New research has shed light on how skewed X chromosome inactivation may be linked to the development of cancer and cardiovascular disease, according to a novel study published by Roberts et al in eLife.
Background
Because the X chromosome has so many more genes than the Y chromosome, in every cell that has two X chromosomes, one of the two is silenced in the process of X chromosome inactivation. This happens early in development and is fixed for every cell, ensuring that each body cell has one functional copy of the X chromosome.
Which X chromosome is silenced is selected at random, and so it is expected that each X chromosome will be silenced in 50% of cells. However, as individuals age and develop new immune blood cells, some develop a pattern of X chromosome inactivation—skewed X chromosome inactivation—that strays from the expected 50:50 ratio.
Study Methods and Results
Researchers examined the health data of 1,575 female patients and found that those with the skewed pattern in their blood cells were twice as likely to develop cancer in a 10-year period, and were also at a higher risk of developing cardiovascular disease.
“The consequences of age-acquired [skewed X chromosome inactivation] on [individuals’] risk of chronic [diseases] have largely been unexplored. Understanding what causes skewing may help us understand who is at risk of developing age-related chronic [diseases] and could ultimately lead to better prevention," says lead study author Amy L. Roberts, a postdoctoral research fellow within the Regulatory Genomics Group in the Department of Twin Research and Genetic Epidemiology at King’s College London.
Dr. Roberts and her colleagues assessed changes in the frequency of skewed X chromosome inactivation across increasing age groups—and found that 12% of individuals younger than 40 years, 28% aged 40 to 59 years, 37% aged 60 to 69 years, and 44% older than 70 years presented with the condition.
Extreme skewed X chromosome inactivation was seen at a consistent rate of around 3% to 4% for individuals younger than 60 years, but jumped to 7% for those aged 60 to 69 years, and further to 9% for those older than 70 years. These results suggest that a jump in skewed X chromosome inactivation prevalence may occur around age 40 years and then again after age 60 years—where the first jump in extreme skewed X chromosome inactivation was also seen.
For 31 individuals in the cohort, the researchers could access a DNA sample taken 15 to 17 years prior to the study. All of the individuals who presented with skewed X chromosome inactivation in the prior sample also had skewed X chromosome inactivation or a progression to extreme skewed X chromosome inactivation during the study period. This finding indicated that skewed X chromosome inactivation may persist over extended periods of time and increase over an individual’s lifetime.
Additionally, the researchers used the atherosclerotic cardiovascular disease risk score to determine whether skewed X chromosome inactivation was indicative of an increased risk of cardiovascular disease. Analyzing the health data of 228 individuals, the researchers discovered that 23.5% of those with extreme skewed X chromosome inactivation had a high risk and 35.3% of individuals had an intermediate risk of atherosclerotic cardiovascular disease.
Further, they conducted a prospective 10-year follow-up study and found that even modest skewed X chromosome inactivation was indicative of an increased probability of a future cancer diagnosis—for all types of cancers.
“From our results, we hypothesize that [skewed X chromosome inactivation] in blood tissue does not directly cause cancer later in life. Rather, [skewed X chromosome inactivation] is likely to be a marker of chronic inflammation, which can stimulate tumor growth,” Dr. Roberts outlined.
The study also showed that neither smoking nor obesity were risk factors for X chromosome inactivation skewing to happen.
"Our study demonstrates that [skewed X chromosome inactivation] has clinical potential as a unique biomarker of chronic disease risk. Further studies are needed to understand the mechanisms of this phenomenon and determine whether it can be utilized to help prevent chronic disease risk down the line," concluded study co-author Kerrin S. Small, PhD, reader in genomics in the Department of Twin Research and Genetic Epidemiology at King’s College London, and Deputy Director of the TwinsUK Resource.
Disclosure: For full disclosures of the study authors, visit elifesciences.org.
