ESPE Abstracts

Background: Turner syndrome (TS) is associated with short stature, hypogonadism, autoimmune diseases and metabolic conditions. Genome-wide changes in TS affect both transcriptome and methylome. Genomic studies have primarily focused on 45,X, but only 35-45% of the TS population has 45,X, while the remaining TS have other karyotypes.

Methods: We used 5 study cohorts. A “genomic cohort” of TS with 45,X karyotype(TS 45,X)(n = 32) and other karyotypes(n = 24), alongside age-matched women(n = 33) and a ”45,X; 46,XX; 46,XY; 47,XXY cohort”. We analyzed DNA methylation and gene expression profiles from blood and clinical similarities between groups. Leucocytes were studied using flow cytometry and compared to healthy blood donors in ratio 1:5. The “Outpatient cohort” with routinely sampled biochemistry from TS (n = 135) and Klinefelter syndrome (KS)(n = 139) from the outpatient clinic. The “epidemiological cohort” included autoimmune, metabolic, and infectious disease history on TS (n = 1156), KS (n = 1155), 47,XXX (n = 160) and matched controls.

Results: We show a shared phenotype in the “genomic cohort” and an near-identical autosomal transcriptome and methylome between TS 45,X and TS other karyotypes, with shared expression profile for pseudoautosomal-1 (PAR1) and X/Y homologues on X, validated in the ”45,X; 46,XX; 46,XY; 47,XXY cohort”. Combining DNA methylation, gene expression and white blood cell counts, we observed higher neutrophil count (P <0.01) increased neutrophil activation among TS and gene expression of neutrophil activation markers (myeloperoxidase, neutrophil elastase, S100A8/9, P <0.01), suggesting pathological activation of neutrophils with concomitant release of pro-inflammatory mediators, and further validated the increase of neutrophils in TS in an independent cohort using “flow cytometry cohort” (P <0.01). We found an upregulation of the TBLX1 gene in TS which correlated with the neutrophil fraction (P <0.0001). In the “outpatient cohort” we show consistently higher neutrophil count already present during childhood. In the "epidemiological cohort," we conducted a gender-adjusted comparison between TS and KS, revealing an increased risk of autoimmune and metabolic diseases but a decreased risk of infections in TS.

Conclusions: The X chromosomal p-arm, in particular PAR1, appear to be the main driver influencing the genome-wide transcriptome and methylome in all TS. The presence of neutrophil-driven chronic inflammatory stress adds a new layer to the understanding of the molecular pathophysiology associated with TS and creates new links to the TS phenotype. We suggest that chronic inflammatory stress to be a forerunner of metabolic syndrome, type-2 diabetes, and hypertension, and could be involved in the greatly increased risk of any autoimmune conditions in TS.