A prevalent CTLA4 missense variant significantly associates with inhibitor development in Argentine patients with severe haemophilia A

ZUCCOLI, J.R.; NEME, D.; DE BRASI, C.D.; ZUCCOLI, J.R.; ABELLEYRO, M.M.; NEME, D.; CANDELA, M.; DE BRASI, C.D.; ROSSETTI, L.C.; ABELLEYRO, M.M.; CANDELA, M.; ROSSETTI, L.C.; MARCHIONE, V.D.; RADIC, C.P.; DE TEZANOS PINTO, M.; MARCHIONE, V.D.; RADIC, C.P.; DE TEZANOS PINTO, M.

HAEMOPHILIA THE OFFICIAL JOURNAL OF THE WORLD FEDERATION OF HEMOPHILIA

Blackwell Publishing Ltd

Lugar: Oxford; Año: 2017 vol. 23 p. 166 - 169

1351-8216

As a complex trait, FVIII inhibitor formation in haemophilia A (HA) involves genetic and environmental factors. To identify secondary genetic factors in Argentine patients with severe-HA, we confirmed the inhibitor risks associated with each F8-genotype in a large cohort of severe-HA patients (n=390), characterised the intron 22 inversion (Inv22) strata and analysed polymorphisms in IL10, TNFA and CTLA4 in the Inv22-positive strata (n=140-148) and in a comprehensive series of patients with severe-HA (n=213-222).IL10 c.-1117A>G (rs1800896) showed a neutral non-significant odds ratio (OR). TNFA c.-488G>A (rs1800629) showed a non-significant increase in inhibitor risk OR(95%CI) of 1.78(0.84-3.77) in severe-HA and 1.67(0.68-4.08) in the Inv22-strata. CTLA4 c.-319C>T (rs5742909), previously reported as inhibitor protective hardly confirmed this trend in our population showing non-significant ORs of 0.63(0.26-1.52) in severe-HA and 0.47(0.16-1.40) in the Inv22-strata. Interestingly, CTLA4 c.49A>G p.Thr17Ala (rs231775) showed significantly increased inhibitor risks associating the [G/_] genotypes with ORs of 1.89(1.04-3.45)(p=0.0398) in severe-HA; and 2.61(1.27-5.36)(p=0.0096) in the Inv22-strata.Our findings agree with previous theoretical speculations about regional differences in non-modifiable (secondary) inhibitor risk-factors. CTLA4 p.Thr17Ala, previously proved to down-regulate T-cell CTLA-4 surface expression predisposing to typical autoinmune diseases, significantly increased the inhibitor risk in our severe-HA population.