Association of plasma ceramide with decline in kidney function in patients with type 2 diabetes.

Circulating ceramide levels are dysregulated in kidney disease. However their associations with rapid decline in kidney function (RDKF) and end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) are unknown. In this prospective study of 1746 T2D participants, we examined the association of plasma ceramide Cer16:0, Cer18:0, Cer24:0 and Cer24:1 with RDKF, defined as an estimated glomerular filtration rate (eGFR) decline of 5ml/min/1.73m2/yr or greater, and ESKD defined as eGFR <15/min/1.73m2 for at least three months, on dialysis, or renal death at follow-up. We performed multivariable logistic and cox regression analyses adjusted for traditional cardio-renal risk factors, including baseline renal functions. During a median (interquartile range) follow-up period of 7.7 (4.7-8.9) years, 197 (11%) patients experienced RDKF. Ceramide Cer24:0 (odds ratio [OR]=0.71, 95%CI 0.56-0.90) and ratios Cer16:0/Cer24:0 (OR=3.54, 95%CI 1.70-7.35), Cer18:0/Cer24:0 (OR=1.89, 95%CI 1.10-3.25) and Cer24:1/Cer24:0 (OR=4.01, 95%CI 1.93-8.31) significantly associated with RDKF in multivariable analysis. 124 patients developed ESKD. The ratios Cer16:0/Cer24:0 (hazard ratio [HR]=3.10, 95%CI 1.44-6.64), and Cer24:1/Cer24:0 (HR=4.66, 95%CI 1.93-11.24) significantly associated with a higher risk of ESKD. The Cer24:1/Cer24:0 ratio improved risk discrimination for ESKD beyond traditional risk factors by small but statistically significant margin (Harrell C-index difference 0.01; P=0.022). A high ceramide risk score, constructed using individual ceramide level and ceramide ratios, also associated with RDKF (OR=2.28, 95%CI 1.26-4.13) compared to lower risk score. In conclusion, specific ceramide levels and their ratios are associated with RDKF and conferred an increased risk of ESKD, independently of traditional risk factors in patients with T2D.

Association of plasma angiogenin with risk of major cardiovascular events in type 2 diabetes.

BACKGROUND: Angiogenin, an enzyme belonging to the ribonucleases A superfamily, plays an important role in vascular biology. Here, we sought to study the association of plasma angiogenin and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes (T2D). METHODS: This prospective study included 1083 T2D individuals recruited from a secondary hospital and a primary care facility. The primary outcome was a composite of four-point MACE (nonfatal myocardial infarction, stroke, unstable angina pectoris leading to hospitalization and cardiovascular death). Circulating angiogenin was measured by a proximity extension assay. Cox regression models were used to evaluate the association of baseline plasma angiogenin with the risk of MACE. RESULTS: During a median follow-up of 9.3 years, 109 (10%) MACE were identified. Plasma angiogenin was significantly higher in participants with MACE than in those without MACE (P < 0.001). Doubling of plasma angiogenin concentration was associated with a 3.10-fold (95% CI 1.84-5.22) increased risk for MACE. The association was only moderately attenuated after adjustment for demographic and cardiometabolic risk factors (adjusted HR 2.38, 95% CI 1.34-4.23) and remained statistically significant after additional adjustment for estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (uACR) (adjusted HR 1.90, 95% CI 1.02-3.53). A consistent outcome was obtained when plasma angiogenin was analysed as a categorical variable in tertiles. CONCLUSIONS: Plasma angiogenin was associated with the risk of future cardiovascular events in patients with T2D and may be a promising novel biomarker for identifying high-risk T2D patients for early management.

Plasma Tryptophan-Kynurenine Pathway Metabolites and Risk for Progression to End-Stage Kidney Disease in Patients With Type 2 Diabetes.

OBJECTIVE: We sought to study the associations between plasma metabolites in the tryptophan-kynurenine pathway and the risk of progression to end-stage kidney disease (ESKD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Plasma tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, and xanthurenic acid concentrations were measured in discovery (n = 1,915) and replication (n = 346) cohorts. External validation was performed in Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes (n = 1,312). The primary outcome was a composite of incident ESKD (progression to estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2, sustained dialysis, or renal death). The secondary outcome was annual eGFR decline. RESULTS: In the discovery cohort, tryptophan was inversely associated with risk for ESKD, and kynurenine-to-tryptophan ratio (KTR) was positively associated with risk for ESKD after adjustment for clinical risk factors, including baseline eGFR and albuminuria (adjusted hazard ratios [HRs] 0.62 [95% CI 0.51, 0.75] and 1.48 [1.20, 1.84] per 1 SD). High levels of kynurenic acid and xanthurenic acid were associated with low risks of ESKD (0.74 [0.60, 0.91] and 0.74 [0.60, 0.91]). Consistently, high levels of tryptophan, kynurenic acid, and xanthurenic acid were independently associated with a slower eGFR decline, while a high KTR was predictive of a faster eGFR decline. Similar outcomes were obtained in the replication cohort. Furthermore, the inverse association between kynurenic acid and risk of ESKD was externally validated in CRIC participants with diabetes (adjusted HR 0.78 [0.65, 0.93]). CONCLUSIONS: Accelerated catabolism of tryptophan in the kynurenine pathway may be involved in progressive loss of kidney function. However, shunting the kynurenine pathway toward the kynurenic acid branch may potentially slow renal progression.

Clinical variable-based cluster analysis identifies novel subgroups with a distinct genetic signature, lipidomic pattern and cardio-renal risks in Asian patients with recent-onset type 2 diabetes.

AIMS/HYPOTHESIS: We sought to subtype South East Asian patients with type 2 diabetes by de novo cluster analysis on clinical variables, and to determine whether the novel subgroups carry distinct genetic and lipidomic features as well as differential cardio-renal risks. METHODS: Analysis by k-means algorithm was performed in 687 participants with recent-onset diabetes in Singapore. Genetic risk for beta cell dysfunction was assessed by polygenic risk score. We used a discovery-validation approach for the lipidomics study. Risks for cardio-renal complications were studied by survival analysis. RESULTS: Cluster analysis identified three novel diabetic subgroups, i.e. mild obesity-related diabetes (MOD, 45%), mild age-related diabetes with insulin insufficiency (MARD-II, 36%) and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII, 19%). Compared with the MOD subgroup, MARD-II had a higher polygenic risk score for beta cell dysfunction. The SIRD-RII subgroup had higher levels of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (phosphatidylethanolamine and phosphatidylcholine), whereas the MARD-II subgroup had lower levels of sphingolipids and glycerophospholipids but higher levels of lysophosphatidylcholines. Over a median of 7.3 years follow-up, the SIRD-RII subgroup had the highest risks for incident heart failure and progressive kidney disease, while the MARD-II subgroup had moderately elevated risk for kidney disease progression. CONCLUSIONS/INTERPRETATION: Cluster analysis on clinical variables identified novel subgroups with distinct genetic, lipidomic signatures and varying cardio-renal risks in South East Asian participants with type 2 diabetes. Our study suggests that this easily actionable approach may be adapted in other ethnic populations to stratify the heterogeneous type 2 diabetes population for precision medicine.

Association of leukocyte telomere length with chronic kidney disease in East Asians with type 2 diabetes: a Mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) is common among people with type 2 diabetes (T2D), and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length (LTL) is associated with CKD in patients with T2D. We previously reported single-nucleotide polymorphisms (SNPs) associated with LTL in an Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using the Mendelian randomization (MR) approach. METHODS: The cross-sectional association of 16 LTL SNPs with CKD, defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2, was assessed among 4768 (1628 cases and 3140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in T2D and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analyzed. RESULTS: Genetically determined shorter LTL was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio = 1.51, 95% confidence interval 1.12-2.12, P = 0.007, Phet = 0.547). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (ß = 0.010, P = 0.751). CONCLUSIONS: Our findings suggest that genetically determined LTL is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression.

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10-14-6.94×10-10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.

Association of Genetic Variants for Plasma LRG1 With Rapid Decline in Kidney Function in Patients With Type 2 Diabetes.

CONTEXT: Elevated levels of plasma leucine-rich α-2-glycoprotein 1 (LRG1), a component of transforming growth factor beta signaling, are associated with development and progression of chronic kidney disease in patients with type 2 diabetes (T2D). However, whether this relationship is causal is uncertain. OBJECTIVES: To identify genetic variants associated with plasma LRG1 levels and determine whether genetically predicted plasma LRG1 contributes to a rapid decline in kidney function (RDKF) in patients with T2D. DESIGN AND PARTICIPANTS: We performed a genome-wide association study of plasma LRG1 among 3694 T2D individuals [1881 (983 Chinese, 420 Malay, and 478 Indian) discovery from Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes cohort and 1813 (Chinese) validation from Diabetic Nephropathy cohort]. One- sample Mendelian randomization analysis was performed among 1337 T2D Chinese participants with preserved glomerular filtration function [baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2)]. RDKF was defined as an eGFR decline of 3 mL/min/1.73 m2/year or greater. RESULTS: We identified rs4806985 variant near LRG1 locus robustly associated with plasma LRG1 levels (meta P = 6.66 × 10-16). Among 1337 participants, 344 (26%) developed RDKF, and the rs4806985 variant was associated with higher odds of RDKF (meta odds ratio = 1.23, P = 0.030 adjusted for age and sex). Mendelian randomization analysis provided evidence for a potential causal effect of plasma LRG1 on kidney function decline in T2D (P < 0.05). CONCLUSION: We demonstrate that genetically influenced plasma LRG1 increases the risk of RDKF in T2D patients, suggesting plasma LRG1 as a potential treatment target. However, further studies are warranted to elucidate underlying pathways to provide insight into diabetic kidney disease prevention.

Correlation of Telomere Length in Adipose Tissue and Leukocytes and its Association with Postsurgical Weight Loss.

OBJECTIVE: The aim of this study was to determine the relationship between telomere length (TL) in subcutaneous adipose tissue (SAT), visceral adipose tissues (VAT), and leukocytes, as well as to examine the associations of TL in these tissues with postsurgical weight loss in Asians with severe obesity. METHODS: Presurgery TL was measured in leukocytes, SAT, and VAT of 91 patients who underwent weight loss surgery. Correlation between TL in multiple tissues was assessed using Pearson correlation. The association of presurgery TL and postsurgical weight loss at 6 or 12 months, expressed as a percentage of weight loss, was determined using linear regression in 70 patients. RESULTS: Telomeres were longer in VAT compared with those in leukocytes and SAT (P < 0.001) but were highly correlated between tissues. The strongest correlation was observed between TL in VAT and leukocytes (r = 0.739, P = 6.22 × 10-17 ). Compared with individuals in the highest tertile, those in the lowest tertile of VAT TL showed greater weight loss (ß = 6.23, SE = 3.10, P = 0.044) independent of age, sex, ethnicity, types of surgery, diabetes condition, preoperative BMI, and follow-up period. CONCLUSIONS: Among patients with severe obesity, TL in leukocytes and adipose tissue was highly correlated. However, there was variability in the association of TL in these tissues with weight loss after surgery.

Loci for human leukocyte telomere length in the Singaporean Chinese population and trans-ethnic genetic studies.

Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10-8). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10-7] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10-4) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.

Ethnic disparities in relationships of obesity indices with telomere length in Asians with type 2 diabetes.

BACKGROUND: Obesity and shorter telomeres increase the risk for diabetes complications and mortality. However, the relationship between obesity and telomere length in diverse Asian populations with type 2 diabetes (T2D) is not well understood. This study examined the association of baseline and changes in obesity indices with telomere length in multiethnic Asian populations with T2D. METHODS: Leukocyte telomere length (LTL) was measured by quantitative polymerase chain reaction in the SMART2D cohort (n = 1431 at baseline, n = 1039 after 3.2 years median follow-up). Associations between obesity indices and LTL were assessed by linear regression. RESULTS: Compared with Chinese, LTL was longer in Malays (P < 0.0001) and similar in Indians. Cross-sectionally, body mass index (BMI)-adjusted (residual) visceral fat area (VFA; ß = -0.004, P = 0.006), and waist-to-hip ratio (ß = -1.95, P = 0.030) were significantly associated with LTL in Chinese but not in Malays and Indians. Changes in BMI (r = -0.080; P = 0.053) and VFA (r = -0.126; P = 0.002) were inversely correlated with changes in LTL only in Chinese. Furthermore, in Chinese, 1-SD incremental changes in BMI (ß = -0.070; P = 0.040) and VFA (ß = -0.088, P = 0.028) were significantly associated with larger telomere attrition, independent of age, sex, diabetes condition, baseline LTL, obesity, and inflammation markers. CONCLUSIONS: Three-year changes in BMI and VFA were associated with telomere dynamics in Chinese but not in Malays and Indians with T2D. Reducing obesity may reduce the risk of diabetes complications associated with shorter LTL in the Chinese population.

Author Correction: Genetic markers for urine haptoglobin is associated with decline in renal function in type 2 diabetes in East Asians.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Short Leukocyte Telomere Length Predicts Albuminuria Progression in Individuals With Type 2 Diabetes.

INTRODUCTION: Telomere length, a marker for biological aging, is implicated with diabetic kidney disease (DKD); however, the association between telomere length and albuminuria progression among Asian patients with type 2 diabetes (T2D) is not well understood. Here, we aim to study whether leukocyte telomere length (LTL) may independently predict albuminuria progression in patients with T2D with preserved renal filtration function (estimated GFR >60 ml/min per 1.73 m2 and urine albumin-to-creatinine ratio [uACR] <300 mg/g). METHODS: The baseline LTL was measured by real-time polymerase chain reaction in the SMART2D cohort (n = 691) with a median follow-up of 3 years. Albuminuria progression was defined as a change in albuminuria category to a higher category and at least 30% increase in uACR from baseline in 3 years. RESULTS: Progressors (n = 123) had significantly shorter median LTL compared with nonprogressors (n = 568) (0.58 [0.38-0.79] vs. 0.62 [0.45-0.88], P = 0.039). Compared with subjects with longer LTL (fourth quartile), subjects with shorter LTL (first quartile) had 1.93-fold (1.04-3.60, P = 0.038) increased risk for albuminuria progression after adjustment for traditional risk factors. The association of LTL with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria (odds ratio [OR]: 1.54; 95% confidence interval [CI]: 1.02-2.32; P = 0.042 vs. OR: 1.13; 95% CI: 0.91-1.40; P = 0.263 per 1-SD decrement in natural log-transformed LTL). CONCLUSION: Therefore, our results demonstrated that in patients with T2D with preserved renal filtration function, LTL predicts albuminuria progression beyond traditional risk factors, suggesting LTL may be novel biomarker for DKD progression.

Genetic markers for urine haptoglobin is associated with decline in renal function in type 2 diabetes in East Asians.

Urine haptoglobin (uHP) level prospectively predicts diabetic kidney disease (DKD) progression. Here, we aim to identify genetic determinants of uHP level and evaluate association with renal function in East Asians (EA) with type 2 diabetes (T2D). Genome-wide association study (GWAS) among 805 [236 Chinese (discovery) and 569 (57 Malay and 512 Chinese) (validation)] found that rs75444904/kgp16506790 variant was robustly associated with uHP level (MetaP = 1.21 × 10-60). rs75444904 correlates well with plasma HP protein levels and multimerization in EA but was not in perfect LD (r2 = 0.911 in Chinese, r2 = 0.536 in Malay) and is monomorphic in Europeans (1000 G data). Conditional probability analysis indicated weakening of effects but residual significant associations between rs75444904 and uHP when adjusted on HP structural variant (MetaP = 8.22 × 10-7). The rs75444904 variant was associated with DKD progression (OR = 1.77, P = 0.014) independent of traditional risk factors. In an additional validation-cohort of EA (410 end-stage renal disease (ESRD) cases and 1308 controls), rs75444904 was associated with ESRD (OR = 1.22, P = 0.036). Furthermore, increased risk of DKD progression (OR = 2.09, P = 0.007) with elevated uHP level through Mendelian randomisation analysis provide support for potential causal role of uHP in DKD progression in EA. However, further replication of our findings in larger study populations is warranted.