Investigating the causal relationship and mediating mechanisms between Clonal hematopoiesis and vitamin D levels: A Mendelian randomization study

Clonal hematopoiesis (CH) is defined by the clonal proliferation of hematopoietic cells that acquire somatic mutations in specific driver genes. Growing evidence suggests that vitamin D (VD), beyond its well-established role in calcium and bone homeostasis, also participates in diverse physiological processes, including cell cycle regulation and immune modulation. Although recent studies have suggested a potential link between CH and VD, the causal nature of this relationship remains to be determined. We conducted a 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship between CH and VD. Five CH subtypes were analyzed: overall CH (CH-overall), CH with DNMT3A mutations (CH-DNMT3A), CH with TET2 mutations (CH-TET2), large clones (CH-large), and small clones (CH-small). Genetic instruments were derived from genome-wide association studies (GWAS), and the inverse-variance weighted (IVW) method was used as the primary analytical approach. Sensitivity analyses and reverse MR were performed to assess the reliability and directionality of the observed associations. Additionally, a 2-step MR framework was applied to explore potential underlying mechanisms and determine whether inflammatory cytokines mediated the CH-VD relationship. MR analysis identified a statistically significant positive association between CH-large and VD (odds ratio: 1.21, 95% CI: 1.02-1.43, P = .026), suggesting a potentially protective effect of large CH clones on VD. No significant associations were found for other CH subtypes. Reverse MR analysis provided no evidence of a bidirectional causal relationship between VD and any CH phenotype. Two-step MR results indicated that MMP-10 may partially mediate the causal link between CH-large and VD, accounting for approximately 8.09% of the total effect. No significant horizontal pleiotropy was detected, supporting the validity of the MR assumptions. Our findings suggest a positive association between large CH clones and VD levels, with MMP-10 potentially serving as a mediator in this pathway. These results provide preliminary evidence for a broader biological interaction between CH and VD. Further research is warranted to elucidate the molecular mechanisms underlying this association and its potential implications in immune and metabolic health.