is significantly different from that of the well-shaped analogous MO cubosome and hexosome particles. Conclusions/Significance: Our study reveals a direct liposomes-cubosomes transition in ME dispersion. The obtained results suggest that the polymeric stabilizer F127 esp. plays a significant role in the membrane fusion processes. F127 incorporates in considerable amt. into the internal nanostructure and leads to the formation of a highly swollen Im3m phase.
|
|
| 207. |
- Yao Mattisson, Ingrid, et al.
(författare)
-
Elevated Markers of Death Receptor-Activated Apoptosis are Associated with Increased Risk for Development of Diabetes and Cardiovascular Disease
- 2017
-
Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 26, s. 187-197
-
Tidskriftsartikel (refereegranskat)abstract
- Background An increased rate of cell death by apoptosis has been implicated in both diabetes and atherosclerosis. Apoptosis can be induced through activation of the death receptors TNF receptor 1 (TNFR-1), TRAIL receptor 2 (TRAILR-2) and Fas. Soluble forms of these receptors are found in plasma. The objective of this study was to determine if soluble death receptors are markers of receptor-activated apoptosis and predict risk for development of diabetes and cardiovascular events. Methods Fas ligand was used to induce apoptosis in peripheral blood mononuclear cells and INS-1 pancreatic β-cells and release of TNFR-1, TRAILR-2 and Fas measured by ELISA. Proximity Extension Assay was used to analyze plasma levels of TNFR-1, TRAILR-2 and Fas in baseline samples of 4742 subjects in the Malmö Diet and Cancer Study and related to development of diabetes and cardiovascular events during 19.2 years of follow-up. Results Activation of apoptosis by Fas ligand was associated with release of soluble Fas, TNFR-1 and TRAILR-2 in both cell types. Circulating levels of all three receptors were higher in subjects with diabetes and correlated with markers of impaired glucose metabolism in non-diabetic subjects. Among the latter, those in the highest tertile of soluble Fas, TNFR-1 and TRAILR-2 had increased risk for development of diabetes and cardiovascular events. These associations became weaker when adjusting for cardiovascular risk factors in Cox regression models, but remained significant for TRAILR-2 with incident diabetes, cardiovascular mortality, myocardial infarction and ischemic stroke, and for TNFR-1 with myocardial infarction. Conclusion The present study demonstrates an association between several cardiovascular risk factors and elevated levels of circulating markers of apoptotic cell death. It also shows that subjects with high levels of these biomarkers have increased risk of diabetes and CVD. This implies that soluble death receptors are markers of β-cell and vascular injury and potentially could be used as surrogate markers of therapeutic efficiency in risk factor interventions.
|
|
| 208. |
- Zarkoob, Hadi, et al.
(författare)
-
Utilization of genetic data can improve the prediction of type 2 diabetes incidence in a Swedish cohort
- 2017
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:7
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to measure the impact of genetic data in improving the prediction of type 2 diabetes (T2D) in the Malmö Diet and Cancer Study cohort. The current study was performed in 3,426 Swedish individuals and utilizes of a set of genetic and environmental risk data. We first validated our environmental risk model by comparing it to both the Finnish Diabetes Risk Score and the T2D risk model derived from the Framingham Offspring Study. The area under the curve (AUC) for our environmental model was 0.72 [95% CI, 0.69–0.74], which was significantly better than both the Finnish (0.64 [95% CI, 0.61–0.66], p-value < 1 x 10?4) and Framingham (0.69 [95% CI, 0.66–0.71], p-value = 0.0017) risk scores. We then verified that the genetic data has a statistically significant positive correlation with incidence of T2D in the studied population. We also verified that adding genetic data slightly but statistically increased the AUC of a model based only on environmental risk factors (RFs, AUC shift +1.0% from 0.72 to 0.73, p-value = 0.042). To study the dependence of the results on the environmental RFs, we divided the population into two equally sized risk groups based only on their environmental risk and repeated the same analysis within each subpop-ulation. While there is a statistically significant positive correlation between the genetic data and incidence of T2D in both environmental risk categories, the positive shift in the AUC remains statistically significant only in the category with the lower environmental risk. These results demonstrate that genetic data can be used to increase the accuracy of T2D prediction. Also, the data suggests that genetic data is more valuable in improving T2D prediction in populations with lower environmental risk. This suggests that the impact of genetic data depends on the environmental risk of the studied population and thus genetic association studies should be performed in light of the underlying environmental risk of the population.
|
|
