title: 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.
authors.affiliation: Laboratory of Haematology, La Timone Hospital, Marseille, France.|Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé(UMR_S) 1062, Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Suchon
authors.affiliation: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics &Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Germain
authors.affiliation: Université de Brest, EA3878 and CIC1412, 29238 Brest, France.
authors.forename: A
authors.initials: A
authors.lastname: Delluc
authors.affiliation: Service d'hématologie biologique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France, Inserm UMR-S1140, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Smadja
authors.affiliation: INSERM, UMR-S970, Department of Epidemiology, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.|APHP, Georges Pompidou European Hospital, Department of Cardiology, Paris, France.
authors.forename: X
authors.initials: X
authors.lastname: Jouven
authors.affiliation: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics &Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Gyorgy
authors.affiliation: Laboratory of Haematology, La Timone Hospital, Marseille, France.
authors.forename: N
authors.initials: N
authors.lastname: Saut
authors.affiliation: Laboratory of Haematology, La Timone Hospital, Marseille, France.|Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé(UMR_S) 1062, Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Ibrahim
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, 91057 Evry, France.|CEPH, Fondation Jean Dausset, Paris, France.
authors.forename: J F
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Laboratory of Haematology, La Timone Hospital, Marseille, France.|Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé(UMR_S) 1062, Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, Marseille, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Alessi
authors.affiliation: Laboratory of Haematology, La Timone Hospital, Marseille, France.|Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé(UMR_S) 1062, Nutrition Obesity and Risk of Thrombosis, Aix-Marseille University, Marseille, France.
authors.forename: P E
authors.initials: PE
authors.lastname: Morange
authors.affiliation: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics &Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: D A
authors.initials: DA
authors.lastname: Trégouët
mesh_terms: D020022:Genetic Predisposition to Disease; D006801:Humans; D020125:Mutation, Missense; D010949:Plasma / Q000737:chemistry; D017293:Protein S / Q000032:analysis / Q000235:genetics*; D018570:Risk Assessment; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics*
chemical_list: D017293:Protein S; C499867:protein S Heerlen