Protein S Heerlen mutation heterozygosity is associated with venous thrombosis risk

Abstract

Hereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06–10.64] (p = 1.73 10−14). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10−6, mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals.

A large‐scale exome array analysis of venous thromboembolism

“…The most strongly associated rare (MAF < 0.01) variant we observed was rs121918472 (OR: 1.93; 95% CI: 1.46–2.56; P = 3.55 × 10 −6 ), a nonsynonymous variant located in the Protein S ( PROS1 ) gene, also known as the p.Ser501Pro or PS Herleen mutation, MAF = 0.005. This variant is also known to be associated with VTE (Suchon et al, ). After excluding known loci, only one single variant remained significant after adjusting for multiple testing but this signal was driven exclusively by the MARTHA study ( p = 1.96 × 10 –15 when including MARTHA and p = 0.37 after excluding MARTHA).…”

A novel rare c. -39C>T mutation in thePROS15’UTR causing PS deficiency by creating a new upstream translation initiation codon and inhibiting the production of the natural protein

“…As an example, Suchon et al . demonstrated that the PROS1 Heerlen mutation was associated with an OR for VT of ∼6 but a moderate decrease in free PS levels (∼ 70%)(Suchon et al , 2017).…”

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

“…Interestingly, two of these genes ( PROS1 and SERPINC1 ) have been found to harbour less uncommon polymorphisms that also modulate the susceptibility to VTE. As far PROS1 is concerned, a meta‐analysis of 4 French case‐control studies for VTE demonstrated that the rs121918472, also referred to as the Protein S Heerlen mutation, a non synonymous Serine to Proline (Ser501Pro) substitution with a frequency of <1% in the general population and previously considered as a benign polymorphism, was associated with an ~6‐fold increased risk of VTE (Suchon et al , ). The rs121918474 (Lys196Glu) is another PROS1 coding mutation associated with increased risk of VTE [odds ratio (OR) ~5] by lowering PS anticoagulant activity but this mutation is specific to the Japanese population, approximately 1/12 000 individuals being homozygous for the 196Glu allele (Kimura et al , ; Liu et al , ).…”