Statin Therapy Is Associated with Reduced Clonal Expansion in TET2 Mutated Clonal Haematopoiesis of Indeterminate Potential

Introduction:

Clonal haematopoiesis of indeterminate potential (CHIP) is the acquisition of somatic mutations in leukaemia associated genes in haematopoietic progenitors with age. It increases the risk of haematological malignancy, cardiovascular disease and mortality. CHIP-associated inflammation is thought to drive CHIP clonal expansion, with larger clones posing higher risks of adverse health outcomes. Many commonly prescribed medications have anti-inflammatory properties, but their effect on CHIP clone size has not been reported. This analysis characterises the English Longitudinal Study of Ageing (ELSA), a longitudinal cohort of individuals aged >50 running since 2002, as a novel CHIP cohort and investigates the effect of biomedical parameters, comorbidities and prescribed medication on TET2 CHIP clone size.

Methods:

DNA was extracted from 13270 ELSA peripheral blood samples and sequenced with a custom myeloid amplicon panel. Individuals with samples collected between 2017-2019 were used in these analyses. To validate epidemiological associations in the ELSA cohort, CHIP cases and controls were matched for age, sex and smoking status and odds ratios (OR) of common comorbidities were calculated. To identify determinants of TET2 CHIP clone size, individuals with TET2 CHIP were split 70:30% into test and train cohorts. Stepwise forward regression was used to identify the most important predictors of high variant allele frequency (VAF) (>=10%) versus low VAF (<10%) TET2 CHIP (including mutation characteristics, comorbidities, medications and laboratory parameters) in the train cohort. A logistic regression model was constructed, and its accuracy assessed in the unseen test cohort with receiver operating characteristic (ROC) curve analysis.

Results:

The ELSA cohort had a median age of 66 years (range 59 - 99) and was 55.3% female. The mean sequencing coverage per sample was 1395x. CHIP was detected in 21% (2846) samples, with 3989 variants detected. Similar to other cohorts, the most commonly mutated genes were DNMT3A and TET2 (accounting for 42% and 37% of the mutations detected, respectively). CHIP was associated with an increased risk of ischaemic heart disease (OR (95% confidence interval (CI): 2.89 (1.67, 5.24)), non-ischaemic heart disease (OR (95% CI): 1.97 (1.38, 3.68) and also hypertension (OR (95% CI): 2.02 (1.61, 2.55)) when correcting for age, sex and smoking status, validating the ELSA cohort both in terms of mutational profile and epidemiological associations.

There were 555 individuals with TET2 mutated CHIP between 2017-2019. The median VAF was 3.6% (range 2-51%) and 17.2% of individuals had a TET2 VAF >= 10%. The train cohort included 60 cases of high VAF TET2 CHIP. The 5 most important predictors of TET2 VAF were included in a multivariate logistic regression model with OR (95% CIs) as follows: age in years (1.05 (1.02-1.09), p < 0.01), statin treatment (0.32 (0.15-0.67)), p < 0.01), asthma diagnosis (3.04 (1.36-6.54), p < 0.01), haemoglobin concentration (g/dL) (0.98 (0.95-1.00), p=0.06) and serum cholesterol (0.76 (0.55-1.05), p = 0.10). These associations were confirmed in age-adjusted univariate analyses with OR (95% CIs) as follows: statin treatment (mmol/L) (0.51 (0.27, 0.94)), p = 0.03), asthma diagnosis (2.66 (1.21, 5.60), p = 0.01), haemoglobin concentration (g/dL) (0.98 (0.96, 1.00), p=0.08) and serum cholesterol (mmol/L) (0.95 (0.73, 1.22), p = 0.67). The model was cross validated in the test cohort, with an area under the ROC curve of 0.72, indicating arguably good performance for a complex clinical trait.

Conclusion:

Here, we validate the ELSA cohort as a CHIP cohort and show that statin treatment is associated with a lower risk of having large TET2 CHIP clones, independent of serum cholesterol. We also identify an association between TET2 CHIP clone size and asthma. These findings were robust in univariate analyses and cross validation. To our knowledge, this is the first analysis suggesting that statins, known to modify progression of myeloid malignancy (Afzal et al., 2023) may modify TET2 CHIP clonal expansion, potentially mitigating the health risks posed by TET2 CHIP. Although TET2 CHIP has been associated with asthma and chronic obstructive pulmonary disease previously (Buscarlet et al., 2017), this study suggests that this relationship is also related to TET2 CHIP clone size with implications for further research into CHIP and adult asthma.

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