Skewed X Chromosome Associated with Cancer and Chronic Disease Risk

X chromosome inactivation is a process that equalizes gene expression between members of different chromosomal sexes. This process involves randomly silencing either maternal or paternal X chromosomes in each cell. While the XCI status in inherited by daughter cells is typically observed at a 1:1 ratio, that’s not always the case. Researchers at King’s College London found how deviations from this ratio, like those observed in XCI-skew, are associated with increased risk of an individual developing cardiovascular disease and cancer.

There are two primary types of XCI-skew – one that occurs during zygotic development, and another age-related skew that’s more common and pronounced in blood tissue. “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.”

The team’s work, published in the journal eLife, measured XCI in blood-derived DNA using the PCR-based Human Androgen Receptor Assay (HUMARA), which differentiates between genes in the active and inactive X chromosome. The results from HUMARA gave the patients an XCI variable between 0-100%, where 50% is perfectly balanced XCI. The researchers defined XCI-skew to be one standard deviation from the mean value of the cohort (≥75%), and an extreme XCI-skew was defined as two standard deviations (≥ 91%).

Roberts and colleagues 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. They also observed extreme XCI-skew at a consistent rate of 3-4% in participants below the age of 60, but that figure jumps up with age – 7% with 60-69 years old and 9% for those over 70 years old.

The team also assessed a previous DNA sample from 31 individuals in their sample, taken 15-17 years before the study. All the individuals who displayed XCI-skew in the previous sample also displayed SCI-skew in this study, or had progressed even more to extreme XCI-skew. This suggests that XCI-skew persists over extended periods of time, even increasing with age.

After observing the association between XCI-skew and age, the team ran a linear regression mixed effects model and found that XCI-skew was independent of traditional markers of biological aging. For future work, however, they wish to probe into this relationship further with a larger sample size, particularly with extreme XCI-skew individuals.

The researchers also used the atherosclerotic cardiovascular disease (ASCVD) risk score to determine whether XCI-skew was indiciative of increased risk of cardiovascular disease. They found that, in a population of 228 individuals, 23.5% of those with extreme SCI-skew had a high ASCVD risk and 35.5% of individuals showed an intermediate risk.

Additionally, the team conducted a prospective 10-year follow up study and found that even slight XCI-skew indicated an increase probability of future cancer diagnosis. The authors found XCI-skew to be predictive of diagnoses of all cancer types, but still 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,” says 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.”