Association between COL4A3 variant rs55703767 and susceptibility to diabetic kidney disease in patients with type 2 diabetes mellitus: results from the INDEED cohort study.
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SUBMITTER: Li Z
PROVIDER: S-EPMC9276394 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Association between COL4A3 variant rs55703767 and susceptibility to diabetic kidney disease in patients with type 2 diabetes mellitus: results from the INDEED cohort study.
Li Zihan Z Sun Zijun Z Chang Dongyuan D Zhu Li L Chen Min M Zhao Minghui M
Chinese medical journal 20220505 9
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Project description:Background and objectivesDespite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents.Design, setting, participants, & measurementsWhole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants.ResultsHNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY.ConclusionsThe genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.
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Project description:Type 1 diabetes mellitus (T1DM) is an autoimmune disorder that affects an estimated 30 million people worldwide. It is characterized by the destruction of pancreatic β cells by the immune system, which leads to lifelong dependency on exogenous insulin and imposes an enormous burden on patients and health-care resources. T1DM is also associated with an increased risk of comorbidities, such as cardiovascular disease, retinopathy, and diabetic kidney disease (DKD), further contributing to the burden of this disease. Although T cells are largely considered to be responsible for β-cell destruction in T1DM, increasing evidence points towards a role for B cells in disease pathogenesis. B cell-depletion, for example, delays disease progression in patients with newly diagnosed T1DM. Loss of tolerance of islet antigen-reactive B cells occurs early in disease and numbers of pancreatic CD20+ B cells correlate with β-cell loss. Although the importance of B cells in T1DM is increasingly apparent, exactly how these cells contribute to disease and its comorbidities, such as DKD, is not well understood. Here we discuss the role of B cells in the pathogenesis of T1DM and how these cells are activated during disease development. Finally, we speculate on how B cells might contribute to the development of DKD.
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Project description:ObjectivesThis case-control study aims to clarify the impact of single nucleotide polymorphisms (SNPs) within the P2X7 gene on susceptibility to type 2 diabetes mellitus (T2DM) and to evaluate their association with diabetic complications.MethodsThis study is comprised with 200 T2DM cases and 200 healthy controls. Seven candidate SNP loci were screened, and TaqMan-MGB real-time PCR technology was used to determine the polymorphic variants of P2X7. Different genotype and allele frequencies were compared by Pearson's χ2 tests and logistic regression analysis.ResultsThree P2X7 SNPs were found to be associated with T2DM risk. Specifically, rs7958311 GA (OR = 1.323, p = 0.002), rs7958311 AA (OR = 1.508, p = 0.038), rs208294 CC (OR = 1.854, p = 0.042) showed a higher susceptibility to T2DM, whilst rs11065464 CA (OR = 0.614, p = 0.022) was associated with a reduced risk. Logistic regression analysis indicated that rs7958311 was linked to an increased risk for nephropathy (OR = 1.833, p = 0.022), but with a decreased risk for peripheral artery disease (OR = 0.550, p = 0.042). Additionally, rs208294 was identified as a risk factor for peripheral neuropathy (OR = 2.101, p = 0.016).ConclusionsWe found that P2X7 polymorphisms are significantly associated with the risk of T2DM and its complications, suggesting that targeting P2X7 may offer a novel therapeutic strategy for the prevention and personal treatment of T2DM.
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Project description:Diabetes mellitus (DM) after transplantation remains a crucial clinical problem in kidney transplantation. To obtain insights into molecular mechanisms underlying the development of post-transplant diabetes mellitus (PTDM) and its early impact on glomerular structures, here we comparatively analyze the proteome of histologically normal appearing glomeruli from patients with PTDM from normoglycemic (NG) transplant recipients, and from recipients with pre-existing type 2 DM (PTDM)
2023-10-24 | PXD042188 | Pride
Project description:BackgroundGlobally, diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease, imposing substantial social and economic costs. This meta-analysis was designed to provide valuable insights into gene-disease interactions by investigating the potential association between lipid metabolism gene polymorphisms and the risk of DKD.MethodsAn electronic literature search was conducted on MEDLINE Complete, Web of Science, Embase, and PubMed. A total of 18 studies on the peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala variant and 20 publications concerning apolipoprotein E (ApoE) gene polymorphism were included in the meta-analysis.ResultsOverall, the PPARγ Pro12Ala polymorphism was found to be significantly associated with a decreased DKD risk (OR = 0.74, 95% CI: 0.62-0.88). In subgroup analysis, Ala carriers were less susceptible to DKD than Pro homozygotes among Asian (OR = 0.73, 95% CI: 0.56-0.95) and Caucasian populations (OR = 0.74, 95% CI: 0.59-0.93). Subgroup analysis stratified by albuminuria categories showed that the PPARγ Pro12Ala polymorphism reduced the risk of both microalbuminuria and macroalbuminuria with corresponding ORs of 0.58 (95% CI: 0.43-0.78) and 0.68 (95% CI: 0.53-0.86). Sensitivity analysis confirmed the robustness of the meta-analysis results. However, publication bias was identified in the subgroup analysis of the Caucasian population. The primary analysis of the ApoE gene polymorphism yielded significant findings, indicating that ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes increase the risk of DKD (ε2/ε2 vs. ε3/ε3: OR = 1.93, 95% CI: 1.03-3.61; ε2/ε3 vs. ε3/ε3: OR = 1.63, 95% CI: 1.19-2.25; ε2/ε4 vs. ε3/ε3: OR = 1.87, 95% CI: 1.37-2.55). However, sensitivity analysis suggested that influential and Hardy-Weinberg equilibrium (HWE)-violating studies may impact the overall effect estimates.ConclusionsA meta-analysis showed that PPARγ gene polymorphism may be a protective factor for DKD, whereas the ApoE ε2/ε2, ApoE ε2/ε3, and ApoE ε2/ε4 genotypes are associated with an increased risk of DKD. However, the role of ApoE gene polymorphism in susceptibility to DKD is less certain and requires further evaluation.
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Project description:Diabetic type 2 patients compared to nondiabetic patients exhibit an increased risk of developing diabetic kidney disease (DKD), the leading cause of end-stage renal disease. Hyperglycemia, hypertension, oxidative stress (OS), and genetic background are some of the mechanisms and pathways implicated in DKD pathogenesis. However, data on OS pathway susceptibility genes show limited success and conflicting or inconclusive results. Our study is aimed at exploring OS pathway genes and variants which could be associated with DKD. We recruited 121 diabetes mellitus type 2 (DM2) patients with DKD (cases) and 220 DM2, non-DKD patients (control) of Greek origin and performed a case-control association study using genome-wide association data. PLINK and EIGENSOFT were used to analyze the data. Our results indicate 43 single nucleotide polymorphisms with their 21 corresponding genes on the OS pathway possibly contributing or protecting from DKD: SPP1, TPO, TTN, SGO2, NOS3, PDLIM1, CLU, CCS, GPX4, TXNRD2, EPHX2, MTL5, EPX, GPX3, ALOX12, IPCEF1, GSTA, OXR1, GPX6, AOX1, and PRNP. Therefore, a genetic OS background might underlie the complex pathogenesis of DKD in DM2 patients.
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Project description:BackgroundThe association between blood pressure change and kidney damage in patients with abnormal blood glucose remains unclear. The current study aimed to identify systolic blood pressure (SBP) trajectories among the prediabetic population and to determine their association with kidney damage after a long-term follow-up.MethodsThe incidence, development, and prognosis of diabetic kidney disease (INDEED) study is nested in the Kailuan cohort study with a focus on population with diabetes and prediabetes. We screened out people with prediabetes in 2006 and with more than three SBP records from 2006 to 2014 biennially. We used the latent mixture modeling to fit five groups of trajectories of SBP. In 2016, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio (uACR), and urinary α1-microglobulin (α1MG), transferrin and α1-acid glycoprotein were measured, and the association between SBP trajectories and these markers was analyzed by linear regression and logistic regression models.ResultsTotally, 1451 participants with prediabetes and without kidney damage were identified in 2006. Five heterogeneous SBP trajectories were detected based on the longitudinal data from 2006 to 2014, as low-stable group (n = 323), moderate-stable group (n = 726), moderate-increasing group (n = 176), moderate-decreasing group (n = 181), and high-stable group (n = 45). Linear regression analysis showed that the moderate and high SBP groups had lower eGFR, higher uACR, higher urinary α1MG, higher transferrin, and higher α1-acid glycoprotein than the low-stable group. Multivariable analysis attenuated the association but did not change the statistical significance.ConclusionsPrediabetic patients with persistent high-level SBP trajectory or gradually increased SBP trajectory had severer kidney damage during follow-up.
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Project description:AimsRenalase (RNLS) is an enzyme with monoamine oxidase activity that metabolizes circulating catecholamines. The RNLS gene Asp37Glu missense polymorphism (rs2296545) has been associated with hypertension, cardiac hypertrophy and dysfunction, and stroke. The purpose of our study was to investigate the potential involvement of this polymorphism in the microvascular complications of type 2 diabetes (T2DM).MethodsIn this case-control study, the polymorphism was genotyped in 860 patients with T2DM and 400 healthy controls. The genotype and allele distribution was compared in subgroups of patients: with diabetic nephropathy (DN+) (n = 405) versus DN- (independently of the presence of DR) and, similarly, patients with diabetic retinopathy (DR+) (n = 328) versus DR- (independently of the presence of DN).ResultsNo significant association was detected between analyzed polymorphism and DN. In contrast, the retinopathy subgroup showed a significantly higher frequency of G allele (OR 1.4, 95% CI 1.16-1.72, p = 0.0005) and GG genotype (OR 1.86, 95% CI 1.26-2.75, p = 0.001) than DR- patients. The effect of RNLS Glu37Asp polymorphism on DR remained significant after adjustments for age, gender, BMI, and duration of T2DM (p = 0.005).ConclusionsThis is the first study to investigate RNLS gene polymorphism in microvascular complications of T2DM. The results suggest that RNLS rs2296545 SNP might be considered a risk factor for diabetic retinopathy in T2DM patients. This can provide new insight into the role of renalase gene in the pathophysiology of microvascular complications of diabetes.
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Project description:The purpose of this study is to investigate potential associations between optical coherence tomography angiography (OCTA) parameters and diabetic kidney disease (DKD) categories in type 1 diabetes mellitus (T1DM) patients and controls. A complete ocular and systemic examination, including OCTA imaging tests and bloods, was performed. OCTA parameters included vessel density (VD), perfusion density (PD), foveal avascular zone area (FAZa), perimeter (FAZp) and circularity (FAZc) in the superficial vascular plexus, and DKD categories were defined according to glomerular filtration rate (GFR), albumin-creatinine ratio (ACR) and KDIGO prognosis risk classifications. A total of 425 individuals (1 eye/1 patient) were included. Reduced VD and FAZc were associated with greater categories of GFR (p = 0.002, p = 0.04), ACR (p = 0.003, p = 0.005) and KDIGO risk prognosis classifications (p = 0.002, p = 0.005). FAZc was significantly reduced in greater KDIGO prognosis risk categories (low risk vs. moderate risk, 0.65 ± 0.09 vs. 0.60 ± 0.07, p < 0.05). VD and FAZc presented the best diagnostic performance in ROCs. In conclusion, OCTA parameters, such as VD and FAZc, are able to detect different GFR, ACR, and KDIGO categories in T1DM patients and controls in a non-invasive, objective quantitative way. FAZc is able to discriminate within T1DM patients those with greater DKD categories and greater risk of DKD progression.
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Project description:ObjectiveThis study aims to explore the link between iron deficiency anemia (IDA) and diabetic kidney disease (DKD) and assess the safety of iron supplementation. It also investigates key mechanisms and molecules involved in iron deficiency's role in disease development.MethodsA retrospective analysis was conducted on 1,398 T2DM patients using propensity score matching to identify risk factors for DKD. Mendelian randomization (MR) was used to explore causal relationships between IDA, iron supplementation, liver iron content, and DKD. The GSE27999 dataset was analyzed to examine how an iron-deficient diet affects kidney-related gene expression. Key pathways and molecules were identified through GSEA, GO/KEGG, and PPI analysis.ResultsRetrospective data showed a correlation between hemoglobin levels and DKD risk. Logistic regression confirmed that IDA increased DKD risk independently of other factors. MR revealed a causal link between IDA and DKD, with no significant effect from iron supplementation. GSE27999 analysis identified 580 differentially expressed genes, enriched in pathways like cytokine signaling, oxidative biology, and small molecule transport. PPI analysis highlighted 10 key hub genes, including Cyp2d26 and Fgf4.ConclusionIDA increases susceptibility to DKD, possibly through oxidative stress and altered small molecule transport. However, iron supplementation does not appear to increase the risk of DKD.
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