| 1. |
- Boeger, Carsten A., et al.
(författare)
-
CUBN Is a Gene Locus for Albuminuria
- 2011
-
Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 22:3, s. 555-570
-
Tidskriftsartikel (refereegranskat)abstract
- Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 x 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
|
|
| 2. |
- 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. - : Oxford University Press (OUP). - 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.
|
|
| 3. |
- Kraemer, Bernhard K., et al.
(författare)
-
Tacrolimus-Based, Steroid-Free Regimens in Renal Transplantation : 3-Year Follow-Up of the ATLAS Trial
- 2012
-
Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 94:5, s. 492-498
-
Tidskriftsartikel (refereegranskat)abstract
- Background. Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. Methods. This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. Results. Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. Conclusion. Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.
|
|
| 4. |
- Köttgen, Anna, et al.
(författare)
-
New loci associated with kidney function and chronic kidney disease
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:5, s. 376-384
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
|
|
| 5. |
- 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 >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.
|
|
| 6. |
- Pattaro, Cristian, et al.
(författare)
-
Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
- 2012
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002584-
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
|
|
| 7. |
- Adolph, C., et al.
(författare)
-
Azimuthal asymmetries of charged hadrons produced in high-energy muon scattering off longitudinally polarised deuterons
- 2018
-
Ingår i: European Physical Journal C. - : SPRINGER. - 1434-6044 .- 1434-6052. ; 78:11
-
Tidskriftsartikel (refereegranskat)abstract
- Single hadron azimuthal asymmetries of positive and negative hadrons produced in muon semi-inclusive deep inelastic scattering off longitudinally polarised deuterons are determined using the 2006 COMPASS data and also combined all deuteron COMPASS data. For each hadron charge, the dependence of the azimuthal asymmetry on the hadron azimuthal angle f is obtained by means of a fiveparameter fitting function that besides a f-independent term includes four modulations predicted by theory: sin f, sin 2f, sin 3f and cos f. The amplitudes of the five terms have been extracted, first, for the hadrons in the whole available kinematic region. In further fits, performed for hadrons from a restricted kinematic region, the f-dependence is determined as a function of one of three variables (Bjorken-x, fractional energy of virtual photon taken by the outgoing hadron and hadron transverse momentum), while disregarding the others. Except thef-independent term, all themodulation amplitudes are very small, and no clear kinematic dependence could be observed within experimental uncertainties.
|
|
| 8. |
- Adolph, C., et al.
(författare)
-
First measurement of the Sivers asymmetry for gluons using SIDIS data
- 2017
-
Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 772, s. 854-864
-
Tidskriftsartikel (refereegranskat)abstract
- The Sivers function describes the correlation between the transverse spin of a nucleon and the transverse motion of its partons. For quarks, it was studied in previous measurements of the azimuthal asymmetry of hadrons produced in semi-inclusive deep inelastic scattering of leptons off transversely polarised nucleon targets, and it was found to be non-zero. In this letter the evaluation of the Sivers asymmetry for gluons is presented. The contribution of the photon-gluon fusion subprocess is enhanced by requiring two high transverse-momentum hadrons. The analysis method is based on a Monte Carlo simulation that includes three hard processes: photon-gluon fusion, QCD Compton scattering and the leading-order virtual-photon absorption process. The Sivers asymmetries of the three processes are simultaneously extracted using the LEPTO event generator and a neural network approach. The method is applied to samples of events containing at least two hadrons with large transverse momentum from the COMPASS data taken with a 160 GeV/c muon beam scattered off transversely polarised deuterons and protons. With a significance of about two standard deviations, a negative value is obtained for the gluon Sivers asymmetry. The result of a similar analysis for a Collins-like asymmetry for gluons is consistent with zero. (C) 2017 The Author(s). Published by Elsevier B.V.
|
|
| 9. |
- Adolph, C., et al.
(författare)
-
Interplay among transversity induced asymmetries in hadron leptoproduction
- 2016
-
Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 753, s. 406-411
-
Tidskriftsartikel (refereegranskat)abstract
- In the fragmentation of a transversely polarized quark several left-right asymmetries are possible for the hadrons in the jet. When only one unpolarized hadron is selected, it exhibits an azimuthal modulation known as the Collins effect. When a pair of oppositely charged hadrons is observed, three asymmetries can be considered, a di-hadron asymmetry and two single hadron asymmetries. In lepton deep inelastic scattering on transversely polarized nucleons all these asymmetries are coupled with the transversity distribution. From the high statistics COMPASS data on oppositely charged hadron-pair production we have investigated for the first time the dependence of these three asymmetries on the difference of the azimuthal angles of the two hadrons. The similarity of transversity induced single and di-hadron asymmetries is discussed. A new analysis of the data allows quantitative relationships to be established among them, providing for the first time strong experimental indication that the underlying fragmentation mechanisms are all driven by a common physical process.
|
|
| 10. |
- Adolph, C., et al.
(författare)
-
Multiplicities of charged kaons from deep-inelastic muon scattering off an isoscalar target
- 2017
-
Ingår i: Physics Letters B. - : ELSEVIER SCIENCE BV. - 0370-2693 .- 1873-2445. ; 767, s. 133-141
-
Tidskriftsartikel (refereegranskat)abstract
- Precise measurements of charged-kaon multiplicities in deep inelastic scattering were performed. The results are presented in three-dimensional bins of the Bjorken scaling variable x, the relative virtual-photon energy y, and the fraction z of the virtual-photon energy carried by the produced hadron. The data were obtained by the COMPASS Collaboration by scattering 160 GeV muons off an isoscalar (LiD)-Li-6 target. They cover the kinematic domain 1 (GeV/c)(2) < Q(2) < 60 (GeV/c)(2) in the photon virtuality, 0.004 < x < 0.4, 0.1 < y < 0.7, 0.20 < z < 0.85, and W > 5 GeV/c(2) in the invariant mass of the hadronic system. The results from the sum of the z-integrated K+ and K- multiplicities at high x point to a value of the non-strange quark fragmentation function larger than obtained by the earlier DSS fit.
|
|
