PB0264 - Questions about the role of X-chromosome inactivation for coagulation factors in hemophilia carriers

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

Keiko Shinozawa, PhD

Assistant Professor
Department of Laboratory Medicine, Tokyo Medical University/Japan
Shinjuku-ku, Tokyo, Japan

Co-Author(s)

Hiroshi Inaba

Associate Professor
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan
Masato Bingo, MD, PhD

Assistant Professor
Department of Laboratory medicine, Tokyo Medical University
Shinjukuku, Tokyo, Japan
TH

Takeshi Hagiwara

Associate professor
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan
AM

Ayano Mitsuhashi

Endowed researcher
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan
KA

Kagehiro Amano

Professor
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan
EK

Ei Kinai

Professor
Department of Laboratory Medicine, Tokyo Medical University
Shinjuku, Tokyo, Japan

Background: Coagulation factor levels in hemophilia carriers are generally considered to be determined by X-chromosome inactivation (XCI). However, studies evaluating the association between XCI and factor levels are limited.

Aims: To evaluate the association between X-chromosome inactivation (XCI) and coagulation factor levels in hemophilia carriers with null or non-null variants.

Methods: Hemophilia carriers were diagnosed by genetic analysis with reference to variants of hemophiliacs in the same family. XCI was quantitatively estimated using androgen receptor gene (AR) methylation sensitive systems, and coagulation factor levels were compared according to XCI patterns (XIP) and null/non-null variants. A skewed XCI was defined as ratios ≥70:30.

Results: Fifty-eight female family members with hemophiliac patient were enrolled, including 31 hemophilia A (HA) carriers, 6 hemophilia B (HB) carriers and 21 non-carriers. The median of factor levels were 65.0 IU/dL in HA carriers and 39.3 IU/dL in HB carriers. The median of XIP of 37 carriers and 21 non-carriers were almost comparable (52% (IQR:36-58) in carriers vs. 64% (IQR:38-81) in non-carriers, p = 0.320) (Fig. 1), and a skewed XCI was observed in 21.6% (8/37) and 38.1% (8/21) in carriers and non-carriers, respectively. There was no correlation between XIP and factor activity in 37 carriers (r = -0.36). Of note, FVIII levels were comparable between HA carriers with skewed XCI of null variant (n=6) and those with random XCI of non-null variants (n=9) (60.6 (IQR 34-85) vs. 65.0 (IQR 50-90) IU/dL, p= 0.469) (Table 1). Eight carriers with skewed XCI (median FVIII:C; 44.3 IU/dL, F8 inversion (n=5), F8 1-bp insertion, F8 p.T174I, F9 p.R384*) had menorrhagia and excessive bleeding after tooth extraction.

Conclusion(s): In our small study, XCI was not associated with the factor levels in hemophilia carriers even in those who have null variants. Further research using larger population involving other confounding factors are needed.