F8 GENOTYPE AND NOT POLYMORPHISMS IN IL10, TNFA AND CTLA4 INFLUENCES INHIBITOR DEVELOPMENT IN ARGENTINE PATIENTS WITH SEVERE HA.

ROSSETTI LC; RADIC CP; ZUCCOLI J; SZURKALO I; ABELLEYRO MM; FRANZI L; PRIMIANI L; CANDELA M; PEREZ BIANCO R; DE TEZANOS PINTO M; LARRIPA IB; DE BRASI CD

Congreso; XXX International Congress of the World Federation of Hemophilia; 2012

Development of FVIII inhibitors (INH) is a severe treatment complication that affects ~20% of patients with severe haemophilia A (HA). Both genetic and environmental factors have been implicated in inhibitor formation. The objective was to characterize genetic factors associated with inhibitors in Argentine patients with severe HA. We characterized the HA-causative mutation in 170 patients classified by INH status by application of a laboratory algorithm including inverse shifting-PCR for F8 inversions, 37 PCR-amplifications for gross deletion detection, and for small-mutation screening by CSGE, and DNA-sequencing. To explore other genetic factors, we studied DNA polymorphisms in the genes encoding for interleukin-10 (IL10) (-1082:A/G), tumour necrosis factor-alpha (TNFA) (-308:G/A), and cytotoxic T-lymphocyte antigen-4 (CTLA4) (-318:C/T) that have been implicated as inhibitor risk factors in other populations. An unbiased series of 119 Argentine patients with severe HA with an absolute inhibitor prevalence of 17.6% (21) was analysed to show the natural distribution of F8 mutation type/location. We classified this mutation series in three INH risk groups: High-risk (8/14=57%) including multi-exon deletions (5/7=71%) and nonsense in the FVIII Light-Chain defects (3/7=43%); Intermediate-risk (13/88=15%) including nonsense in the Heavy-Chain (0/6), frameshifts Ins/Del (3/19=16%), Intron 22 inversions (9/55=16%,), splicing defects (1/4) and single-exon deletions (0/4); and Low-risk (0/17=0%) including in-frame-Ins/Del (0/2), Intron 1 inversions (0/2) and missense mutations (0/13=0%). In contrast with previous studies from other populations, we found no significant differences in the inhibitor risk of polymorphisms in the genes for IL10, TNFA and CTLA4 in Argentina, suggesting other ethnical or environmental differences.    In agree with the literature, our population showed enhanced INH risks in severe HA patients with gross F8-rearrangements and nonsense mutations in the FVIII Light-Chain, and low risks in patients with missense mutations, highlighting the importance of F8 genotype as the first conditioning for INH formation in HA.