Dataset Information

Clonal hematopoiesis as a novel risk factor for type 2 diabetes mellitus in patients with hypercholesterolemia.

ABSTRACT:

Introduction

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with atherosclerosis and cardiovascular disease. It has been suggested that CHIP may be related to diabetes, so we investigated the association between CHIP and new-onset type 2 diabetes.

Methods

This study included 4,047 subjects aged >=40 years without diabetes. To detect CHIP, targeted gene sequencing of genomic DNA from peripheral blood cells was performed. The incidence of new-onset type 2 diabetes during the follow-up period was evaluated.

Results

Of the total subjects, 635 (15.7%) had CHIP. During the median follow-up of 5.1 years, the incidence of new-onset diabetes was significantly higher in CHIP carriers than in subjects without CHIP (11.8% vs. 9.1%, p = 0.039). In a univariate analysis, CHIP significantly increased the risk of new-onset diabetes (HR 1.32, 95% CI 1.02-1.70, p = 0.034), but in a multivariate analysis, it was not significant. The CHIP-related risk of new onset diabetes differed according to LDL cholesterol level. In the hyper-LDL cholesterolemia group, CHIP significantly increased the risk of diabetes (HR 1.64, 95% CI 1.09-2.47, p = 0.018), but it did not increase the risk in the non-hyper-LDL cholesterolemia group. The subjects with CHIP and hyper-LDL-cholesterolemia had approximately twice the risk of diabetes than subjects without CHIP and with low LDL cholesterol (HR 2.05, 95% CI 1.40-3.00, p < 0.001).

Conclusion

The presence of CHIP was a significant risk factor for new-onset type 2 diabetes, especially in subjects with high LDL cholesterol. These results show the synergism between CHIP and high LDL cholesterol as a high-risk factor for diabetes.

SUBMITTER: Kim MJ

PROVIDER: S-EPMC10345505 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Clonal hematopoiesis as a novel risk factor for type 2 diabetes mellitus in patients with hypercholesterolemia.

Kim Min Joo MJ Song Han H Koh Youngil Y Lee Heesun H Park Hyo Eun HE Choi Sung Hee SH Yoon Ji Won JW Choi Su-Yeon SY

Frontiers in public health 20230628

<h4>Introduction</h4>Clonal hematopoiesis of indeterminate potential (CHIP) is associated with atherosclerosis and cardiovascular disease. It has been suggested that CHIP may be related to diabetes, so we investigated the association between CHIP and new-onset type 2 diabetes.<h4>Methods</h4>This study included 4,047 subjects aged >=40 years without diabetes. To detect CHIP, targeted gene sequencing of genomic DNA from peripheral blood cells was performed. The incidence of new-onset type 2 diabe ...[more]

PMID: 37457265

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Project description:AimBoth clonal hematopoiesis of indeterminate potential (CHIP) and type 2 diabetes mellitus (T2DM) are conditions closely associated with advancing age. This study delves into the possible implications and prognostic significance of CHIP and T2DM in patients diagnosed with ST-segment elevation myocardial infarction (STEMI).MethodsDeep-targeted sequencing employing a unique molecular identifier (UMI) for the analysis of 42 CHIP mutations-achieving an impressive mean depth of coverage at 1000 × -was conducted on a cohort of 1430 patients diagnosed with acute myocardial infarction (473 patients with T2DM and 930 non-DM subjects). Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and T2DM was evaluated by the comparison of (i) the prevalence of CHIP mutations among individuals with diabetes versus those without, (ii) the clinical characteristics delineated by CHIP mutations within the cohort of diabetic patients and (iii) the prognostic significance and correlation of CHIP mutations with mortality rates in T2DM subjects. Furthermore, a two-sample bidirectional Mendelian randomization study was performed using genetic instruments from the genome-wide association study for TET2 mutation CH from the UK Biobank (UKB) (2041 cases,173,918 controls) to investigate the causal relationship with T2DM from the FinnGen consortium (65,085 cases and 335,112 controls), and vice versa.Results(i) Most commonly CHIP mutations exhibiting a variant allele fraction of ≥ 2.0% were identified in 50/473 (10.6%) patients with T2DM, demonstrating a greater prevalence compared to non-DM subjects [69/930 (7.4%); P < 0.05] across various age groups. (ii) After multivariable adjustment, the mortality of any CHIP mutations were 2.03-fold higher in DM [adjusted hazard ratio (HR) 2.03; 95% confidence interval (CI) 1.07-3.84, P < 0.05]. (iii) In gene-specific analyses, TET2 somatic mutation presented the highest association with mortality among T2DM (adjusted HR 5.24; 95% CI 2.02-13.61, P = 0.001). ASXL1 CHIP mutation which displayed a striking correlation with cardiac death (HR: 3.14; 95% CI 1.24-7.93; P < 0.05) with consistent associations observed among T2DM subgroup (HR: 4.51; 95% CI 1.30-15.6; P < 0.05). (iv) The correlation between PCSK9 and the Tet2-CHIP mutation was observed in both the T2DM cohort (correlation = 0.1215, P = 0.011) and the overall enrolled cohort (correlation = 0.0578, P = 0.0382). (v) Bidirectional Mendelian randomization studies indicated that the development of T2DM increases the propensity for CHIP. However, CHIP does not subsequently accelerate the onset of T2DM.ConclusionCHIP mutations, particularly TET2, are more prevalent in patients with T2DM compared to individuals without diabetes. The presence of these mutations is associated with adverse clinical outcomes, notably increased mortality rates. Moreover, bidirectional Mendelian randomization analyses provide supporting evidence for a potential causal relationship between TET2-related CHIP and the development of T2DM.

Project description:BackgroundRisk of atherothrombotic events is not uniform in patients with type 2 diabetes mellitus (T2DM). Tailored risk assessment may help guide selection of pharmacotherapies for cardiovascular primary and secondary prevention.ObjectivesThe purpose of this study was to develop a risk model for atherothrombosis in patients with T2DM.MethodsWe developed and validated a risk model for myocardial infarction (MI) or ischemic stroke (IS) in a pooled cohort of 42,181 patients with T2DM from 4 TIMI (Thrombolysis In Myocardial Infarction) clinical trial cohorts. Candidate variables were assessed with multivariable Cox regression, and independent variables (P < 0.05) were retained in the final model. Discrimination and calibration were assessed. Treatment interactions with dapagliflozin (sodium-glucose cotransporter-2 inhibitor) and evolocumab (proprotein convertase subtilisin/kexin type 9 inhibitor) were explored in the DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events-Thrombolysis In Myocardial Infarction 58) and FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trials, respectively.ResultsSixteen variables were independent predictors of MI or IS. The model identified a >8-fold gradient of MI or IS rates between the top vs bottom risk quintiles in the validation cohort (3-year Kaplan-Meier rate: 14.9% vs 1.4%; P < 0.0001). C-indexes were 0.704 and 0.706 in the derivation and validation cohorts, respectively. The model was well-calibrated in both primary and secondary prevention. Absolute reduction in the rates of MI or IS tended to be greater in patients with higher baseline predicted risk for both dapagliflozin (absolute risk reduction: 2.1% vs 0.2%) and evolocumab (absolute risk reduction: 3.2% vs 1.0%).ConclusionsWe developed and validated a risk score for atherothrombotic events, leveraging 16 routinely assessed clinical variables in patients with T2DM. The score has the potential to improve risk assessment and inform clinical decision-making.

Project description:BackgroundClonal hematopoiesis of indeterminate potential (CHIP) was associated with diabetes and cardiovascular diseases (CVD). However, the effect of CHIP on CVD have not been evaluated among patients with diabetes, and whether maintaining the healthy indictors could mitigate the adverse influence was also unclear.MethodsA total of 22,239 adults from the UK Biobank with diabetes and available whole-exome sequence data, and free of CVD were included. Multivariable-adjusted Cox regressions were used to explore the associations of any CHIP (variant allele fraction ≥ 2%), large CHIP (variant allele fraction ≥ 10%), and the top 10 commonly mutated driver genes for CHIP and with risk of CVD. The joint associations between health indicators (body mass index [BMI], HbA1c, blood pressure [BP], and low-density lipoprotein cholesterol [LDL]) and CHIP were further investigated.ResultsOver a median follow-up of 13.2 years, 5366 participants with diabetes developed CVD events. The hazard ratios (HRs) (95% confidence intervals [CIs]) of any CHIP and large CHIP were (1.21, 1.08-1.36) and (1.25, 1.09-1.43) for incident CVD, respectively. Significant associations between any CHIP and coronary heart disease (HR, 95%CI: 1.18, 1.03-1.36) and heart failure (1.73, 1.46-2.06) were observed, but not for stroke (1.14, 0.89-1.48). Gene-specific analyses suggested that the greatest association were for SF3B1 (HR, 95%CI: 2.50, 1.25-5.01) and TET2 (HR, 95%CI: 1.36, 1.07-1.77) with risk of CVD. There was no significant interaction between the four health indicators and CHIP in relation to incident CVD. Compared to patients without CHIP, those with any CHIP and ideal health indicators still exhibited significantly or nonsignificantly higher HRs (BMI: 1.18, 0.82-1.68; HbA1c: 1.12, 0.96-1.30; BP: 1.24, 1.03-1.49; LDL: 1.29, 1.09-1.53). Similar results were demonstrated using large CHIP.ConclusionsCHIP is independently associated with an increased risk of CVD in patients with diabetes, regardless of health indicator levels. Diabetic patients with CHIP but ideal health indicators still exhibited higher CVD risk compared with diabetic patients without CHIP.

Dataset Information

Clonal hematopoiesis as a novel risk factor for type 2 diabetes mellitus in patients with hypercholesterolemia.

Introduction

Methods

Results

Conclusion

Publications

Clonal hematopoiesis as a novel risk factor for type 2 diabetes mellitus in patients with hypercholesterolemia.

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