Susceptibility To Diabetic Nephropathy Research Articles

Association between nitric oxide synthase (NOS3) gene polymorphisms and diabetic nephropathy: An updated meta-analysis

Polymorphisms located within NOS3 gene have been investigated as susceptibility variants for diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM) in a large number of studies. However, these previous articles yielded inconsistent results and we aimed at elucidating the impact of NOS3 variants on DN risk in T2DM by conducting an updated systematic data synthesis. A total of 36 studies (12,807 participants) were selected for qualitative data synthesis, while 33 records with 11,649 subjects were included in the meta-analysis. The pooled analysis demonstrated the association of minor alleles of rs2070744 and rs1799983 with an increased susceptibility to DN (P < 0.001 and P = 0.015 for allelic model, respectively). For both of these variants, a significant effect of subgrouping according to ethnicity was found. Rs869109213 displayed an association with DN susceptibility, with pooled effect measures indicating a predisposing effect of the minor allele a (Prec = 0.002, ORrec = 1.960, 95%CI 1.288–2.983; Paavs. bb = 0.001, ORaavs. bb = 2.014, 95%CI 1.316–3.083). These findings support the effects of NOS3 variants on the risk of developing DN in T2DM.

Associations of genetic variants contributing to gut microbiota composition in diabetic nephropathy.

The gut microbiota is strongly associated with multiple kidney diseases, and since microbial composition is heritable, we hypothesized that genetic variations controlling gut microbiota composition were associated with diabetic nephropathy susceptibility or clinical subphenotypes. The genetic variations associated with gut microbiota were retrieved from the genome-wide association study database and analysed in our diabetic nephropathy susceptibility gene screening cohort. Candidate microorganisms with possible genetic associations were identified using the annotation of microbial quantitative trait loci. Finally, the candidate microorganisms were verified by 16S rDNA gene sequencing. There were 13 genetic variation loci associated with susceptibility to diabetic nephropathy. The TCF7L2 risk genotype was associated with a long duration of diabetes and high diastolic blood pressure, the ZCWPW2 risk genotype was associated with increased glycosylated hemoglobin, and the ZNRF3 risk genotype was associated with an increased urinary microalbumin-to-creatinine ratio. Both the ZNRF3 and SPECC1L risk genotypes were associated with the abundance of Lactococcus. 16S rDNA sequencing confirmed that there was indeed a significant difference in the Lactococcus genus between DN and DM patients. In this study, we preliminarily confirmed that the gut microbiota of diabetic nephropathy patients is influenced by host genetics and provide a new basis for future accurate diagnosis and treatment.

Association of Apolipoprotein E Gene Polymorphism with Type 2 Diabetic Nephropathy in the Southern Chinese Population.

Common polymorphisms within the apolipoprotein E (APOE) gene are rs429358 and rs7412, which result in three major alleles (ɛ2, ɛ3, and ɛ4) and six genotypes (E2/E2, E2/E3, E3/E3, E3/E4, E4/E4, and E2/E4). Although APOE gene polymorphisms have been suggested to be associated with the development of diabetic nephropathy (DN), their potential association remains unclear in different regions. This study aims to unveil the genetic effects of APOE gene polymorphisms on DN susceptibility and serum lipid profiles in southern Chinese population. A total of 306 DN patients and 483 type 2 diabetic patients as controls were included in the study. The APOE gene polymorphisms were analyzed by polymerase chain reaction (PCR) microarray gene chip. Relevant medical records and information of these participants were collected. There were statistically significant differences (p < 0.05) in gender, SBP, hypertension, hyperuricemia, UTP, TG and HDL-C between DN patients and controls. DN patients exhibited a higher frequency of the ε2 allele and E2/E3 genotype than controls (p < 0.001). Logistic regression analysis indicated that the ε2 allele and E2/E3 genotype were independent risk factors (adjusted OR: 3.237, 95% CI: 1.789-5.854, p < 0.001; adjusted OR: 3.453, 95% CI: 1.873-6.368, p < 0.001), while the ε3 allele or E3/E3 genotype might serve as protective role (adjusted OR: 0.395, 95% CI: 0.255-0.612, p < 0.001) for development of DN. Our study indicates a correlation between APOE polymorphisms and DN in the southern Chinese Hakka population. Specifically, individuals carrying the APOE ε2 allele and E2/E3 genotype are at a higher risk of developing DN. Conversely, those with the APOE ε3 allele and E3/E3 genotype have a lower risk of DN in southern Chinese population.

SAT091 Genetic Investigation Of The Susceptibility To Develop Type 1 Diabetes And Diabetic Nephropathy

Abstract Disclosure: I. Brema: None. A. Aljuryyan: None. B. Bradley: None. A.E. Osman: None. Diabetic Nephropathy (DN) is one of the leading causes of end-stage renal disease (ESRD) worldwide and is a major cause of morbidity and mortality in subjects with type 1 diabetes (T1DM). Several single nucleotide polymorphisms (SNP) have been found in various gene variants such as the ACE, NOS 3, and FRMD 3 genes that play a major role in genetic susceptibility to DN, however, there is lack of wide replication of these studies, particularly in non-Caucasian ethnic groups. Therefore, the aim of this study was to identify SNPs that increase the susceptibility to develop T1DM as well as microalbuminuria (the hallmark of DN) in a Saudi cohort of subjects with T1DM. We conducted a case-control study in 179 subjects with T1DM and 180 healthy normal controls comparing genotype frequency of 11 SNPs that have been shown to increase the susceptibility to develop DN in subjects with T1DM, namely, rs1799983, rs2070744 (NOS3 gene); rs560807, rs 1059982 (CAT gene), rs1888747, rs10868025, rs361525, rs1800629 (FRMD3 gene), rs182052, rs 17300539 (ADIPOQ gene) and rs1799752(ACE gene). We report that the A/G rs361525 (FRMD3) genotype has significantly higher frequency in controls compared to subjects with T1DM (9 % vs 0), p value 0.01) and it seems to be protective against the risk of T1DM development. Moreover, the A/A rs17300539 (ADIPOQ gene) genotype has significant higher frequency in controls compared to subjects with T1DM (7 % vs 0.5), p value 0.02) and seems to be protective against type 1 development as well. We did not detect any further associations between the remaining 9 genotype SNPs and the risk of T1DM. On the other hand, we report no association between all the 11 studied SNPs referenced above and the risk of developing diabetic nephropathy. We have studied several DN susceptibility SNPs that have been shown to increase the risk of albuminuria and ESRD development in Caucasians with T1DM , however, we were unable to replicate previous findings in this Saudi cohort of patients with T1DM. Future larger multicenter studies are needed in larger numbers of patients to replicate the findings of the studies that were done in Caucasians and other ethnic groups, ideally Genome-wide association studies. Presentation: Saturday, June 17, 2023

PS-BPB08-4: IMPAIRED TCA CYCLE METABOLISM IN DIABETIC NEPHROPATHY IS LINKED TO ALBUMINURIA AND KIDNEY INJURY

Objective: Recent work has highlighted potential contributions of impaired renal energy metabolism, including mitochondrial dysfunction and altered fatty acid metabolism, in chronic kidney diseases including diabetic nephropathy (DN). However, causal connections between specific metabolic abnormalities and pathophysiology of DN have been difficult to establish. Here, we approach this question using a mouse model recapitulating characteristic features of human DN and a targeted metabolomics platform designed to assess key metabolic pathways involving amino acids, fatty acids, glycolysis and the TCA cycle. Design and method: We generated a mouse model of DN with underlying activation of the renin-angiotensin system (RAS) by a renin transgene (R) driven by the albumin promoter on the Akita background of type I diabetes (A). We have shown that on a susceptible 129/Sv background, Akita-ReninTg (AR) mice exhibit cardinal characteristics of human DN including high-grade albuminuria and glomerulosclerosis, whereas AR mice on a C57BL/6 background do not develop DN. To assess the impact of genetic background on energy metabolism in DN, kidneys from 24-week-old male AR mice on both backgrounds were evaluated by the targeted metabolome analysis. To further distinguish the impact of RAS activation on relevant pathways associated with kidney disease development, 12-week-old male 129/Sv AR mice were treated with the angiotensin receptor blocker (ARB) losartan 10 mg/kg/day for 12 weeks. 24-hour urine samples were collected in metabolic cages and urine albumin levels were measured by EIA. Kidneys from age-matched parental 129/Sv and C57BL/6 wild-type mice were analyzed as controls. Results: A distinct metabolic profile was observed in kidneys of DN-susceptible 129/Sv AR mice including reduced levels of C2 acetyl-carnitine that reflect a deficiency in acetyl-CoA, perturbations of TCA cycle intermediates and increased lactate levels. In addition, levels of phosphorylated-AMPK were reduced. These metabolic changes were absent in DN-resistant C57BL/6 AR mice. Treatment of 129/Sv AR mice with the ARB dramatically reduced albuminuria (906 ± 169 vs 193 ± 42 μg/day, p &lt; 0.01) and attenuated kidney pathology while restoring levels of C2 acetyl-carnitine, TCA intermediates, lactate and phosphorylated-AMPK toward normal. ARB treatment also increased kidney ATP content. In 129/Sv mice, there were statistically significant correlations between albuminuria and kidney levels of lactate, acetyl-carnitine, citrate and succinate. Conclusions: Thus, there is a distinct profile of impaired energy metabolism associated with DN susceptibility that is attenuated by RAS blockade. Impaired TCA cycle function and coincident increases in lactate are linked to albuminuria in mice with DN, and may contribute to kidney injury.

Epithelial nitric oxide synthases (eNOS) 894 G &lt; T polymorphism and diabetic nephropathy susceptibility: A meta-analysis

Abstract Objective To investigate the epithelial nitric oxide synthases (eNOS) 894 G &lt; T polymorphism and diabetic nephropathy (DN) susceptibility by pooling the open published data. Methods Studies relevant to eNOS 894 G &lt; T polymorphism and DN susceptibility published in PubMed, EMBASE, Medline, CNKI, and Wanfang databases were systematically screened by using the text words of endothelial nitric oxide synthase, eNOS, NOS-3, G894T, rs179983, polymorphism, diabetic nephropathy, and DN. The correlation between eNOS 894 G &lt; T polymorphism and DN susceptibility was demonstrated by odds ratio (OR) and corresponding 95% confidence interval (95% CI). The data were combined through fixed or random effect model according to statistical heterogeneity. The publication bias was assessed by Begg’s funnel plot and Egger’s line regression test. Results Twenty-six case-control studies relevant to eNOS 894 G &lt; T polymorphism and DN susceptibility were identified by electronic searching of the related databases. Type 2 diabetes mellitus (T2MD) patients with T allele had increased susceptibility to DN compared with G allele under homologous gene model (TT vs GG) (OR = 1.40, 95% CI: 1.16–1.69, p = 0.001), dominant gene model (TT + GT) vs GG (OR = 1.61, 95% CI: 1.30–2.00, p = 0.000) and recessive gene model TT vs (GT + GG) (OR = 1.39, 95% CI: 1.16–1.66, p = 0.000). Publication bias was not statistically significant for homologous and recessive gene model. Conclusion Based on the present evidence, DN risk was increased in T2MD cases with T allele compared to G allele.

Genetic variations of tumor necrosis factor-α and prostaglandin-endoperoxide synthase 2 genes among Egyptian patients with type 2 diabetes mellitus and diabetic nephropathy

ObjectivesThe current study aimed to determine whether genetic differences in the tumor necrosis factor-α (TNF-α) and prostaglandin-endoperoxide synthase 2 (PTG2) genes are linked to type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). BackgroundDN is a major cause of chronic kidney disease (CKD). Unfortunately, the precise pathogenic mechanisms of DN are not completely understood. Recent data suggest a link between inflammatory cytokines and the chronic complications of T2DM. TNF-α and PTG2 are key mediators of inflammation. Subjects and methodsThis is a case-control study that includes 100 patients (group 1: 50 diabetic patients with diabetic nephropathy and group 2: 50 patients without diabetic nephropathy) and 50 age- and sex-matched healthy controls (group 3). Genotyping of TNF-α (rs3651525) and PTGS2 (rs689466) by real-time PCR was applied. ResultsTNF-α (rs3651525) and PTGS2 (rs689466) genotype frequency and allelic distribution are in Hardy-Weinberg equilibrium (HWE). When T2DM patients with nephropathy were compared to those without DN, regression analysis for the PTGS2 rs689466 and TNF-rs361525 single nucleotide polymorphisms (SNPs) demonstrated that none of the SNP genotypes showed a major risk factor for DN susceptibility. As regards TNF-α rs361525, GA and AA genotypes were significantly associated with a higher risk of T2DM when compared to GG, and A allele showed a 3.721-fold increased risk.TNF-α rs361525 AA genotype (OR, 10.980; 95% CI 1.385–87.066) and TNF-rs361525 GA genotype (OR, 3.050; 95% CI 1.315–7.0758) are the most substantially linked parameters with the risk of diabetes mellitus in univariate analysis.According to the multivariate analysis, the AA and GA genotypes of the SNP rs361525 significantly affect the development of diabetes mellitus. No remarkable association was found between the PTGS2 (rs689466) polymorphism and diabetes mellitus and diabetic nephropathy. ConclusionIn contrast to the lack of a significant correlation between PTGS2 (rs689466) and DM or DN, TNF-α rs361525 was connected to the possibility of developing diabetes mellitus in our study.

MTHFR C667T polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus: An updated meta-analysis

Abstract Background Numerous studies indicated that there exists a relationship between methylenetetrahydrofolate reductase (MTHFR) C667T polymorphism and diabetic nephropathy (DN) susceptibility; nonetheless, available proof reported from individual studies has not been consistent, so we performed an updated meta-analysis to evaluate the relationship between MTHFR C667T variant and DN. Materials and methods Relevant studies published before February 2022 were searched from the electronic databases PubMed, Embase, Scopus, Chinese Biology Medicine and the Chinese National Knowledge Infrastructure. The strength of the association was examined by odds ratio (OR) with 95% confidence interval (CI). Results The findings illustrated that there was a significant relationship between the polymorphism of C677T and DN compared with that to DM controls in allele (OR = 1.59, 95% CI = 1.39–1.82), dominant (OR = 1.76, 95% CI = 1.47–2.11) and recessive (OR = 1.85, 95% CI = 1.56–2.20) models in all populations. Moreover, as compared with the healthy controls, a significant relationship between C677T and DN was found in three genetic comparison models (allele: OR = 1.81, 95% CI = 1.43–2.29; dominant: OR = 2.09, 95% CI = 1.54–2.85; recessive: OR = 2.02, 95% CI = 1.51–2.70). Furthermore, stratifying data by race, diabetes duration and whether in Hardy–Weinberg equilibrium revealed substantially augmented vulnerability to DN in all subgroups. Conclusion The current meta-analysis highlighted conclusive results for the robust association between C677T polymorphisms and DN susceptibility.

Association of the Transcription Factor 7-Like 2 (TCF7L2) rs7903146 Polymorphism with the Risk of Diabetic Nephropathy: A Meta-Analysis.

Transcription factor 7-like 2 (TCF7L2) polymorphism plays an essential role in the occurrence and development of patients living with diabetes, but the current conclusions are inconsistent on the relationship between TCF7L2 polymorphism and the risk of diabetic nephropathy. This meta-analysis aims to explore the exact association between TCF7L2 rs7903146 locus polymorphism and susceptibility to diabetic nephropathy. PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and China Wanfang databases were searched for studies on the relationship between single nucleotide polymorphism at TCF7L2 rs7903146 locus and susceptibility to diabetic nephropathy until January 10, 2022. The data were analyzed by Stata 15.0 software. A total of 7 articles were included, covering 1443 patients with diabetic nephropathy and 2129 diabetic non-nephropathy patients. The results showed that allele C at TCF7L2 rs7903146 locus, compared to allele T, the pooled odds ratio (OR)=0.69 (95% CI: 0.56-0.85, p≤0.05). In the dominant gene inheritance model, recessive gene inheritance model, homozygous genetic model, and heterozygous genetic model, the pooled OR was 0.47 (95% CI: 0.36-0.61), 0.63 (95% CI: 0.54-0.73), 0.39 (95% CI: 0.29-0.51), and 0.59 (95% CI: 0.45-0.78), respectively, and the differences were statistically significant. In conclusion, TCF7L2 rs7903146 polymorphism is associated with susceptibility to diabetic nephropathy. Allele T and genotype TT can increase the risk of diabetic nephropathy.

A Novel Study of Protein Kinase C Beta Gene Polymorphism (rs3760106) and Protein Kinase C Activity Levels as a Predictor of Nephropathy Complications in Iraqi Diabetic Patients

Objective: This study aimed to investigate the relation between the risk of (PRKCB-1504 C/T) gene polymorphisms and diabetic nephropathy pathogenesis and its association with its levels and some other biomarkers in serum of Iraqi diabetic nephropathy patients.&#x0D; Methods: A cross-sectional study was performed on 130 samples obtained from Al-Hussein Teaching Hospital / Kerbala – Iraq during Feb., 2020 to March. 2021. Seventy three patients of them with type 2 diabetes mellitus (T2D) and the remaining patients with type 2 diabetes mellitus with nephropathy complications (DN). Phenotypic analysis included determination of protein kinase C (PKC) activity levels, HbA1c%, serum insulin levels and renal function tests. Five ml of whole blood was obtained from each patients, 4.0 ml was centrifuged for serum separation used for biomarkers determinations and the remaining 1.0 ml was used for genomic DNA extraction for molecular analysis and polymorphism of PRKCB (rs3760106) by allele specific-amplification refractory mutational system-polymerase chain reaction (allele specific ARMS-PCR), followed by electrophoresis on 1% agarose gel. Various statistical analyses were applied to analyze the obtained data.&#x0D; Results: The amplification of the PRKCB gene gives one genotypes as indicated by (200 bp) bands for those with homozygous wild type (CC), homozygous mutant (TT) genotypes and two genotypes bands (200 bp) for those with heterozygous (CT). Genotype frequencies of rs3760106 polymorphism were found to be consistent with Hardy–Weinberg equilibrium. Allele frequencies (23.3 %, 26.7 %, 50 %) of CC, CT, TT in cases of DN group. While the frequencies in the non-DN group were (30 %, 45%, 25%) and for healthy control group were (50%, 33.4%, 16.6%) for wild, heterozygous, and homozygous in an order. In healthy control group, the risk of diabetic nephropathy was significantly higher among carriers of T allele under codominant TT (OR=6.42, 95%CI=(1.66-24.85), P=0.007), dominant CT+TT (OR=3.2, 95%CI = (1.08-9.95),P=0.03) and recessive model (OR=5, 95%CI = (1.51-16.56), P=0.008) while in T2DM without nephropathy the risk of diabetic nephropathy was significantly higher among carrier of T allele under recessive model (0R=3, 95%CI = (1.09-28.25), P= 0.003). Serum level of PKC-B1 activity was significantly higher among DN group than T2DM and control groups (43.35 ± 18.69, 30.35 ± 11.96, 27.42 ± 10.31, P=0.001), also PKC-B1 activity in DN group was significantly correlated with fasting blood glucose, HOMA-IR and renal function tests such as GFR, urea and creatinine.&#x0D; Conclusion: This study indicates that the PRKCB (C/T-1504) rs3760106 single nucleotide polymorphism was significantly associated with increased diabetic nephropathy susceptibility of Iraqi patients with T2DM and serum level of PKCB activity was associated with increase the risk of diabetic nephropathy complications.

The M235T polymorphism in the angiotensinogen gene is not a major risk factor for diabetic nephropathy; a meta-analysis

Introduction: Diabetic nephropathy (DN) is the leading cause of chronic kidney disease in diabetes patients. The angiotensin AGT M235T gene polymorphism, which is linked to the renin-angiotensin-aldosterone system (RAAS), has been extensively studied in DN patients, but the results are still conflicting. The current study’s goal is to conduct a meta-analysis to assess the relationship between AGT M235T gene polymorphism and DN susceptibility. Methods: Fourteen case-control studies related to AGT M235T polymorphism and DN were searched using PubMed, Web of Science and Google Scholar databases. Genotype data from the T2DM and T2DN groups were collected from all papers. The pooled odds ratio (OR) and 95 percent confidence interval (95% CI) were calculated employing a random-effects model to assess the relationship. Results: There were no statistically significant link between AGT M235T and DN risk in dominant (P=0.801, OR: 0.95; 95% CI: 0.66-1.38), allelic (P=0.933, OR: 1.01; 95% CI: 0.75-1.37) and recessive (P=0.374, OR: 1.21; 95% CI: 0.80-1.83) genetic models. Further, the stratified analysis based on ethnicity did not reveal significant link between AGT M235T and DN risk in Asian (Dom OR: 1.07; 95% CI: 0.63-1.82) and the Caucasian populations (Dom OR: 0.77; 95% CI: 0.49-1.21). In all three models, there was a high degree of heterogeneity between studies. Publication bias was not seen. Conclusion: Our findings suggest that the AGT gene M235T polymorphism does not contribute to DN risk. However, validation of this association will require multi-center and large population-based studies.

Association between polymorphisms of cytokine genes and diabetic nephropathy: A comprehensive systematic review and meta-analysis.

Diabetic nephropathy (DN) is one of the microvascular complications of diabetes, leading to renal failure. In this study, we sought to systematically investigate the cytokine gene polymorphisms association with DN. A structured bibliographic search on PubMed, Scopus, and EMBASE databases has been performed to identify related papers. The odds ratio and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. Overall, the pooled results showed that the dominant models of TNF-α rs1800629, IL-1β rs16944, IL-8 rs4073, and IL-10 rs1800896 were associated with increased susceptibility to DN. Also, the pooled analyses of the mutant allele vs wild allele of TNF-α rs1800629, rs1799964, IL-1β rs16944, and IL-8 rs4073 were associated with increased susceptibility to DN. Rs1800629, rs16944, rs4073, and rs1800896 polymorphisms were significantly associated with DN susceptibility, suggesting its potential use as a genetic risk marker in the population.

Transcription factor 7-like 2 gene- smoking interaction on the risk of diabetic nephropathy in Chinese Han population

ObjectivesTo evaluate the relationship between transcription factor 7-like 2 (TCF7L2) gene polymorphism and diabetic nephropathy (DN) risk, as well as the effect of gene-environment interactions on DN risk in Chinese Han population.MethodsThe Hardy-Weinberg equilibrium (HWE) and the relationship between TCF7L2 gene single nucleotide polymorphism (SNPs) and DN susceptibility were evaluated by SNPStats. The interaction among four SNPs and environmental factors were tested by generalized multifactor dimensionality reduction (GMDR). The consistency of cross validation, accuracy of test balance and sign test were calculated to evaluate the interaction of each selection. The logistic regression was used to test the interaction between rs7903146 and current smoking by stratified analysis.ResultsLogistic regression analysis indicated that the DN risk of rs7903146-T allele carriers were obviously higher than that in CC genotype carriers (CT + TT versus CC), adjusted OR (95 %CI) = 1.64 (1.24–2.06). However, we also discovered that people with rs12255372, rs11196205 and rs290487 minor allele had non-significant difference risk of DN compared with people with major allele. The GMDR model found a significant two-locus model (p = 0.0100) including rs7903146 and current smoking, suggesting a potential gene–environment interaction between rs7903146 and current smoking. Compared with never smokers with rs7903146- CC genotype, current smokers with rs7903146- CT or TT genotype had the highest DN risk. After covariate adjustment, OR (95 %CI) was 2.15 (1.58–2.78).ConclusionsWe found a significant relationship of rs7903146-T alleles, and the interaction between rs7903146-T and current smoking with increased DN risk.

Genetic association between interleukin-10 gene rs1518111 and rs3021094 polymorphisms and risk of type 1 diabetes and diabetic nephropathy in Egyptian children and adolescents.

Genetic and environmental factors have been implicated in etiopathogenesis and progression of type 1 diabetes mellitus (T1DM) and diabetic nephropathy (DN). Genetic association between interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) with T2DM and DN was recently established. We aimed to explore the potential genetic risk of IL-10 gene rs1518111 and rs3021094 SNPs in susceptibility to T1DM and DN. Cross-sectional study included 140 T1DM children, of whom 74 had DN and 90 controls. IL-10 gene rs1518111 and rs3021094 SNP were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique of the extracted genomic DNA from participants. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to explore the association between IL-10 gene polymorphisms and the risk of T1DM and DN. For rs1518111 SNP, AA genotype was associated with high risk of T1DM (OR = 4.53; CI = 2.11-9.74; p < 0.001), while A allele was associated with high risk of both T1DM (OR = 3.35; CI = 2.20-5.09; p < 0.001) and DN (OR = 2.36; CI = 1.27-4.38; p = 0.006). For rs3021094 SNP, AC genotype displayed lower risk to develop T1DM (OR = 0.35; CI = 0.13-0.94; p = 0.037), while A allele displayed higher risk to develop T1DM (OR = 1.69; CI = 1.11-2.56; p = 0.013). GA and AC haplotypes of rs1518111 and rs3021094 had lower ORs for having T1DM and DN, while GC had lower OR for having T1DM. AA genotype and A allele of IL-10 rs1518111 SNP could be linked to increased risk for T1DM and DN among Egyptian children. None of rs3021094 genotypes or alleles displayed significant association with DN. GA and AC haplotypes could be protective against T1DM and DN susceptibility.

Association of eNOS and MCP-1 Genetic Variants with Type 2 Diabetes and Diabetic Nephropathy Susceptibility: A Case-Control and Meta-Analysis Study.

Type 2 diabetes (T2D) and its secondary complications result from the complex interplay of genetic and environmental factors. To understand the role of these factors on disease susceptibility, the present study was conducted to assess the association of eNOS and MCP-1 variants with T2D and diabetic nephropathy (DN) in two ethnically and geographically different cohorts from North India. A total of 1313 subjects from two cohorts were genotyped for eNOS (rs2070744, rs869109213 and rs1799983) and MCP-1 (rs1024611 and rs3917887) variants. Cohort-I (Punjab) comprised 461 T2D cases (204 T2D with DN and 257 T2D without DN) and 315 healthy controls. Cohort-II (Jammu and Kashmir) included 337 T2D (150 T2D with DN and 187 T2D without DN) and 200 controls. Allele, genotype and haplotype frequencies were compared among the studied participants, and phenotype–genotype interactions were determined. Meta-analysis was performed to investigate the association between the selected variants and disease susceptibility. All three eNOS variants were associated with 1.5–4.0-fold risk of DN in both cohorts. MCP-1 rs1024611 conferred twofold risk towards DN progression in cohort-II, while rs3917887 provided twofold risk for both T2D and DN in both cohorts. eNOS and MCP-1 haplotypes conferred risk for T2D and DN susceptibility. Phenotype–genotype interactions showed significant associations between the studied variants and anthropometric and biochemical parameters. In meta-analysis, all eNOS variants conferred risk towards DN progression, whereas no significant association was observed for MCP-1 rs1024611. We show evidences for an association of eNOS and MCP-1 variants with T2D and DN susceptibility. Supplementary InformationThe online version contains supplementary material available at 10.1007/s10528-021-10041-2.

Association of MMP-9 polymorphisms with diabetic nephropathy risk: A protocol for systematic review and meta-analysis.

Background:Diabetic nephropathy (DN) is a multifactorial disease with gene–environment interaction resulting in progressive renal function damage. Multiple studies have assessed the association between matrix metalloproteinase-9 (MMP-9) gene promoter polymorphism and DN susceptibility. However, the results are inconclusive. In the present study, we will conduct a meta-analysis to further examine this relationship more precisely.Methods:Electronic databases (Pubmed, Web of Science, Embase, Google Scholar, Wanfang, China Biological Medicine and China National Knowledge Infrastructure) will be used to search clinical case–control studies about MMP-9 polymorphism and DN published until 18 August 2020. The language will be restricted to Chinese and English. Two reviewers will take charge of completing the selection of study, the extraction of data as well as the assessment of study quality independently. The Newcastle-Ottawa Scale will be used to evaluate the study quality. We will evaluate the association under 5 genetic models. Fixed-effects or random-effects models will be used to calculate the effect sizes of odds ratio and 95% confidence intervals. Afterwards, subgroup analysis will be conducted in terms of the ethnicity and genotyping method. Additionally, sensitivity analysis will be performed via sequentially omitting each of the included studies one at a time. The funnel plots, Egger regression test, and Begg rank correlation test will be used to test the potential publication bias. All the statistical analyses will be performed using Review Manager 5.3 and Stata 12.0.Results:This protocol reported according to the Preferred Reporting ltems for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. This study will provide a better understanding of the association between MMP-9 polymorphisms and DN risk.Conclusion:Publishing this protocol will minimize the potential bias related to data mining, thus contributing to generation of reliable evidence.OSF registration number:DOI 10.17605/OSF.IO/H5FS4

Effects of TNF-α-308G/A Polymorphism on the Risk of Diabetic Nephropathy and Diabetic Retinopathy: An Updated Meta-Analysis.

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the major factors of morbidity and mortality in the patients with diabetes mellitus (DM). Growing studies have investigated the relationship between the TNF-α-308G/A polymorphism and the susceptibility to DN and DR, without achieving consensus. Thus, we conducted this meta-analysis to reach more comprehensive conclusions for these issues. Eligible studies were retrieved through electronic databases such as PubMed, Embase, Web of Science and China National Knowledge Infrastructure. Summary of odds ratios (OR) and 95% confidence intervals (CIs) were generated to evaluate the intensity of the associations. Statistical analyses were performed by STATA 11.0 and RevMan 5.2. There are fourteen eligible publications involving nineteen studies in this meta-analysis. TNF-α-308G/A polymorphism was significantly related to increasing risk of DN under recessive model (OR=1.37, 95% CI=1.03-1.83) and homozygous model (OR=1.54, 95% CI=1.15-2.06). Moreover, the similar results were also obtained in Asian groups for DN (recessive: OR=1.69, 95% CI=1.18-2.42; homozygous: OR=1.99, 95% CI=1.38-2.86; respectively), and significant association was also detected between TNF-α-308G/A and DN susceptibility in type 2 DM in recessive model (OR=1.39, 95% CI=1.02-1.89). No significant association was observed between TNF-α-308G/A and DR susceptibility in total analyses and subgroup analyses by ethnicity and type of DM. TNF-α-308G/A polymorphism may enhance the susceptibility to diabetic nephropathy, especially in Asian population and in T2DM patients, but not diabetic retinopathy.

Genetic risk score for risk prediction of diabetic nephropathy in Han Chinese type 2 diabetes patients

We evaluated whether genetic information could offer improvement on risk prediction of diabetic nephropathy (DN) while adding susceptibility variants into a risk prediction model with conventional risk factors in Han Chinese type 2 diabetes patients. A total of 995 (including 246 DN cases) and 519 (including 179 DN cases) type 2 diabetes patients were included in derivation and validation sets, respectively. A genetic risk score (GRS) was constructed with DN susceptibility variants based on findings of our previous genome-wide association study. In derivation set, areas under the receiver operating characteristics (AUROC) curve (95% CI) for model with clinical risk factors only, model with GRS only, and model with clinical risk factors and GRS were 0.75 (0.72–0.78), 0.64 (0.60–0.68), and 0.78 (0.75–0.81), respectively. In external validation sample, AUROC for model combining conventional risk factors and GRS was 0.70 (0.65–0.74). Additionally, the net reclassification improvement was 9.98% (P = 0.001) when the GRS was added to the prediction model of a set of clinical risk factors. This prediction model enabled us to confirm the importance of GRS combined with clinical factors in predicting the risk of DN and enhanced identification of high-risk individuals for appropriate management of DN for intervention.

The Impact of Vitamin D Receptor Gene Polymorphisms on the Susceptibility of Diabetic Vascular Complications: A Meta-Analysis.

Background: To determine whether vitamin D receptor (VDR) gene polymorphisms are correlated with susceptibility to diabetic vascular complications. Methods: We included all eligible studies, and used Stata12.0 to calculate the pooled results. Results: Eight thousand eleven diabetic patients and 1635 normal controls from 27 studies were included. Our results showed that there was no correlation between VDR gene TaqI variants and diabetic nephropathy (DN) or diabetic retinopathy (DR) susceptibility. In comparison with diabetic patients without DN, there was a link between the VDR gene ApaI variant and DN susceptibility under allelic model (p = 0.029) in all populations. In addition, the VDR gene BsmI variant correlated with DN under both dominant (p = 0.005) and allelic (p = 0.003) models in Asian populations. The VDR gene FokI variant was also correlated with DN susceptibility under the recessive model (p = 0.027) in the Asian subgroup. In comparison with diabetic patients without DR, we identified a link between the VDR gene ApaI variant and DR susceptibility under the dominant model (p = 0.034) in all populations. Also, the VDR gene FokI variant was correlated with DR under the recessive (p = 0.016), the allelic (p = 0.001), and the dominant (p < 0.001) models in all populations. When compared with healthy controls, the VDR gene BsmI variant was associated with DR under the additive (p = 0.014), the allelic (p = 0.033), and the dominant (p < 0.001) models in Indian populations. Conclusions: The VDR gene BsmI, ApaI, and FokI gene variants are associated with DN and DR susceptibility. No association was found between the VDR gene TaqI gene variants and diabetic vascular complications.

Association Between IL-6 Polymorphisms and Diabetic Nephropathy Risk: A Meta-analysis

BackgroundThe objective of this work was to evaluate the relevance of frequent interleukin-6 (IL-6) polymorphisms and diabetic nephropathy (DN) susceptibility by a systematic meta-analysis. Materials and MethodsThe included studies related to the relationship between IL-6 and DN risk were searched from Pubmed, Embase and the Cochrane Library, and the Newcastle-Ottawa Scale was used to evaluate the study quality. A heterogeneity test was performed to determine the appropriate effect models based on the Q test and I2 statistic. Odds ratios with 95% confidence intervals were used to determine the strength of associations. Afterwards, subgroup analysis was conducted to assess the effect of specific factors on the corresponding results. Additionally, publication bias and sensitivity analysis were also undertaken. ResultsIn total, 11 eligible articles were obtained. The meta-analysis revealed that the “C”allele of IL-6 rs1800795 was related to the decreased risk of DN (C versus G: P = 0.0471). The “G”allele of IL-6 rs1800796 was predominately associated with higher DN risks (GG versus CC: P = 0.0194; GG versus CC + GC: P = 0.0196). The “C”allele of IL-6 rs1800797 was implicated with higher prevalence of DN (C versus G: P = 0.0001; CC versus GG: P = 0.0003; CC versus GG + CG: P = 0.0227; CC + CG versus GG: P = 0.0001) while IL-6 rs2069837 and rs2069840 were not correlated with the susceptibility to DN. ConclusionsThis meta-analysis indicated that IL-6 rs1800795, rs1800796 and rs1800797 played important roles in DN development while IL-6 rs2069837 and rs2069840 might not be related to DN.