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Sökning: WFRF:(Helmer Catherine)

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1.
  • Chasman, Daniel I., et al. (författare)
  • Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
  • 2012
  • Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
  • Tidskriftsartikel (refereegranskat)abstract
    • In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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2.
  • Del Gobbo, Liana C., et al. (författare)
  • omega-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease Pooling Project of 19 Cohort Studies
  • 2016
  • Ingår i: JAMA Internal Medicine. - 2168-6106 .- 2168-6114. ; 176:8, s. 1155-1166
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE The role of omega-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. OBJECTIVE To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20: 5 omega-3), docosapentaenoic acid (DPA; 22: 5 omega-3), and docosahexaenoic acid (DHA; 22: 6 omega-3) and plant-derived alpha-linolenic acid (ALA; 18: 3 omega-3) for incident CHD. DATA SOURCES A global consortium of 19 studies identified by November 2014. STUDY SELECTION Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue omega-3 biomarkers and ascertained CHD. DATA EXTRACTION AND SYNTHESIS Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, omega-6 levels, and FADS desaturase genes. MAIN OUTCOMES AND MEASURES Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). RESULTS The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with omega-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the omega-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. CONCLUSIONS AND RELEVANCE On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived omega-3 fatty acids are associated with a modestly lower incidence of fatal CHD.
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3.
  • Del Gobbo, Liana C., et al. (författare)
  • ω-3 Polyunsaturated fatty acid biomarkers and coronary heart disease : Pooling project of 19 cohort studies
  • 2016
  • Ingår i: JAMA Internal Medicine. - American Medical Association. - 2168-6106. ; 176:8, s. 1155-1166
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. Objective: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5 ω-3), docosapentaenoic acid (DPA; 22:5 ω-3), and docosahexaenoic acid (DHA; 22:6 ω-3) and plant-derived α-linolenic acid (ALA; 18:3 ω-3) for incident CHD. Data Sources: A global consortium of 19 studies identified by November 2014. Study Selection: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD. Data Extraction and Synthesis: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes. Main Outcomes and Measures: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). Results: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baselinewas 59 years (range, 18-97 years), and 28 660 (62.8%)were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHAwere associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95%CI, 0.84-0.98) for ALA, 0.90 (95%CI, 0.85-0.96) for DPA, and 0.90 (95%CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95%CI, 0.90-0.99), ALA (RR, 1.00; 95%CI, 0.95-1.05), EPA (RR, 0.94; 95%CI, 0.87-1.02), and DHA (RR, 0.95; 95%CI, 0.91-1.00)were not. Significant associations with nonfatal MIwere not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. Conclusions and Relevance: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.
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4.
  • Dybjer, Elin, et al. (författare)
  • Pre-diabetes and diabetes are independently associated with adverse cognitive test results : : A cross-sectional, population-based study
  • 2018
  • Ingår i: BMC Endocrine Disorders. - BioMed Central. - 1472-6823. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Diabetes is a risk factor for cognitive impairment, but whether there is also a link between pre-diabetes and cognitive dysfunction is not yet fully established. The aim of this observational study was to investigate associations between pre-diabetes/diabetes and cognitive test results, and also between glucose levels measured during the Oral Glucose Tolerance Test (OGTT) and cognitive outcomes. Methods: During 2007-2012, in all 2994 people (mean age 72 years), residing in Malmö, Sweden, underwent a clinical examination including the OGTT, cardiovascular measurements including carotid-femoral pulse wave velocity (c-f PWV) and two cognitive tests, the Mini Mental State Examination (MMSE), measuring global cognitive function, and A Quick Test of Cognitive Speed (AQT), measuring processing speed and executive functioning. Regression analyses were performed to investigate associations between: (a) categories of normal or impaired glucose metabolism, and (b) OGTT measurements, respectively, as exposure variables and cognitive test results as outcomes. Adjustments were made for demographics, lifestyle factors and cardiovascular risk factors. Results: Participants with pre-diabetes and diabetes scored slightly worse cognitive test results compared to the control group. Results of participants with a long disease duration of diabetes since the baseline examination 13 years earlier were poorer (mean AQT test time 17.8 s slower than controls, p < 0.001). Linear associations were found between fasting and 2-h glucose and cognitive outcomes in the whole population, but also in a sub-analysis including only individuals without diabetes (for 2-h glucose and MMSE results: B = - 2.961, p = 0.005). Associations were stronger for older or less physically active individuals. When adjusting for cardiovascular risk factors, most correlations were non-significant. Conclusions: Pre-diabetes and diabetes are associated with minor deficits in global cognitive function, processing speed and executive functioning. Long-standing diabetes is associated with bigger deficits. There appears to be a continuous inverse correlation between glucose levels and cognitive test results, also for people without diabetes. Associations are stronger in older and less physically active individuals. Cardiovascular factors are important mediating factors in the pathway between diabetes and cognitive dysfunction.
5.
  • Fretts, Amanda M., et al. (författare)
  • Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes : a pooled analysis of prospective cohort studies
  • 2019
  • Ingår i: American Journal of Clinical Nutrition. - OXFORD UNIV PRESS. - 0002-9165 .- 1938-3207. ; 109:4, s. 1216-1223
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed.Objective: We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies.Methods: Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants.Results: There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides.Conclusions: Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.
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6.
  • Gorski, Mathias, et al. (författare)
  • 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
  • 2017
  • Ingår i: Scientific Reports. - 2045-2322 .- 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • HapMap imputed genome-wide association studies (GWAS) have revealed &gt;50 loci at which common variants with minor allele frequency &gt;5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value &lt; 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR &lt; 0.05) genes and 127 significantly (FDR &lt; 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
7.
  • Imamura, Fumiaki, et al. (författare)
  • Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes A pooled analysis of prospective cohort studies
  • 2018
  • Ingår i: PLoS Medicine. - 1549-1277 .- 1549-1676. ; 15:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15: 0 and 17: 0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, tri-glycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men ((pinteraction) &lt; 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.
8.
  • Marklund, Matti, et al. (författare)
  • Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality : An Individual-Level Pooled Analysis of 30 Cohort Studies
  • 2019
  • Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 139:21, s. 2422-2436
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies.Methods:We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available).Results:In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15198 incident cardiovascular events occurred among 68659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships.Conclusions:In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
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9.
  • Parsa, Afshin, et al. (författare)
  • Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
  • 2013
  • Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:12, s. 2105-2117
  • Tidskriftsartikel (refereegranskat)abstract
    • Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency &gt;5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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10.
  • Pattaro, Cristian, et al. (författare)
  • Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
  • 2016
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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