Abstract Number: PB0831
Meeting: ISTH 2020 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic
Background: Inhibitors development affects about 30% of patients with severe hemophilia A (HA). Different environmental and genetic risk factors are involved in this process.[1,2] Recently, we identified a SNV (rs3754689) in the LCT gene potentially linked with this predisposition.[3] Since this variant is benign [4] and is located in a conserved haplotype block, we hypothesized that the association signal captured by this variant is probably located in coinherited, neighboring genes (R3HDM1, UBXN4, CXCR4, MCM6, miRNA-128-1). R3HDM1, UBXN4 and miRNA-128-1 have been previously linked with autoimmune disorders, therefore they are potential clinically relevant targets.
Aims: To identify novel genetic risk factors associated with inhibitor development in coding regions of R3HDM1, UBXN4, CXCR4, MCM6, miRNA-128-1 genes in a cohort of Italian patients with severe HA with or without inhibitor.
Methods: A cohort of 246 Italian patients with severe HA with (72) or without (174) inhibitor was subjected to target sequencing by TruSeq Custom Amplicon (Illumina). Data were analyzed according to the guidelines reported by the Broadinstitute (https://software.broadinstitute.org/gatk/best-practices/). Statistical analysis was performed by Plink, PlikSeq. ENCODE project and Enhancer Atlas were consulted to evaluate the role of the variants in the gene expression.
Results: 228 variants passed the quality controls: 56 common (MAF≥1%) and 172 rare (MAF< 1%). Logistic regression of common variants confirmed the protective role of the rs3754689 missense variant previously identified. Moreover, other 4 variants resulted significantly associated (Tab.1). Two of these (rs3213892; rs3816155) are localized in the intron 13 of the LCT; a genomic region involved in the regulation of the UBXN4 expression (Tab.2). Rare variants resulted not associated with the development of inhibitor.
Conclusions: This study confirmed the association of the chromosomal region around the LCT locus with inhibitor development in patients with severe HA. Further investigations are necessary to evaluate the expression of target genes and miR-128-1.
| SNP | OR | 95% IC | FDR_BH | P<0.05 | Position | Gene | Annotation |
| rs1050115 | 0.5611 | 0.3608-0.8724 | 0.2624 | 0.01072 | exonic | UBXN4 | NM_014607:exon4:c.A303G:p.E101E |
| rs3087343 | 0.5577 | 0.354-0.8787 | 0.2624 | 0.01356 | intronic | MCM6 | . |
| rs3213892 | 0.5884 | 0.3829-0.9041 | 0.2624 | 0.01498 | intronic | LCT | . |
| rs3816155 | 0.6096 | 0.3978-0.9342 | 0.2687 | 0.0231 | intronic | LCT | . |
| rs3754689 | 0.6497 | 0.4273-0.9879 | 0.4214 | 0.04664 | exonic | LCT | NM_002299:exon2:c.G655A:p.V219I |
[Tab.1 Common variants association]
| Peaks | Type | Target Genes | Cell resource |
| chr2:136552517-136552517 | Enhancer | UBXN4 | UBXN4 GM12891,HL-60,Fetal_thymus GM12891,Fetal_thymus |
| chr2:136552526-136552526 | Enhancer | UBXN4 | GM12891,HL-60,Fetal_thymus |
[Tab.2 EnancherAtlas 2.0 results]
To cite this abstract in AMA style:
Cairo A, Pappalardo E, Spena S, Mancuso M, Peyvandi F. Identification of Novel Genetic Risk Factors in the Conserved Haplotype Region Surrounding the LCT Locus on Chromosome 2q21 [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/identification-of-novel-genetic-risk-factors-in-the-conserved-haplotype-region-surrounding-the-lct-locus-on-chromosome-2q21/. Accessed September 29, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/identification-of-novel-genetic-risk-factors-in-the-conserved-haplotype-region-surrounding-the-lct-locus-on-chromosome-2q21/