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1دورية أكاديمية
المؤلفون: Jie Zhang, Peter Yu, Ying Bao, Cathy W Critchlow, Corina Bennett, Fang He, Julia Zhu, Zhongyuan Wei, Qian Xia, Jenny Jiang, Olulade Ayodele, Brian D Bradbury, Corinne Brooks, Carolyn A Brown, Alvan Cheng, Giovanna Devercelli, Kathleen Gondek, Ajit A Londhe, Junjie Ma, Michele Jonsson-Funk, Hillary A Keenan, Kaili Ren, Lynn Sanders, Linyun Zhou, John H Page, J Michael Sprafka, Megan Braunlin, Prista Charuworn, Karminder Gill, Jeffrey Petersen, Katherine B Carlson, Shun-Chiao Chang, Kimberly A Roehl, Luyang Wang
المصدر: BMJ Open, Vol 12, Iss 2 (2022)
مصطلحات موضوعية: Medicine
وصف الملف: electronic resource
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2دورية أكاديمية
المؤلفون: Jie Zhang, Peter Yu, Sudhakar Manne, Ying Bao, Cathy W Critchlow, Julia Zhu, Zhongyuan Wei, Manasi Suryavanshi, Xiu Chen, Qian Xia, Jenny Jiang, Olulade Ayodele, Brian D Bradbury, Corinne Brooks, Carolyn A Brown, Alvan Cheng, Giovanna Devercelli, Vivek Gandhi, Kathleen Gondek, Ajit A Londhe, Junjie Ma, Michele Jonsson-Funk, Hillary A Keenan, Kaili Ren, Lynn Sanders, Linyun Zhou
المصدر: BMJ Open, Vol 11, Iss 8 (2021)
مصطلحات موضوعية: Medicine
الوصف: Objective To examine age, gender, and temporal differences in baseline characteristics and clinical outcomes of adult patients hospitalised with COVID-19.Design A cohort study using deidentified electronic medical records from a Global Research Network.Setting/Participants 67 456 adult patients hospitalised with COVID-19 from the USA; 7306 from Europe, Latin America and Asia-Pacific between February 2020 and January 2021.Results In the US cohort, compared with patients 18–34 years old, patients ≥65 had a greater risk of intensive care unit (ICU) admission (adjusted HR (aHR) 1.73, 95% CI 1.58 to 1.90), acute respiratory distress syndrome(ARDS)/respiratory failure (aHR 1.86, 95% CI 1.76 to 1.96), invasive mechanical ventilation (IMV, aHR 1.93, 95% CI, 1.73 to 2.15), and all-cause mortality (aHR 5.6, 95% CI 4.36 to 7.18). Men appeared to be at a greater risk for ICU admission (aHR 1.34, 95% CI 1.29 to 1.39), ARDS/respiratory failure (aHR 1.24, 95% CI1.21 to 1.27), IMV (aHR 1.38, 95% CI 1.32 to 1.45), and all-cause mortality (aHR 1.16, 95% CI 1.08 to 1.24) compared with women. Moreover, we observed a greater risk of adverse outcomes during the early pandemic (ie, February–April 2020) compared with later periods. In the ex-US cohort, the age and gender trends were similar; for the temporal trend, the highest proportion of patients with all-cause mortality were also in February–April 2020; however, the highest percentages of patients with IMV and ARDS/respiratory failure were in August–October 2020 followed by February–April 2020.Conclusions This study provided valuable information on the temporal trends of characteristics and outcomes of hospitalised adult COVID-19 patients in both USA and ex-USA. It also described the population at a potentially greater risk for worse clinical outcomes by identifying the age and gender differences. Together, the information could inform the prevention and treatment strategies of COVID-19. Furthermore, it can be used to raise public awareness of COVID-19’s impact on vulnerable populations.
وصف الملف: electronic resource
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3دورية أكاديمية
المؤلفون: Daniel Scarr, Leif E Lovblom, Nancy Cardinez, Andrej Orszag, Mohammed A Farooqi, Genevieve Boulet, Alanna Weisman, Julie A Lovshin, Mylan Ngo, Narinder Paul, Hillary A Keenan, Michael H Brent, David Z Cherney, Vera Bril, Bruce A Perkins
المصدر: PLoS ONE, Vol 13, Iss 4, p e0196647 (2018)
الوصف: Point-of-care nerve conduction devices (POCD) have been studied in younger patients and may facilitate screening for polyneuropathy in non-specialized clinical settings. However, performance may be impaired with advanced age owing to age-related changes in nerve conduction. We aimed to evaluate the validity of a POCD as a proxy for standard nerve conduction studies (NCS) in older adults with type 1 diabetes (T1D).Sural nerve amplitude potential (AMP) and sural nerve conduction velocity (CV) was measured in 68 participants with ≥ 50 years T1D duration and 71 controls (from age/sex-matched subgroups) using POCD and NCS protocols. Agreement was determined by the Bland-Altman method, and validity was determined by receiver operating characteristic curves.T1D were 53% female, aged 66±8yr and had diabetes duration 54yr[52,58]. Controls were 56%(p = 0.69) female and aged 65±8yr(p = 0.36). Mean AMPPOCD and CVPOCD for the 139 participants was 7.4±5.8μV and 45.7±11.2m/s and mean AMPNCS and CVNCS was 7.2±6.1μV and 43.3±8.3m/s. Mean difference of AMPPOCD-AMPNCS was 0.3±3.8μV and was 2.3±8.5m/s for CVPOCD-CVNCS. A AMPPOCD of ≤6μV had 80% sensitivity and 80% specificity for identifying abnormal AMPNCS, while a CVPOCD of ≤44m/s had 81% sensitivity and 82% specificity to identify abnormal CVNCS. Abnormality in AMPPOCD or CVPOCD was associated with 87% sensitivity, while abnormality in both measures was associated with 97% specificity for polyneuropathy identification.The POCD has strong agreement and diagnostic accuracy for identification of polyneuropathy in a high-risk subgroup and thus may represent a sufficiently accurate and rapid test for routinely detecting those with electrophysiological dysfunction.
وصف الملف: electronic resource
العلاقة: http://europepmc.org/articles/PMC5927425?pdf=renderTest; https://doaj.org/toc/1932-6203Test
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4دورية أكاديمية
المؤلفون: Nigar Sekercioglu, Leif Erik Lovblom, Petter Bjornstad, Julie A. Lovshin, Yuliya Lytvyn, Geneviève Boulet, Mohammed A. Farooqi, Andrej Orszag, Vesta Lai, Josephine Tse, Leslie Cham, Hillary A. Keenan, Michael H. Brent, Narinder Paul, Vera Bril, Bruce A. Perkins, David Z. I. Cherney
المصدر: Renal Failure, Vol 41, Iss 1, Pp 427-433 (2019)
مصطلحات موضوعية: type 1 diabetes, diabetic kidney disease, diabetic neuropathy, diabetic retinopathy, Diseases of the genitourinary system. Urology, RC870-923
الوصف: Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m2 and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.
العلاقة: http://dx.doi.org/10.1080/0886022X.2019.1614057Test; https://doaj.org/toc/0886-022XTest; https://doaj.org/toc/1525-6049Test; https://doaj.org/article/e5474eaf563e403b8c103cc886b356e5Test
الإتاحة: https://doi.org/10.1080/0886022X.2019.1614057Test
https://doaj.org/article/e5474eaf563e403b8c103cc886b356e5Test -
5دورية أكاديمية
المؤلفون: Daniel Scarr, Petter Bjornstad, Leif E. Lovblom, Julie A. Lovshin, Genevieve Boulet, Yuliya Lytvyn, Mohammed A. Farooqi, Vesta Lai, Andrej Orszag, Alanna Weisman, Hillary A. Keenan, Michael H. Brent, Narinder Paul, Vera Bril, David Z.I. Cherney, Bruce A. Perkins
المصدر: Kidney International Reports, Vol 4, Iss 6, Pp 786-796 (2019)
مصطلحات موضوعية: Diseases of the genitourinary system. Urology, RC870-923
الوصف: Introduction: Glomerular filtration rate (GFR) is routinely used for clinical assessment of kidney function. However, the accuracy of estimating equations in older adults is uncertain. Methods: In 66 adults with ≥50 years type 1 diabetes (T1D) duration and 73 nondiabetic controls from age/sex-matched subgroups (65 ± 8 years old and 77[55%] were women) we evaluated the performance of estimated GFR (eGFR) by creatinine (Modification of Diet and Renal Disease [MDRD], Chronic Kidney Disease–Epidemiology [CKD-EPI]cr), cystatin C (CKD-EPIcys, CKD-EPIcr-cys), and β2-microglobulin (β2M) compared with measured GFR by inulin clearance (mGFR). Performance was evaluated using metrics of bias (mean difference), precision (SD), and accuracy (proportion of eGFR that differed by >20% of mGFR). Results: Mean mGFR was 104 ± 18 ml/min per 1.73 m2 (range: 70–154 ml/min per 1.73 m2) and was not different between T1D and controls (103 ± 17 vs. 105 ± 19 ml/min per 1.73 m2, P = 0.39). All equations significantly underestimated mGFR (bias: −15 to −30 ml/min per 1.73 m2, P < 0.001 for all comparisons) except for β2M, which had bias of 1.9 ml/min per 1.73 m2 (P = 0.61). Bias was greatest in cystatin C–based equations. Precision was lowest for β2M (SD: 43.5 ml/min per 1.73 m2, P < 0.001 for each comparison). Accuracy was lowest for CKD-EPIcysC (69.1%, P < 0.001 for each comparison). Cystatin C–based equations demonstrated greater bias and lower accuracy in older age subgroups (<60, 60–69, ≥70 years). All equations demonstrated greater bias across higher ranges of mGFR (60–89, 90–119, ≥120 ml/min per 1.73 m2). Results were similar between T1D and controls except that β2M had lower performance in T1D. Conclusion: Better estimates of GFR in older adults are needed for research and clinical practice, as this subgroup of the population has an amplified risk for the development of chronic kidney disease (CKD) that requires accurate GFR estimation methods. Keywords: β2-microglobulin, creatinine, cystatin C, estimating equations, ...
العلاقة: http://www.sciencedirect.com/science/article/pii/S2468024919300713Test; https://doaj.org/toc/2468-0249Test; https://doaj.org/article/c292c75b1ebd4628986a5c56d7f5c87fTest
الإتاحة: https://doi.org/10.1016/j.ekir.2019.02.010Test
https://doaj.org/article/c292c75b1ebd4628986a5c56d7f5c87fTest -
6دورية أكاديمية
المؤلفون: Ernesto Maddaloni, Yu Xia, Kyoungmin Park, Stephanie D’Eon, Liane J. Tinsley, Ronald St-Louis, Mogher Khamaisi, Qian Li, George L. King, Hillary A. Keenan
المصدر: Cardiovascular Diabetology, Vol 16, Iss 1, Pp 1-11 (2017)
مصطلحات موضوعية: Osteocalcin, Type 1 diabetes, Cardiovascular disease, HDL, Monocytes, Calcifying monocytes, Diseases of the circulatory (Cardiovascular) system, RC666-701
الوصف: Background Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M). Methods CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. Results Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = −0.424, p = 0.02), large (r = −0.413, p = 0.02) and intermediate (r = −0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05). Conclusions Low OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation.
العلاقة: http://link.springer.com/article/10.1186/s12933-017-0599-2Test; https://doaj.org/toc/1475-2840Test; https://doaj.org/article/28f3f38e93574f5e90d3fe6d40c44a43Test
الإتاحة: https://doi.org/10.1186/s12933-017-0599-2Test
https://doaj.org/article/28f3f38e93574f5e90d3fe6d40c44a43Test -
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المؤلفون: Mark Dant, Joseph Muenzer, Hillary A. Keenan, Nicole Muschol, Roberto Giugliani
المصدر: Repositório Institucional da UFRGS
Universidade Federal do Rio Grande do Sul (UFRGS)
instacron:UFRGS
Archives of Disease in Childhoodمصطلحات موضوعية: Male, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Delayed Diagnosis, Mucopolysaccharidosis I, medicine.medical_treatment, Time to treatment, Hematopoietic stem cell transplantation, Disease, Severity of Illness Index, Time-to-Treatment, 03 medical and health sciences, Mucopolysaccharidosis type I, 0302 clinical medicine, multidisciplinary team-care, metabolic, therapeutics, medicine, Humans, Enzyme Replacement Therapy, In patient, Registries, Child, Original Research, Retrospective Studies, 0303 health sciences, Tempo para o tratamento, business.industry, 030305 genetics & heredity, Hematopoietic Stem Cell Transplantation, nutritional and metabolic diseases, Infant, Enzyme replacement therapy, Mucopolissacaridose I, monitoring, Child, Preschool, Pediatrics, Perinatology and Child Health, Disease Progression, Female, Observational study, business, 030217 neurology & neurosurgery, Time to diagnosis
الوصف: ObjectiveEarly diagnosis and treatment initiation are important factors for successful treatment of mucopolysaccharidosis type I (MPS I). The purpose of this observational study was to assess whether age at diagnosis and time to first treatment for individuals with MPS I have improved over the last 15 years.Study designData from the MPS I Registry (NCT00144794) for individuals with attenuated or severe disease who initiated therapy with laronidase enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT) between 1 January 2003 and 31 December 2017 were included.ResultsData were available for 740 individuals with attenuated (n=291) or severe (n=424) MPS I (unknown n=25). Median age at diagnosis for attenuated disease did not change over time and ranged between 4.5 and 6 years of age while the median duration from diagnosis to first ERT decreased from 5.6 years before/during 2004 to 2.4 months in 2014–2017. For severe MPS I treated with HSCT, median age at diagnosis was less than 1 year and median time to first treatment was less than 3 months throughout the 15-year observation period.ConclusionsTimes to diagnosis and HSCT initiation for individuals with severe MPS I were consistent over time. For individuals with attenuated MPS I, the time to ERT initiation after diagnosis has improved substantially in the last 15 years, but median age at diagnosis has not improved. Efforts to improve early diagnosis in attenuated MPS I are needed to ensure that patients receive appropriate treatment at the optimal time.
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aa875d1fe4db217830fe4592780a2e08Test
https://doi.org/10.1136/archdischild-2020-319040Test -
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المؤلفون: Yuliya Lytvyn, Rehab Albakr, Petter Bjornstad, Leif Erik Lovblom, Hongyan Liu, Julie A. Lovshin, Genevieve Boulet, Mohammed A. Farooqi, Alanna Weisman, Hillary A. Keenan, Michael H. Brent, Narinder Paul, Vera Bril, Bruce A. Perkins, David Z.I. Cherney
المصدر: Journal of diabetes and its complications. 36(11)
مصطلحات موضوعية: Adult, Canada, Endocrinology, Diabetes Mellitus, Type 1, Endocrinology, Diabetes and Metabolism, Albumins, Longevity, Internal Medicine, Hemodynamics, Humans, Diabetic Nephropathies, Glomerular Filtration Rate
الوصف: To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls.Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RHigher mTCNS associated with lower renal blood flow (β ± SE:-9.29 ± 4.20, p = 0.03) and greater RAlthough neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0c0fd5422dcefb05189397c3a7ce1c69Test
https://pubmed.ncbi.nlm.nih.gov/36201892Test -
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المؤلفون: Tomas Vaisar, Angela Irwin, Karin E. Bornfeldt, George L. King, Hetal Shah, Hillary A. Keenan, I-Hsien Wu, Carla J. Greenbaum, John Gauthier, Vanessa Bahnam, Jake Wimberger, Jay W. Heinecke, Emily Wolfson, Jenny E. Kanter
المصدر: Diabetes Care
مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Time Factors, Lipoproteins, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Pathophysiology/Complications, Aged, Advanced and Specialized Nursing, High concentration, Type 1 diabetes, biology, Aryldialkylphosphatase, business.industry, Cholesterol, Cholesterol, HDL, Paraoxonase, nutritional and metabolic diseases, Middle Aged, Atherosclerosis, medicine.disease, PON1, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Endocrinology, chemistry, biology.protein, Female, lipids (amino acids, peptides, and proteins), business, Diabetic Angiopathies, Ex vivo, Cohort study
الوصف: OBJECTIVE A subset of people with long-standing type 1 diabetes (T1D) appears to be protected from microvascular and macrovascular complications. Previous studies have focused on improved abilities to respond to glucose and its downstream effects as protective mechanisms. It is unclear whether lipoproteins play a role in the vascular health of these people. We therefore determined whether HDL particle concentration, size, function, and/or protein composition associate with protection from vascular complications. RESEARCH DESIGN AND METHODS We studied two independent cross-sectional cohorts with T1D: the T1D Exchange Living Biobank (n = 47) and the Joslin Medalist Study (n = 100). Some of the subjects had vascular complications, whereas others never exhibited vascular complications, despite an average duration of diabetes in the cohorts of 45 years. We assessed HDL particle size and concentration by calibrated ion mobility analysis, the HDL proteome by targeted mass spectrometry, and HDL function ex vivo by quantifying cholesterol efflux capacity and inhibition of monocyte adhesion to endothelial cells. RESULTS In both cohorts, people without vascular complications exhibited significantly higher concentrations of medium-sized HDL particles (M-HDL) independently of total and HDL cholesterol levels. While no consistent differences in HDL functions were observed ex vivo, people without vascular complications had higher levels of HDL-associated paraoxonase 1 (PON1), an enzyme that inhibits atherosclerosis in animal models. CONCLUSIONS Elevated concentrations of M-HDL particles and elevated levels of HDL-associated PON1 may contribute to long-term protection from the vascular complications of diabetes by pathways that are independent of total cholesterol and HDL cholesterol.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::897d83b3cf31d6798c5e128bc886384cTest
https://doi.org/10.2337/dc19-0772Test -
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المؤلفون: Rachel G. Miller, Erkka Valo, Jani K. Haukka, Tina Costacou, Barbara E.K. Klein, Beata Gyorgy, Joseph V. Bonventre, Katalin Susztak, Hillary A. Keenan, James H. Warram, Marlon Pragnell, Ivan G. Shabalin, Andrew D. Paterson, Stephen S. Rich, Takaharu Ichimura, Jingjing Cao, Suna Onengut-Gumuscu, Ronald Klein, Kristina O’Neil, Eiichiro Satake, Marcus G. Pezzolesi, Josyf C. Mychaleckyj, Niina Sandholm, Christian Dina, Andrzej T. Galecki, George L. King, Trevor J. Orchard, Samy Hadjadj, Per-Henrik Groop, Adam M. Smiles, Carol Forsblom, Andrzej S. Krolewski, David-Alexandre Trégouët, Tarunveer S. Ahluwalia, Peter Rossing, Ron Korstanje
المساهمون: Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CAMM - Research Program for Clinical and Molecular Metabolism, HUS Abdominal Center, Nefrologian yksikkö, Research Programs Unit, Clinicum, Medicum, Department of Medicine, Per Henrik Groop / Principal Investigator
المصدر: Journal of the American Society of Nephrology
Journal of the American Society of Nephrology, American Society of Nephrology, 2021, 32 (10), pp.2634-2651. ⟨10.1681/ASN.2020101457⟩مصطلحات موضوعية: Gene-based tests, GENES, GENETICS, NEPHROPATHY, DURATION, 030209 endocrinology & metabolism, Hydroxysteroid 17-beta dehydrogenase 14, Diabetic nephropathy, Biology, 03 medical and health sciences, 0302 clinical medicine, Gene expression, medicine, Coding region, GENOME-WIDE ASSOCIATION, Diabetic kidney disease, PREDICTORS, Gene, Exome, 030304 developmental biology, RISK, 0303 health sciences, Type 1 diabetes, Kidney, COMPLICATIONS, End stage kidney disease, MICROALBUMINURIA, Rare variants, General Medicine, medicine.disease, RENAL DECLINE, medicine.anatomical_structure, Nephrology, 3121 General medicine, internal medicine and other clinical medicine, Cancer research, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Kidney disease
الوصف: Background Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of end stage kidney disease (ESKD) in individuals with type 1 diabetes at advanced kidney disease stage. Methods Gene-based exome array analysis of 15,449 genes in 5 large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time-to-ESKD, testing the top gene in a 6th cohort (N=2,372/1,115 events all cohorts) and replicating in two retrospective case-control studies (N=1,072 cases, 752 controls). Deep resequencing of the top associated gene in 5 cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. Results Protein coding variants in the hydroxysteroid 17-beta dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (N=4,196; p-value=3.3x10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other chronic kidney disease-associated renal pathologies. Conclusions HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f1d8ebafcd82a8106854f67bac0a578dTest
http://hdl.handle.net/20.500.12278/123983Test