Differences in DNA methylation may account for the varying risk of chronic lymphocytic leukemia between men and women, a new study has found.

CLL is one of the most common leukemias affecting adults, but it is more prevalent in men than  in women. Researchers have suspected that this could be driven by  the different DNA methylation patterns between the two sexes.

A team of Chinese Academy of Sciences researchers conducted an epigenome-wide association study of CLL and reported the results this week in the journal Biology of Sex Differences. They uncovered more than 1,000 sex-related differentially methylated positions, which overlapped with 18 genes that are differentially expressed by sex, including TRIB1, which has CLL-related functions. These genes could represent both markers for CLL risk as well as potential treatment targets, they added.

"Our study revealed a connection between the sex-related differences in DNA methylation and the CLL disease risk and outcome," senior author Ying Gao from CAS and her colleagues wrote in their paper.

The researchers enrolled 48 CLL patients — 29 women and 19 men — and 28 healthy controls — 19 women and nine men — into their study. They generated genome-wide DNA methylation patterns from participants' CD19⁺ B cells using Illumina's Human Methytlation450 BeadChip.

From this, they identified 1,043 sex-related differentially methylated positions linked to CLL. Of these, 56 were found at autosomal sites, 22 of which were hypermethylated and 34 were hypomethylated in men with CLL compared to women with CLL. These sites showed little difference between healthy men and women, the researchers noted.

They traced these 56 differentially methylated positions to 48 genes, which gene ontology analysis found to be enriched for involvement in metabolic processes, leukocyte and lymphocyte homeostasis, and activation and differentiation, among others.

Meanwhile, the researchers uncovered 987 sex-related differentially methylated positions on the X chromosome. A principal components analysis found that global DNA methylation status on the X chromosome was drastically different between male and female CLL patients, they added.

This high number of differentially methylated positions on the X chromosome, they noted, could be due to X chromosome inactivation escape of many X chromosome genes in female CLL patients.

These 987 positions were located in 407 genes, which were enriched for involvement in cellular component organization, cell-cell signaling, and receptor binding.

The researchers replicated 36 autosomal and 732 X chromosomal differentially methylated positions in a separate cohort of 116 female CLL patients, 185 male CLL patients, nine healthy women, and 12 healthy men.

They then folded in publicly available B cell RNA-sequencing data from 50 female CLL patients, 84 male CLL patients, 17 healthy women, and 24 healthy men. This enabled them to tease out 18 genes with both differences in DNA methylation and gene expression between male and female CLL patients.

One of these genes was TRIB1, which is located on chromosome 8 and contains a differentially hypomethylated position, and the researchers reported that the mRNA of TRIB1 is about twice as abundant in male as in female CLL patients. They further noted that high TRIB1 expression has been shown to activate the NFκB pathway, which suppresses apoptosis and leads to more aggressive tumors.

In addition to giving some insight into the mechanisms of sex-based differences in CLL risk, the differentially methylated positions they identified could also serve as biomarkers for disease and potential drug targets, the researchers said. (genomeweb)