No Evidence of Cis-Acting SNPs In Immune Response Genes Previously Associated with Factor VIII Inhibitors: The San Antonio Family Heart Study

FVIII gene (F8) mutation type is a risk factor for FVIII inhibitors, which develop in ~20-30% of hemophilia A patients following FVIII replacement therapy. Studies have investigated immune response genes to determine why FVIII is immunogenic in some, but not all, patients with the same F8 abnormality. While some studies have found associations between inhibitor status and promoter polymorphisms in CTLA4, TNFA, and/or IL10, others have not. If these promoter polymorphisms influence inhibitor development, their alleles could modulate transcription initiation rates. The goal of this study was to investigate cis-acting genotype-specific differences in mean steady state mRNA levels.

We examined the relationship of lymphocyte CTLA4, TNFA, and IL10 mRNA levels with the genotypes of 49 SNPs located across their structural loci in 1189 Mexican American participants of the San Antonio Family Heart Study (SAFHS). Expression profiles were generated using Illumina's HWG-6 BeadChips and genotypes came from the Illumina Human HapMap 550 SNP panel. Measured genotype association analyses that accounted for non-independence of family members and employed an additive model were performed using the software package SOLAR.

Except for C(-13780)A, located upstream of CTLA4, which was modestly associated with CTLA4 mRNA levels (p<0.005), we observed no cis-acting regulatory variants associated with these genes’ transcription levels.

We observed little evidence for cis-regulation of CTLA4, TNFA, and IL10 in Mexican Americans. It is possible that cis-acting functional variants are rare and not well-represented by the common GWAS SNPs used for these analyses. Because previously implicated polymorphisms were not included in this analysis and linkage disequilibrium patterns between markers are population-specific, we are currently genotyping these SNPs in the SAFHS.

No relevant conflicts of interest to declare.