Volumen: 20 # Number : 3
Publication Date : Septiembre - Diciembre Year: 2016
CTLA4 p.Thr17Ala (c.49A>G) polymorphism associates
with inhibitor development in argentine patients
with severe hemophilia A
Authors: Marchione VD, Radic CP, Abelleyro MM, Primiani L,
Neme D, Candela M, de Tezanos Pinto M,
De Brasi CD, Rossetti LC
Abstract: FVIII inhibitor development in hemophilia A (HA)
is considered a complex trait as it involves genetic
and environmental factors; the causative factor
VIII gene (F8) genotype has been established as
the most important determining factor, followed
by weaker secondary genetic risks factors. Risks
of inhibitor development associated with each F8-
genotype were estimated by a case/control study
in HA-severe patients (n=390), which especially
characterizes strata with Inv22 (intron 22 inversion).
Inhibitor prevalence (IP) and odds ratio (OR) with
confidence intervals of 95% (95%CI) calculations
allowed classifying three risk groups (high, medium
and low) associated with each F8-genotype. The
association of genetic factors was investigated by
analyzing concordance/discordance inhibitor-status
in 17 pairs of brothers with Inv22 vs random pairs
showing 1.83(0.69 to 4.85) (p=0.33), suggesting
a trend to agree the inhibitor status between
siblings. Case/control studies associated risk
inhibitor development with IL10, TNFA and CTLA4
polymorphisms in Inv22-positive strata (n=140-
148) were performed and in IL10 c.-1117A>G,
TNFA c.-488G>A & CTLA4 c.-319C>T trends of
risks or protection, similar to reported ones with
not significant ORs. CTLA4 c.49A>G p.Thr17Ala
showed significantly increased inhibitor risks with
OR of 2.61(1.27-5.36) (p=0.0096). Our findings
agree with previous theoretical speculations about
regional differences in non-modifiable secondary
factors. CTLA4 p.Thr17Ala, contributes to an
increased risk of inhibitor in our population of
patients with HA-severe.
Key words: F8,
HEMA,
FVIII-inhibitors,
CTLA4.
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