Age-associated skewing of X-inactivation ratios of blood cells in normal females: a candidate-gene analysis approach

X-inactivation is a random process that occurs in females early during embryogenesis. Females are mosaics with an equal proportion of cells with the paternal (Xp) or maternal X-chromosome (Xm) in the active state. However, close to 40% of healthy females aged more than 60 y.o. present a significant skewing of X-inactivation ratios (Xp:Xm >3 :1). The exact etiology of this age-associated skewing (AAS) in blood cells is unknown. We hypothesized that AAS is due to hemizygous cell selection caused by allelic variants in hematopoiesis or cell survival genes. To test this hypothesis, we recruited 700 unrelated healthy females of French Canadian ancestry aged more than 60. We determined X-inactivation ratio at the HUMARA locus. We genotyped 81 different SNPs, using TaqMan® technology, in 15 different candidate genes with known role in hematopoiesis, cell cycle, or X-inactivation. Extensive statistical analyses were conducted and demonstrated that none of the 15 candidate genes investigated contribute significantly to AAS.