ABSTRACT
Background and
Aims:
Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of
blood-derived
DNA are structural somatic variants that indicate
clonal hematopoiesis. This study aimed to investigate whether mCAs contribute to the
risk of
cirrhosis and modify the effect of a
polygenic risk score (PRS) on
cirrhosis risk prediction.
Methods:
mCA call sets of individuals with European ancestry were obtained from the
UK Biobank. The PRS was constructed based on 12 susceptible single-
nucleotide polymorphisms for
cirrhosis. Cox
proportional hazard models were applied to evaluate the
associations between mCAs and
cirrhosis risk.
Results:
Among 448,645 individuals with a median follow-up of 12.5 years, we identified 2,681 cases of
cirrhosis, 1,775 cases of compensated
cirrhosis, and 1,706 cases of decompensated
cirrhosis. Compared to non-carriers, individuals with copy-neutral
loss of heterozygosity mCAs had a significantly increased
risk of
cirrhosis (
hazard ratio (HR) 1.42, 95%
confidence interval (CI) 1.12-1.81). This
risk was higher in
patients with expanded
cell fractions of mCAs (
cell fractions ≥10% vs.
cell fractions <10%), especially for the
risk of decompensated
cirrhosis (HR 2.03 [95% CI 1.09-3.78] vs. 1.14 [0.80-1.64]). In comparison to non-carriers of mCAs with low genetic
risk, individuals with expanded copy-neutral
loss of heterozygosity and high genetic
risk showed the highest
cirrhosis risk (HR 5.39 [95% CI 2.41-12.07]).
Conclusions:
The presence of mCAs is associated with increased susceptibility to
cirrhosis risk and could be combined with PRS for personalized
cirrhosis risk stratification.
