Relationship between acquired X chromosome silencing deviation and chronic diseases in middle and old age

Scientists at King's College London have a new understanding of how a process known as X chromosome inactivation shift (XCI-skew) affects an individual's later life, and they published their findings
today in eLife.

XCI-skew is a method
of measuring how many cells in a tissue inactivate the X chromosome of the same parent.
The findings suggest that age-acquired XCI-skew increases an individual's risk of
cardiovascular disease and cancer.
Therefore, it can serve as a biomarker of age-related chronic disease risk in clinical settings
.

X chromosome inactivation (XCI) is a process
that equalizes gene expression between members of different chromosomal sexes.
XCI randomly silences the maternal or paternal X chromosome in each cell, usually during development
.
XCI status is inherited by daughter cells and is expected to be observed
at a 1:1 ratio.

XCI-skew is the deviation
of this ratio.
Secondary or senile XCI-skew is more common and pronounced in blood tissues where mitosis occurs, a type of cell division that produces two genetically identical daughter cells
.

Lead author Amy Roberts, a postdoctoral researcher and postdoctoral fellow in the Department of Twin Studies and Genetic Epidemiology at King's College London, UK, said: "The impact of XCI-skew on people's risk of chronic disease remains largely unexplored
.
To address this, we analysed XCI-skew from 1575 women registered with TwinsUK to determine its relationship
with ageing and chronic disease risk.
”

Roberts and his colleagues used polymerase chain reaction-based human androgen receptor assay (HUMARA) to determine XCI in bloodborne DNA, which distinguishes genes
from active X chromosomes and inactive X chromosomes.
HUMARA's output provided participants with a 0-100% XCI variable, of which 50% was a perfectly balanced XCI.

XCI-skew is defined as one standard deviation from the cohort mean (greater than or equal to 75%), and extreme XCI-skew is defined as two standard deviations (greater than or equal to 91%)
.

The team evaluated changes
in XCI-skew frequency in a growing age group.
They found that 12 percent of those under 40, 28 percent of those aged 40-59, 37 percent of those aged 60-69, and 44 percent of those over 70 showed XCI-skew
.
The XCI-skew rate remained around 3-4% among people under 60, but jumped to 7% between 60-69 and further reached 9%
in people over 70.
These results suggest that the XCI-skew rate jumps around age 40 and then again after age 60, at which point the first jump
of extreme XCI-skew can also be seen.

For the 31 individuals in the cohort, the team could obtain DNA samples
from 15-17 years ago.
All individuals who exhibited XCI-skew in the previous sample also exhibited XCI-skew in the second sample, or progressed to extreme XCI-skew
.
This suggests that XCI-skew lasts for a long time and increases
throughout a person's lifetime.

Given this link between XCI-skew and chronological age, the team sought to determine whether XCI-skew is associated with biological senescence — the result of
cumulative damage to the body's cells and tissues over time.
Using a model called a linear regression mixed-effects model, they demonstrated that XCI-skew is not related to
traditional markers of biological aging.
However, they note that this relationship requires further studies with larger sample sizes, particularly in individuals with extreme XCI-skew
.

The team then used the atherosclerotic cardiovascular disease (ASCVD) risk score to determine whether XCI-skew meant an increased risk of cardiovascular disease, the leading cause
of death worldwide.
Of the 228 individuals, 23.
5% of patients with extreme XCI-skew had a higher risk of ASCVD and 35.
3% had an intermediate risk
.

In addition, they conducted a 10-year prospective follow-up study and found that even modest XCI-skew indicated an increased
likelihood of future cancer diagnoses.
The authors found that XCI-skew can predict all types of cancer diagnoses, but they encourage follow-up studies to assess cancer risk
in specific tissues.

"From our results, we hypothesized that XCI-skew in blood tissue does not directly cause cancer
later in life.
Instead, XCI-skew is likely to be a marker of chronic inflammation, which can stimulate tumor growth," Roberts
explains.

"Our study shows that XCI-skew has clinical potential as a unique biomarker of chronic disease risk," concludes senior author Kerrin Small, who is senior author of the Genomics Department of Twin Studies and Genetic Epidemiology at King's
College London.
"Further research is needed to understand the mechanisms of this phenomenon and determine whether it can be used to help prevent the risk
of chronic disease.
"

Age acquired skewed X chromosome inactivation is associated with adverse health outcomes in humans