Biomedical subjects

Md Mesbah Uddin

Publications and source records attributed to Md Mesbah Uddin.

4 recordsLinked to original sources

PubMed2026

Mechanism of age-related accumulation of mtDNA mutations in human blood.

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.

Humans↗

PubMed2026

Clonal Hematopoiesis and Incident Heart Failure.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with acquired preleukemic variants, has been associated with cardiometabolic diseases, including heart failure (HF). However, prior studies have lacked power to examine less common CHIP driver variants and have not investigated potential mediators of the CHIP-HF association. OBJECTIVE: To test whether specific CHIP subtypes are associated with incident HF and determine the extent to which CHIP-associated comorbidities mediate this association. DESIGN, SETTING, AND PARTICIPANTS: This was a UK Biobank prospective population-based cohort study of community-dwelling adults in the UK, with enrollment from 2006 to 2010 and follow-up through 2020. Included were participants with whole-exome sequencing (WES) and without prevalent HF, hematologic malignancy, or other CHIP-associated comorbidities (coronary artery disease [CAD], atrial fibrillation [AF], type 2 diabetes [T2D], or chronic kidney disease [CKD]) at baseline. Study data were analyzed from April through October 2025. EXPOSURES: Presence of CHIP and gene-specific CHIP subtypes (DNMT3A, non-DNMT3A, TET2, ASXL1, JAK2, DNA damage repair genes, and spliceosome genes). Mediation analyses examined CHIP-associated comorbidities (CAD, AF, T2D, and CKD). MAIN OUTCOMES AND MEASURES: The primary outcome was incident HF. Cox regression tested associations of CHIP and CHIP subtypes with incident HF, adjusted for age, sex, race, and cardiovascular risk factors. RESULTS: Among 417 616 participants (mean [SD] age, 56.1 [8.1] years; 234 868 female [56.2%]), 7183 (1.7%) developed incident HF over a median (IQR) of 11.1 (10.4-11.8) years of follow-up. CHIP was associated with HF risk (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.15-1.40; P < .001), driven by non-DNMT3A subtypes (aHR, 1.52; 95% CI, 1.33-1.75; P < .001), including associations with TET2, ASXL1, JAK2, and spliceosome CHIP. DNMT3A CHIP was more modestly associated with HF (aHR, 1.15; 95% CI, 1.00-1.31; P = .04). In mediation analyses, development of CAD, AF, T2D, and/or CKD collectively accounted for 28.2% of the association (95% CI, 11.6%-45.4%; P = .001) between non-DNMT3A CHIP and HF. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that CHIP, especially non-DNMT3A CHIP, was associated with incident HF. Other CHIP-associated comorbidities explained only a minority of the association between non-DNMT3A CHIP and HF. These findings suggest that CHIP is an HF risk factor and potential therapeutic target.

Adult↗

PubMed2025

Clonal Hematopoiesis and Risk of New-Onset Myocarditis and Pericarditis.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of hematopoietic stem cells with leukemia-associated mutations. Certain CHIP mutations promote atherosclerosis and heart failure through immune-related pathways. OBJECTIVE: To test whether CHIP is associated with the development of myocarditis and pericarditis. DESIGN, SETTING, AND PARTICIPANTS: This observational population-based cohort study used data from the UK Biobank. Enrollment occurred between 2006 and 2010. Participants with whole-exome sequencing, no prevalent cardiovascular disease or hematological malignancy, and complete covariate data were included. Follow-up occurred for a median of 13.6 (IQR, 12.8-14.2) years. Analyses were conducted from November 2024 to July 2025. EXPOSURES: Any CHIP (variant allele frequency [VAF] ≥2%) and large CHIP (VAF ≥10%) constituted coprimary study exposures. Secondary analyses considered DNMT3A and TET2 CHIP as separate exposures. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of incident myocarditis and pericarditis. Cox regression tested associations of CHIP with myocarditis and pericarditis, adjusting for age, sex, race and ancestry, and cardiovascular risk factors. Secondary analyses considered myocarditis and pericarditis as separate outcomes. Additional analyses compared associations of CHIP with myocarditis and pericarditis with those with other cardiovascular diseases, and tested the bidirectional associations between CHIP and noncardiac immune-mediated inflammatory diseases. RESULTS: Among 335 426 participants (mean age, 56.1 years; 185 429 female [55.3%] and 149 997 male [44.7%]), 11 057 had any CHIP (3.3%), 7271 had large CHIP (2.2%), and 382 developed myocarditis or pericarditis (0.11%). Any and large CHIP were associated with multivariable-adjusted hazard ratios of 1.75 (95% CI, 1.14-2.68; P = .01) and 2.07 (95% CI, 1.28-3.33; P = .003), respectively, for the primary composite outcome of incident myocarditis and pericarditis. Increased risks were observed for DNMT3A and TET2 CHIP, with hazard ratios of 2.22 (95% CI, 1.17-4.21; P = .01) for DNMT3A with pericarditis and 3.65 (95% CI, 1.16-11.49; P = .03) for TET2 with myocarditis. CHIP associated with myocarditis and pericarditis more strongly than with other cardiovascular diseases (eg, coronary artery disease and heart failure). Any CHIP was also associated with 1.27-fold risk (95% CI, 1.16-1.39; P < .001) of developing noncardiac immune-mediated inflammatory diseases, without evidence for reverse causation. CONCLUSIONS AND RELEVANCE: In this study, CHIP was a strong risk factor for myocarditis and pericarditis among middle-aged adults. Targeting CHIP and its downstream pathways may represent a strategy for preventing or treating pericarditis and myocarditis.

Adult↗

PubMed2025

Colchicine and Longitudinal Dynamics of Clonal Hematopoiesis: An Exploratory Substudy of the LoDoCo2 Trial.

BACKGROUND: Clonal hematopoiesis (CH) is an aging-related hematologic condition associated with increased risk for cardiovascular events. Larger CH clones associate more strongly with cardiovascular risk. Preclinical data indicate that inflammatory signaling drives expansion of CH clones and CH-associated cardiovascular disease. However, the effect of anti-inflammatory therapies on CH clonal dynamics in humans is unclear. OBJECTIVES: The goal of this study was to test the association of randomization to colchicine vs placebo with CH growth in participants with chronic coronary artery disease. It also assessed the association of colchicine use with change in inflammatory biomarkers over time according to CH status. METHODS: In this exploratory substudy of the LoDoCo2 (Low-Dose Colchicine 2) trial, high-coverage targeted sequencing was used to detect CH driver mutations and to quantify variant allele frequency at 4 timepoints: baseline, after a 30-day open-label colchicine run-in phase (0.5 mg daily), 1 year postrandomization to colchicine or placebo, and at end of study (median follow-up of 25.0 months). Clonal dynamics were assessed by using a generalized linear mixed model. High-sensitivity C-reactive protein and interleukin-6 were additionally measured at baseline, randomization, and 1 year postrandomization. RESULTS: In total, 854 participants contributed 2,047 observations across 4 timepoints, including before and after the prerandomization colchicine run-in period. Randomization to placebo was associated with a 14.9% annual increase in CH clone size (βtime = 0.14; 95% CI: 0.08 to 0.21) vs a nonsignificant 6.3% increase with colchicine (βtime on colchicine: 0.06; 95% CI: -0.01 to 0.14), although this difference between treatment arms was not statistically significant (Pinteraction = 0.13). Compared with placebo, colchicine was associated with attenuated clonal growth in TET2 CH (βtime on colchicine: 0.09 [95% CI: -0.04 to 0.22]; βtime placebo: 0.27 [95% CI: 0.16 to 0.37]; Pinteraction= 0.04). Among individuals with non-DNMT3A CH, interleukin-6 levels increased to a lesser extent in those receiving colchicine vs placebo over 1 year (30.0% vs 98.1% increase, respectively; Pinteraction = 0.01). CONCLUSIONS: In this exploratory analysis, treatment with low-dose colchicine was associated with attenuated clonal expansion in TET2 CH. These findings suggest the potential for colchicine to curb the proliferative advantage of key CH driver mutations and to mitigate their associated risk of cardiovascular disease. Further validation in prospective studies is warranted.

Humans↗