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CD28 Genetic Variants Increase Susceptibility to Diabetic Kidney Disease in Chinese Patients with Type 2 Diabetes: A Cross-Sectional Case Control Study.

ABSTRACT: Few studies have illuminated the genetic role of T cell costimulatory molecule CD28/CD80/CTLA4 variants in diabetic kidney disease (DKD) susceptibility. We aimed to investigate the causal role of genetic polymorphisms in CD28/CD80/CTLA4 with DKD susceptibility in patients with T2DM. A total of 3253 patients with T2DM were recruited for genotyping: including 204 DKD patients and 371 controls in stage 1 and 819 DKD patients and 563 controls in stage 2; besides, 1296 T2DM patients were selected for the analysis of association between loci and DKD-related traits. A subset of 227 T2DM patients (118 patients with DKD and 109 patients without DKD) from the total population above were selected to assess serum soluble CD28 (sCD28) levels. Then, we performed a candidate gene association study to identify single-nucleotide polymorphisms (SNPs) associated with DKD susceptibility and further used those SNPs to perform Mendelian randomization analyses of serum sCD28 level and DKD susceptibility. Under additive genetic models, CD28-rs3116494 (OR = 1.29 [95% CI 1.11, 1.51], P = 0.0011) and CD80-rs3850890 (OR = 1.16 [95% CI 1.02, 1.31], P = 0.0283) were associated with DKD susceptibility adjusted for age, gender, body mass index (BMI), duration of diabetes, and HbA1c. CD28-rs3116494 was associated with serum sCD28 level (β = 0.26 [95% CI 0.08, 0.44], P = 0.0043). The Mendelian randomization analysis showed that CD28-rs3116494 played a causal role in DKD by influencing serum sCD28 levels (β = 1.15 [95% CI 0.46, 1.83], P = 0.0010). In conclusion, we identified that two novel SNPs, CD28-rs3116494 and CD80-rs3850890, were associated with DKD susceptibility. Using the Mendelian randomization analysis, our study provided evidence for a causal relationship between serum CD28 levels and DKD with T2DM in the Chinese population.

SUBMITTER: Li Y

PROVIDER: S-EPMC8075672 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveSystemic immune-inflammation index (SII), a novel inflammatory marker, has been reported to be associated with diabetic kidney disease (DKD) in the U.S., however, such a close relationship with DKD in other countries, including China, has not been never determined. We aimed to explore the association between SII and DKD in Chinese population.MethodsA total of 1922 hospitalized patients with type 2 diabetes mellitus (T2DM) included in this cross-sectional study were divided into three groups based on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR): non-DKD group, DKD stages 1-2 Alb group, and DKD-non-Alb+DKD stage 3 Alb group. The possible association of SII with DKD was investigated by correlation and multivariate logistic regression analysis, and receiver-operating characteristic (ROC) curves analysis.ResultsMoving from the non-DKD group to the DKD-non-Alb+DKD stage 3 Alb group, SII level was gradually increased (P for trend <0.01). Partial correlation analysis revealed that SII was positively associated with urinary ACR and prevalence of DKD, and negatively with eGFR (all P<0.01). Multivariate logistic regression analysis showed that SII remained independently significantly associated with the presence of DKD after adjustment for all confounding factors [(odds ratio (OR), 2.735; 95% confidence interval (CI), 1.840-4.063; P < 0.01)]. Moreover, compared with subjects in the lowest quartile of SII (Q1), the fully adjusted OR for presence of DKD was 1.060 (95% CI 0.773-1.455) in Q2, 1.167 (95% CI 0.995-1.368) in Q3, 1.266 (95% CI 1.129-1.420) in the highest quartile (Q4) (P for trend <0.01). Similar results were observed in presence of DKD stages 1-2 Alb or presence of DKD-non- Alb+DKD stage 3 Alb among SII quartiles. Last, the analysis of ROC curves revealed that the best cutoff values for SII to predict DKD, Alb DKD stages 1- 2, and DKD-non-Alb+ DKD stage 3 Alb were 609.85 (sensitivity: 48.3%; specificity: 72.8%), 601.71 (sensitivity: 43.9%; specificity: 72.3%), and 589.27 (sensitivity: 61.1%; specificity: 71.1%), respectively.ConclusionHigher SII is independently associated with an increased risk of the presence and severity of DKD, and SII might be a promising biomarker for DKD and its distinct phenotypes in Chinese population.

Project description:ObjectivesMitochondrial DNA (mtDNA) plays an important role in the pathogenesis of diabetes. Variants in mtDNA have been reported in diabetes, but studies on the whole mtDNA variants were limited. Our study aims to explore the association of whole mtDNA variants with diabetes and diabetic kidney disease (DKD).MethodsThe whole mitochondrial genome was screened by next-generation sequencing in cohort 1 consisting of 50 early-onset diabetes (EOD) patients with a maternally inherited diabetes (MID) family history. A total of 42 variants possibly associated with mitochondrial diseases were identified according to the filtering strategy. These variants were sequenced in cohort 2 consisting of 90 EOD patients with MID. The association between the clinical phenotype and these variants was analyzed. Then, these variants were genotyped in cohort 3 consisting of 1,571 type 2 diabetes mellitus patients and 496 subjects with normal glucose tolerance (NGT) to analyze the association between variants with diabetes and DKD.ResultsPatients with variants in the non-coding region had a higher percentage of obesity and levels of fasting insulin (62.1% vs. 24.6%, P = 0.001; 80.0% vs. 26.5% P < 0.001). The patients with the variants in rRNA had a higher prevalence of obesity (71.4% vs. 30.3%, P = 0.007), and the patients with the variants in mitochondrial complex I had a higher percentage of the upper tertile of FINS (64.3% vs. 34.3%, P = 0.049). Among 20 homogeneous variants successfully captured, two known variants (m.A3943G, m.A10005G) associated with other mitochondrial diseases were only in the diabetic group, but not in the NGT group, which perhaps indicated its possible association with diabetes. The prevalence of DKD was significantly higher in the group with the 20 variants than those without these variants (18.7% vs. 14.6%, P = 0.049) in the participants with diabetes of cohort 3.ConclusionMtDNA variants are associated with MID and DKD, and our findings advance our understanding of mtDNA in diabetes and DKD. It will have important implications for the individual therapy of mitochondrial diabetes.

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CD28 Genetic Variants Increase Susceptibility to Diabetic Kidney Disease in Chinese Patients with Type 2 Diabetes: A Cross-Sectional Case Control Study.

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