The Influence of X Chromosome Parent-of-Origin on Glycemia in Individuals with Turner Syndrome.

Introduction: The cause of increased diabetes mellitus (DM) risk in individuals with Turner syndrome (TS) is poorly understood. Parent-of-origin effects related to whether the maternal or paternal X chromosome (Xchr) remains intact have been found for several TS phenotypes, including hypercholesterolemia. Therefore, Xchr parent-of-origin may impact DM risk in TS. The aim of this study was to determine whether Xchr parent-of-origin affects glycaemia, as measured by oral glucose tolerance test (OGTT), in TS.

Methods: A total of 81 individuals with 45,X karyotype from the TS: Genotype Phenotype study had Xchr parent-of-origin assessment and completed a 3-h OGTT. Parallel-slopes multiple linear regression modeling was used to test whether Xchr parent-of-origin, age, and/or body mass index (BMI) significantly predicted incremental area under the glucose curve (iAUC). A second analysis included 62 additional individuals with 45,X mosaicism.

Results: All three factors predicted iAUC glucose in the 81 individuals with 45,X karyotype (age: β = 0.36, p = 0.0004; BMI: β = 0.33, p = 0.001; Xchr parent-of-origin: β = 0.21; p = 0.01). The overall model remained statistically significant when including individuals with 45,X mosaicism, but Xchr parent-of-origin was no longer significant.

Conclusions: Maternal Xchr monosomy predicts higher glucose concentration than paternal Xchr monosomy in response to oral glucose in 45,X individuals. This effect is obscured when including individuals who are mosaic, potentially due to the presence of both parent Xchrs in the non-45,X cell line.