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

Abstract

Haemophilia A (HA) (OMIM #306700), an X-linked recessive disorder characterized by reduced activity of coagulation factor VIII (FVIII:C), is caused by deleterious mutations in the F8. HA can be treated by administration of the deficient FVIII. However, about 20%-30% of severe HA patients (biochemically defined as FVIII:C < 1 IU/dL) developed FVIII neutralizing antibodies (inhibitors) making replacement therapy ineffective. Inhibitors result in higher therapy costs and decreased quality-of-life and life expectancy of patients with haemophilia. From the Public Health System perspective, Argentina currently compiles 96 HA patients with clinically identified inhibitors out of a total 2220 [1]. This reduced figure (96/2220) is a successful result of undergoing an extended prophylaxis covering more than 65% of patients, in which therapeutic FVIII is not administered under risk conditions, and immune-tolerance induction treatment for inhibitor eradication.As a typical complex trait (multifactorial) an operative classification of inhibitor development in haemophilia focuses on two main groups of risk factors: modifiable (environmental factors) and non-modifiable (genetic factors, often involving several genes with different relative weight predisposing to the phenotype). Among the former, environmental risk factors include treatment-related factors and immune-system challenges. Among the latter, in HA, the causative F8 genotype has been established as the main factor conditioning inhibitor development (in Argentina [2], and worldwide, reviewed in [3]), but it also counts a group of secondary risk factors, weaker than the F8 genotype, such as family history of inhibitors, ethnicity, human lymphocyte antigen haplotype and polymorphisms linked to immune-system genes, such as

Molecular insights into the mechanism of nonrecurrent F8 structural variants: Full breakpoint characterization and bioinformatics of DNA elements implicated in the upmost severe phenotype in hemophilia A

“…These observations from our population closely agree with the inhibitor risks estimated from the literature (Garagiola, Palla, & Peyvandi, 2018;Marchione et al, 2017).…”

“…The phenotypic features associated with these large F8-deletions, particularly those involving more than one exon, show the upmost clinical severity including the highest predisposition to develop inhibitory antibodies against the therapeutic FVIII (odds ratio [OR; 95% confidence interval]: 7.07 [2.20-22.71], p < .0005; Marchione et al, 2017).…”

Polymorphisms in the cytotoxic T lymphocyte-associated protein-4 immune regulatory gene and their impact on inhibitor development in patients with hemophilia A

“…15,16,27 The CTLA-4-318 C/T SNP in the promoter region –318 bp from the ATG start codon is associated with increased promoter activity, increased protein expression, a negative effect on the immune response, and hence a lower risk of inhibitor formation. 28,29 In the present study, we found no significant protective correlation between inhibitor formation and the –318 T allele in patients with either severe or mild/moderate HA, similar to the findings reported in an Indian study, 30 a Chinese cohort, 31 and a Brazilian study, 32 but in contrast to MIBS and Argentinean cohorts 9,12 that identified a substantial protective correlation between CTLA-4-318 C/T and inhibitor formation. It is noteworthy that most previous reports included only patients with severe HA.…”

“…9–11 Human genetic data support the hypothesis that predisposing factors associated with autosomal genes, including those mentioned above, are ethnically divergent and thus not constant among populations worldwide. 12…”

“…17–21 Furthermore, these two polymorphisms have also been shown to modify the propensity of HA patients to produce inhibitors. 9,12…”