C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies
Por:
Buil, A, Tregouet, DA, Souto, JC, Saut, N, Germain, M, Rotival, M, Tiret, L, Cambien, F, Lathrop, M, Zeller, T, Alessi, MC, de Cordoba, SR, Munzel, T, Wild, P, Fontcuberta, J, Gagnon, F, Emmerich, J, Almasy, L, Blankenberg, S, Soria, JM, Morange, PE
Publicada:
10 jun 2010
Resumen:
Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, alpha(7)beta(1), alpha(6)beta(1), and alpha(7)beta(0), we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with alpha(7)beta(0) levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased alpha(7)beta(0) plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de recidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated. (Blood. 2010;115(23):4644-4650)
Filiaciones:
Buil, A:
Hosp Santa Creu & Sant Pau, Unitat Genom Malalties Complexes, Inst Recerca, Barcelona, Spain
Tregouet, DA:
Univ Paris 06, INSERM, Fac Med, UMR S 937, F-75013 Paris, France
Souto, JC:
Hosp Santa Creu & Sant Pau, Unitat Hemostasia & Trombosis, Serv Hematol, Barcelona, Spain
Saut, N:
INSERM, UMR S 626, F-13385 Marseille, France
Univ Aix Marseille 2, Marseille, France
Lathrop, M:
Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France
Zeller, T:
Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, Mainz, Germany
Alessi, MC:
INSERM, UMR S 626, F-13385 Marseille, France
Univ Aix Marseille 2, Marseille, France
de Cordoba, SR:
Consejo Super Invest Cient, Ctr Invest Biol, Dept Inmunol, Madrid, Spain
Munzel, T:
Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, Mainz, Germany
Wild, P:
Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, Mainz, Germany
Fontcuberta, J:
Hosp Santa Creu & Sant Pau, Unitat Hemostasia & Trombosis, Serv Hematol, Barcelona, Spain
Gagnon, F:
Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON M5S 1A1, Canada
Emmerich, J:
Univ Paris 05, INSERM, U765, Hop Europeen Georges Pompidou, Paris, France
Almasy, L:
SW Fdn Biomed Res, Populat Genet Dept, San Antonio, TX 78284 USA
Blankenberg, S:
Johannes Gutenberg Univ Mainz, Med Klin & Poliklin, Mainz, Germany
Soria, JM:
Hosp Santa Creu & Sant Pau, Unitat Genom Malalties Complexes, Inst Recerca, Barcelona, Spain
Morange, PE:
INSERM, UMR S 626, F-13385 Marseille, France
Univ Aix Marseille 2, Marseille, France
Green Published
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