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Sökning: WFRF:(Brandslund Ivan)

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1.
  • 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
  • 2019
  • 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.
2.
  • 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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3.
4.
  • 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. - 2052-4463. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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 (&gt; 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.</p>
5.
  • 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. ; 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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6.
  • Flannick, Jason, et al. (författare)
  • Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
  • 2014
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 46:4, s. 357-
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1-3, 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) 4 and harbors a common variant (p. Trp325Arg) associated with T2D risk and glucose and proinsulin levels5-7. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 x 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 x 10(-4)). The two most common proteintruncating 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(8,9), and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts(10-15). 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.</p>
  •  
7.
  • Flannick, Jason, et al. (författare)
  • Loss-of-function mutations in SLC30A8 protect against type 2 diabetes
  • 2014
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 46:4, s. 357-363
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1-3, 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) 4 and harbors a common variant (p. Trp325Arg) associated with T2D risk and glucose and proinsulin levels5-7. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 x 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 x 10(-4)). The two most common proteintruncating 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(8,9), and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts(10-15). 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.</p>
  •  
8.
  • 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
    • <p>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 (&gt; 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.</p>
9.
  • Fuchsberger, Christian, et al. (författare)
  • The genetic architecture of type 2 diabetes
  • 2016
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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.</p>
  •  
10.
  • Fuchsberger, Christian, et al. (författare)
  • The genetic architecture of type 2 diabetes
  • 2016
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>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.</p>
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  • Resultat 1-10 av 31
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