Inhibitor risks in Argentine patients with severe HA. F8 genotype, status concordance in sibling pairs and immune gene polymorphisms studies

RADIC CP; NEME D; ROSSETTI LC; ABELLEYRO MM; DE TEZANOS PINTO M; MARCHIONE VD; PRIMIANI L; DE BRASI CD

Orlando, Florida

Congreso; WFH 2016 World Congress; 2016

World Federation of Hemophilia

Introduction and Objective: About 20% of Argentine cases with severe HA (sHA) developed FVIII neutralizing antibodies (inhibitors, INH). Objectives: to estimate our locally specific risks for INH development associated with each F8 genotype in sHA patients, to study the association of concordance/discordance status between siblings vs. non sibling pairs and to explore additional genetic factors (polymorphisms in the genes for IL10, TNFA and CTLA4).Materials and Methods: To estimate the risks for developing INH associated with each F8 mutation type/location, we considered an Argentine unbiased group of sHA patients (n = 107) showing an Inhibitor Prevalence (IP) of 17.6%. The comprehensive population of Argentine patients with sHA (n = 352, 107 cases and 245 controls) used to estimate relative inhibitor risks (OR) and 95% confident intervals (CI) of each F8-genotype included 23 sib pairs (14 with Inv22), subject of the consanguinity/INH status concordance study and 164 cases for polymorphisms analysis.Results: The case/control study (107/245) in sHA patients permitted estimation of F8 genotype-specific inhibitor risks [OR; IP(CI)] classifying a high-risk group including multi-exon deletions [6.21; 82%(32?100)], Inv22 [1.8; 24%(19?28)] and nonsense in FVIII-LCh [1.8; 31%(12?71)] and HCh [1.6; 27%(11?63)]; an intermediate risk group including single-exon deletions and indel frameshifts; and a low-risk group represented by missense defects [0.09; 2%(0.4?6)]. To explore the influence of genetic factors other than F8 genotype, we analysed inhibitor status concordance or discordance in two populations of familiarly related patient pairs, when Inv22 pairs were compared (n = 28) status concordance was found significantly higher than expected by chance in populations with OR(CI) of 3.2 (1.2?8.3) Fisher exact test (FET) P = 0.0201. Immunoregulatory gene polymorphisms? analysis indicated a higher frequency of +49 [G] allele in CTLA4 gene on patients with inhibitor, OR 2.48(1.13?5.45) FET P = 0.03.Conclusions: The Argentine series of sHA patients presents similar global and mutation-specific inhibitor risks than the HA database and published series. Analysis of inhibitor concordance/discordance in related patients indicated the involvement of additional environmental and/or genetic factors other than F8 genotype for inhibitor formation. The finding of CTLA4 gene suggests that the +49A>G polymorphism may contribute to increase the risk for INH development in our population.