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Träfflista för sökning "WFRF:(Brandslund Ivan) "

Sökning: WFRF:(Brandslund Ivan)

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1.
  • Fuchsberger, Christian, et al. (författare)
  • The genetic architecture of type 2 diabetes
  • 2016
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
  • Tidskriftsartikel (refereegranskat)abstract
    • The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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2.
  • Ahluwalia, Tarunveer S., et al. (författare)
  • A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes : results from an exome-wide association study of albuminuria
  • Ingår i: Diabetologia. - : Springer. - 0012-186X. ; 62:2, s. 292-305
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6). Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.
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3.
  • Chew, Michelle, et al. (författare)
  • Effect of modified ultrafiltration on the inflammatory response in paediatric open-heart surgery: a prospective, randomized study
  • 2002
  • Ingår i: Perfusion. - : SAGE Publications. - 1477-111X. ; 17:5, s. 327-333
  • Tidskriftsartikel (refereegranskat)abstract
    • Modified ultrafiltration (MUF) is often used in conjunction with paediatric cardiac surgery with cardiopulmonary bypass (CPB) and is thought to improve clinical outcome. It is unclear whether these improvements (if any) are due to the removal of inflammatory mediators. In this prospective study, 18 children aged 12-24 months undergoing uncomplicated cardiac surgery with methylprednisolone added in the pump prime were randomized to receive CPB with (n = 10) and without (n = 8) MUF. Cytokines (TNFalpha, IL-6, IL-1beta, IL-10, IL-1ra), complement split products (C3d, C4d) and coagulation system activation (F1 + 2, ATIII) were measured pre-, peri- and up to 48 h postoperatively. For clinical outcome, the alveolar-arterial oxygen (A-a) gradient, transfusion requirement, drain loss, mean blood pressure and requirement for inotropic support were registered up to 24 h postoperatively. Our results show an improvement in postoperative oxygenation as well as a tendency towards decreased drain loss and improved haemodynamics in the MUF group. There were no intergroup differences detectable for TNFalpha, IL-1beta, IL-1ra, complement and coagulation markers. We conclude that MUF in itself does not significantly influence TNFalpha, IL-1beta, IL-1ra and the complement and coagulation profiles in children undergoing cardiac surgery with CPB. Despite this, there was some evidence for improved clinical outcome. Our results do not support that MUF improves postoperative organ function by modulation of the measured markers of inflammation.
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5.
  • Flannick, Jason, et al. (författare)
  • Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
  • 2017
  • Ingår i: Scientific Data. - : Nature Publishing Group. - 2052-4463. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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6.
  • Flannick, Jason, et al. (författare)
  • Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
  • 2014
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
  • Tidskriftsartikel (refereegranskat)abstract
    • Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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7.
  • Flannick, Jason, et al. (författare)
  • Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
  • 2017
  • Ingår i: Scientific Data. - : Nature Publishing Group. - 2052-4463. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to 82 K Europeans via the exome chip, and similar to 90% of low-frequency non-coding variants in similar to 44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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8.
  • Hoffmann, Hans Jurgen, et al. (författare)
  • Plasma C3d levels of young farmers correlate with respirable dust exposure levels during normal work in swine confinement buildings
  • 2003
  • Ingår i: Annals of Agricultural and Environmental Medicine. - : Institute of Agricultural Medicine in Lublin, Poland. - 1898-2263. ; 10:1, s. 53-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Work in swine confinement buildings leads to an inflammatory response and may be associated with increased levels of acute phase proteins. We compared the inflammatory response of a control group of young former farm workers with age-matched former farm workers who had previously developed the lower airway symptoms of wheeze, cough, tightness of the chest during work in swine confinement buildings, and because of these symptoms had stopped work. Both groups were subjected to an experimental exposure in a swine confinement building for 3 hours. Complement activation and acute phase proteins were measured in blood samples and broncho-alveolar lavage. Plasma C3d levels correlated with respirable dust, significantly so for individual cases and for the whole cohort. Plasma C3, fibrinogen and alpha (1) -acid glycoprotein peaked 1 and 6 h after exposure start, mannan-binding lectin, C-reactive protein and alpha(1)-antitrypsin peaked after 2 h. Surfactant protein D (SP-D) and alpha (2) -macroglobulin were downregulated. In lavage, only SP-D, alpha (2)-macroglobulin and fibronectin were detected. FEV(1), FVC, TLC and FEV(25-75) did not vary during exposure. There was complement activation in response to respiratory dust, more so amongst cases than in the control group. Acute exposure, with work related levels of organic dust containing endotoxin, leads to a weak systemic inflammatory response.
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9.
  • Justice, Anne E., et al. (författare)
  • Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
  • Tidskriftsartikel (refereegranskat)abstract
    • Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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10.
  • Kraja, Aldi T., et al. (författare)
  • New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals
  • Ingår i: Circulation: Cardiovascular Genetics. - : American Heart Association. - 1942-325X. ; 10:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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