Familial hypercholesterolaemia and thymic ageing in a Chinese cohort
Fangyuan Li, Ju Zhang, Jialing Deng, Hang Zhang, Yu Hao, Jie Peng, Zengtao Wang, Lei Hua, Chenchen Wang, Jiajia Wang, Xue Wu, Xiaoming Liu, Na Li, Shirui Meng, Yuezhe Shi, Zhen Yu, Weimin Li, Chen Chen, Nan Ding, Yaluan Ma, Jie Lin, Hui ZengAbstract
Background and Aims
Lifelong exposure to elevated low-density lipoprotein cholesterol in familial hypercholesterolaemia (FH) patients not only increases the risk of atherosclerotic cardiovascular disease, but also affects other organs beyond the cardiovascular system. In a large FH cohort, this study investigated the effects of hypercholesterolaemia on the thymic output and explored whether lipid-lowering therapy can reverse these effects.
Methods
According to the Dutch Lipid Clinic Network criteria, 562 heterozygous FH patients (236 treatment-naïve, 326 on lipid-lowering therapy) and 295 age-matched healthy controls (HCs) were enrolled. Thymic output was measured by circulating CD4+ recent thymic emigrants (RTEs) with flow cytometry, and T-cell receptor excision circles in sorted naïve CD4+ and CD8+ T cells. Repertoire diversity and clonal expansion were evaluated by T-cell receptor beta sequencing.
Results
Compared with HCs, treatment-naïve FH patients displayed a significantly reduced percentage of CD4+ RTE among naïve CD4+ T cells, particularly in those aged 18–30 years or carrying highly pathogenic LDLR variants. T-cell receptor excision circle analysis supported reduced thymic output in both CD4+ and CD8+ naïve T cells. Quantified thymic ageing further showed that FH patients reached the median CD4+ RTE percentage of HCs ∼6 years earlier (males: 19.12 vs 25.51 years; females: 19.18 vs 25.58 years). Consistent with reduced thymic output, FH patients showed skewing towards high-frequency T-cell receptor beta clones. Statin-treated FH patients, particularly females, showed higher circulating CD4+ RTE levels than statin-naïve FH patients.
Conclusions
Hypercholesterolaemia was associated with reduced thymic output, while statin-treated patients showed partially preserved circulating CD4+ RTE levels, supporting integrated metabolic and immunologic strategies for FH management.