1. Epidemiology and Global Health
  2. Genetics and Genomics

Skewed X chromosome silencing may indicate chronic disease risk

Findings suggest skewed X chromosome inactivation could increase an individual’s risk of developing chronic diseases and cancer.
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Scientists at King’s College London have shed new light on how a process called skewed X chromosome inactivation (XCI-skew) can affect individuals later in life, publishing their results today in eLife.

XCI-skew is a measure of how many cells in a tissue inactivate the same parental X chromosome. The findings suggest that age-acquired XCI-skew increases an individual’s risk of developing cardiovascular disease and cancer. It could therefore be used in a clinical setting as a biomarker of age-related chronic disease risk.

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

XCI-skew is a deviation from this ratio. Secondary, or age-acquired XCI-skew is more common and pronounced in blood tissue where mitosis – a type of cell division which gives rise to two genetically identical daughter cells – occurs.

“The consequences of age-acquired XCI-skew on people’s risk of chronic disease have largely been unexplored,” says first author Amy Roberts, Postdoctoral Research Fellow at the Department of Twin Research and Genetic Epidemiology, King’s College London, UK. “To remedy this, we analysed XCI-skew in 1,575 females from the TwinsUK registry to characterise its relationship with ageing and chronic disease risk.”

Roberts and colleagues measured XCI in blood-derived DNA using the PCR-based Human Androgen Receptor Assay (HUMARA), which differentiates between genes from the active and inactive X chromosome. The output from HUMARA gave an XCI variable between 0–100% for the participants, where 50% is perfectly balanced XCI. XCI-skew was defined as one standard deviation from the mean value of the cohort (greater than, or equal to 75%) and extreme XCI-skew was defined as two standard deviations (greater than, or equal to 91%).

The team assessed changes in the frequency of XCI-skew across increasing age groups. They found that 12% of individuals under 40 years old, 28% of 40–59 year olds, 37% of 60–69 year olds and 44% of over 70 year olds displayed XCI-skew. Extreme XCI-skew was seen at a consistent rate of around 3–4% below the age of 60, but jumped to 7% between 60–69 and further to 9% for those over 70. These results imply a jump in XCI-skew prevalence occurs around the age of 40 and then again after age 60, where the first jump in extreme XCI-skew is also seen.

For 31 individuals in the cohort, the team could access a previous DNA sample from 15–17 years prior. All the individuals who displayed XCI-skew in the previous sample also displayed XCI-skew in the second, or had progressed to extreme XCI-skew. This indicates that XCI-skew persists over extended periods of time and increases over an individual’s lifetime.

Given this association between XCI-skew and chronological age, the team sought to establish whether XCI-skew was associated with biological ageing – the result of damage to cells and tissues in the body that accumulates over time. Using a type of model called linear regression mixed effects models, they demonstrated that XCI-skew is independent of traditional markers of biological ageing. However, they note that this relationship requires further study with a larger sample size, particularly with extreme XCI-skew individuals.

The team then used the atherosclerotic cardiovascular disease (ASCVD) risk score to determine whether XCI-skew was indicative of increased risk of cardiovascular disease – the leading cause of deaths worldwide. In a population of 228 individuals, 23.5% of those with extreme XCI-skew had a high ASCVD risk and 35.3% showed an intermediate risk.

Additionally, they conducted a prospective 10-year follow-up study and found that even modest XCI-skew indicated an increased probability of future cancer diagnosis. The authors found XCI-skew to be predictive of all types of cancer diagnoses, but they encourage follow-up studies to assess the risk of cancer in specific tissues.

“From our results, we hypothesise that XCI-skew in blood tissue does not directly cause cancer later in life. Rather, XCI-skew is likely to be a marker of chronic inflammation, which can stimulate tumour growth,” explains Roberts.

“Our study demonstrates that XCI-skew has clinical potential as a unique biomarker of chronic disease risk,” concludes senior author Kerrin Small, Reader in Genomics at the Department of Twin Research and Genetic Epidemiology, King’s College London. “Further studies are needed to understand the mechanisms of this phenomenon and determine whether it can be utilised to help prevent chronic disease risk down the line.”

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