Rare genetic variants in SMAP1, B3GAT2, and RIMS1 contribute to pediatric venous thromboembolism

Abstract

Recent genome-wide association studies (GWAS) have confirmed known risk mutations for venous thromboembolism (VTE) and identified a number of novel susceptibility loci in adults. Here we present a GWAS in 212 nuclear families with pediatric VTE followed by targeted next-generation sequencing (NGS) to identify causative mutations contributing to the association. Three single nucleotide polymorphisms (SNPs) exceeded the threshold for genome-wide significance as determined by permutation testing using 100 000 bootstrap permutations ( < 10). These SNPs reside in a region on chromosome 6q13 comprising the genes small ARF GAP1 (), an ARF6 guanosine triphosphatase-activating protein that functions in clathrin-dependent endocytosis, and β-1,3-glucoronyltransferase 2 (), a member of the human natural killer 1 carbohydrate pathway. Rs1304029 and rs2748331 are associated with pediatric VTE with unpermuted/permuted values of = 1.42 × 10/2.0 × 10 and = 6.11 × 10/1.8 × 10, respectively. Rs2748331 was replicated ( = .00719) in an independent study sample coming from our GWAS on pediatric thromboembolic stroke (combined = 7.88 × 10). Subsequent targeted NGS in 24 discordant sibling pairs identified 17 nonsynonymous coding variants, of which 1 located in and 3 in, a member of the RIM family of active zone proteins, are predicted as damaging by Protein Variation Effect Analyzer and/or sorting intolerant from tolerant scores. Three SNPs curtly missed statistical significance in the transmission-disequilibrium test in the full cohort (rs112439957: = .08326,; rs767118962: = .08326,; and rs41265501: = .05778,). In conjunction, our data provide compelling evidence for ,, and as novel susceptibility loci for pediatric VTE and warrant future functional studies to unravel the underlying molecular mechanisms leading to VTE.

What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies

“…This review mainly focuses on genes associated with primary VTE in adults and does not mention genetic factors contributing to other forms of VT, including cerebral vein thrombosis, splanchnic vein thrombosis and paediatric VTE. For example, a recent GWAS performed in paediatric VTE cases identified the B3GAT2 locus (Rühle et al , ) as a novel susceptibility locus for paediatric forms of VTE. Investigating this locus further in adults warrants effort.…”

Advances in predicting venous thromboembolism risk in children

“…These genes are involved in vesicle processing in blood cells, but need further functional studies to investigate the underlying biological mechanisms in VTE. Additionally, this study indicated the ABO locus, which determines the blood group and is a well‐established VTE risk factor in adults (Trégouët et al , ), to be also associated with paediatric VTE, albeit shortly missing genome‐wide significance (Rühle et al , ).…”

“…Variants residing in genes less obviously connected to coagulation pathways require hypothesis‐free genome‐wide approaches to be discovered. Recently, the first genome‐wide association study (GWAS) in paediatric VTE has been reported utilizing 212 affected offspring trios and complemented by next generation sequencing (Rühle et al , ). It revealed a new susceptibility region on chromosome 6 comprising the genes small ArfGAP 1 ( SMAP1 ), beta‐1,3‐glucuronyltransferase 2 ( B3GAT2 ) and regulating synaptic membrane exocytosis 1 ( RIMS1 ) (Rühle et al , ).…”

“…Recently, the first genome‐wide association study (GWAS) in paediatric VTE has been reported utilizing 212 affected offspring trios and complemented by next generation sequencing (Rühle et al , ). It revealed a new susceptibility region on chromosome 6 comprising the genes small ArfGAP 1 ( SMAP1 ), beta‐1,3‐glucuronyltransferase 2 ( B3GAT2 ) and regulating synaptic membrane exocytosis 1 ( RIMS1 ) (Rühle et al , ). These genes are involved in vesicle processing in blood cells, but need further functional studies to investigate the underlying biological mechanisms in VTE.…”

Immunological Analysis and Differential Genes Screening of Venous Thromboembolism

“…Studies have shown that genetic factors play a role in the occurrence of VTE [5] . A number of genes have been found to be susceptible to VTE occurrence [6,7] . Recently, some scholars have shown that immune gene mutations may provide new insights into the pathogenesis of VTE [8] .…”