ABCMdb

ABCC8 p.Val34Leu

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Publications

PMID: 17568659 [PubMed] Le Gal G et al: "Fibrinogen Aalpha-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism."

No. Sentence Comment

0 REGULAR ARTICLE Fibrinogen Aα-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism☆ Grégoire Le Gal a,⁎, Bénédicte Delahousse b , Karine Lacut a , Vincent Malaviolle b , Sandra Regina b,c , Marie-Thérèse Blouch d , Francis Couturaud a , Dominique Mottier a , Emmanuel Oger e , Yves Gruel b,c on behalf of the "Groupe d'Etudes sur la Thrombose des Hôpitaux Universitaires du Grand Ouest" (GET-HUGO) a EA 3878, Department of Internal Medicine and Chest Diseases, Brest University Hospital, Brest, France b Department of Haematology-Haemostasis, Trousseau Hospital, Tours, France c INSERM U618 "Protéases et Vectorisation pulmonaires", University Francois Rabelais, Tours, France d Laboratory of Haemostasis, Brest University Hospital, Brest, France e Centre of Clinical Investigations INSERM CIC-0502, Brest University Hospital, Brest, France Received 23 December 2006; received in revised form 6 April 2007; accepted 1 May 2007 Available online 12 June 2007 Abstract Introduction: Fibrinogen Aα-Thr312Ala and Factor XIII Val34Leu polymorphisms have been shown to modify fibrin clot structure and function. Login to comment
2 Methods: We studied the association between these two polymorphisms and VTE in a hospital-based case-control study. We also assessed whether an independent or interactive association exists between Aα-fibrinogen Thr312Ala and FXIII Val34Leu polymorphisms and VTE. Login to comment
3 Fibrinogen Aα-Thr312Ala and FXIII Val34Leu polymorphisms were determined after PCR and restriction endonuclease digestion in 286 patients ☆ GLG collected data, analyzed data and wrote the paper; BD performed research and wrote the paper; KL collected data; VM performed research; SR performed research; MTB collected data; FC collected data; DM designed research; EO designed research and collected data; YG designed research and wrote the paper. Login to comment
13 There was no interaction between the fibrinogen Aα-Thr312Ala and FXIII Val34Leu polymorphisms for the risk of VTE. Login to comment
20 In this regard, a common FXIII-A polymorphism, caused by a G to T point mutation in codon 34 of exon 2 of the FXIII-A subunit gene with a replacement of valine by leucine at position 34 (Val34Leu) in the activation peptide, has been consistently associated with increased activation of factor XIII by thrombin in vitro [2,3]. Login to comment
27 The aim of the present work was therefore to evaluate the association between fibrinogen Aα- Thr312Ala and FXIII-A Val34Leu polymorphisms and idiopathic VTE in a hospital-based case-control study. We also investigated whether an independent or interactive association may exist between these two polymorphisms and VTE, and whether these associations are independent from factor V Leiden and G20210A prothrombin gene mutations. Login to comment
41 Fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms were determined after polymerase chain reaction (PCR) and restriction endonuclease digestion (Rsa I and Hha I, respectively) using procedures adapted from the methods described by Carter et al. [9] and Balogh et al. [12]. Login to comment
44 This sample size was estimated in order to detect (with 80% power) a 0.60 odds-ratio (OR) associated with the heterozygous Val34Leu factor XIII polymorphism for the risk of VTE, with a 45% estimated prevalence of this polymorphism in controls [14]. Login to comment
53 Results 300 pairs of matched cases and controls were selected and DNA was available for analyzing fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms in 286 of them. Login to comment
56 The FXIII-A Leu/Leu genotype was present in 4.2% of cases (12/286) and 7.7% of controls (22/ 286), the FXIII-A Val/Leu genotype in 36% of cases Table 1 FXIII-34 genotypes in patients and controls according to their status for the fibrinogen Aα-Thr312Ala polymorphism FXIII Val34Leu polymorphism Absence of fibrinogen Aα- Thr312Ala polymorphism Presence of fibrinogen Aα- Thr312Ala polymorphism Cases Controls Cases Controls VV 75 (58.6) 82 (51.9) 96 (60.8) 63 (49.2) VL 49 (38.3) 65 (41.1) 54 (34.2) 54 (42.2) LL 4 (3.1) 11 (7.0) 8 (5.1) 11 (8.6) OR (95% CI)a 0.6 (0.4-1.1) 0.4 (0.2-0.8) 95% CI: 95% confidence interval. a For each L allele carried. Login to comment
58 There was no unbalanced Hardy-Weinberg equilibrium for the two polymorphisms studied in controls (p=0.18 and 0.99 for fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms, respectively). Login to comment
59 Association between fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms and VTE Heterozygote status for the fibrinogen Aα-312Ala allele was associated with a significantly increased risk of VTE with an odds-ratio (OR) of 1.6 (95% CI: 1.1 to 2.3, p=0.01). Login to comment
65 A dominant with dose-effect model was therefore retained and subsequent analyses used the FXIII-A Val34Leu polymorphism as an ordinal categorical variable (0, 1, 2 for normal, heterozygous and homozygous status, respectively). Login to comment
67 No interaction between fibrinogen Aα- Thr312Ala and FXIII-AVal34Leu polymorphisms and with factor V Leiden and G20210A prothrombin gene variation in the risk of VTE The effect of FXIII-A Val34Leu polymorphism on the risk of VTE appeared significant only in the presence of fibrinogen Aα-Thr312Ala polymorphism (OR 0.4; 95% CI: 0.2-0.8, Table 1). Login to comment
68 However, there was no statistically significant interaction between the fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms upon the risk of VTE (p=0.72). Login to comment
69 Moreover, both fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms demonstrated an independent association with VTE when included together in the regression model, with ORs of 1.6 (95% CI: 1.1 to 2.2, p=0.01) and 0.7 (95% CI: 0.5 to 0.9, p=0.01), respectively. Login to comment
72 Further adjustment of the association between fibrinogen Aα-Thr312Ala and FXIII-A Val34Leu polymorphisms and VTE for factor V Leiden and G20210A prothrombin gene variation did not modify the results shown above, and the significance and strength of the associations found remained unchanged (data not shown). Login to comment
74 However, no significant difference was found in the association between fibrinogen Aα- Thr312Ala or FXIII-A Val34Leu polymorphisms and VTE according to the location of the VTE (interaction test p values 0.64 and 0.98, for fibrinogen Aα- Thr312Ala and FXIII-A Val34Leu, respectively) (Table 2). Login to comment
75 Discussion In this case-control study, we found that the fibrinogen Aα-312Ala allele was associated with a Table 2 Fibrinogen Aα-312 and FXIII-34 genotypes in cases according to the location of the VTE and in controls Isolated DVT (n=126 pairs) PE±DVT (n=160 pairs) Cases Controls Cases Controls Fibrinogen Aα-Thr312Ala TT 52 (41.3) 68 (54.0) 76 (47.5) 90 (56.3) TA and AA 74 (58.7) 58 (46.0) 84 (52.5) 70 (43.7) OR (95% CI)a 1.8 (1.0-3.0) 1.4 (0.9-2.2) FXIII Val34Leu VV 74 (58.7) 62 (49.2) 97 (60.6) 83 (51.9) VL 46 (36.5) 54 (42.9) 57 (35.6) 65 (40.6) LL 6 (4.8) 10 (7.9) 6 (3.8) 12 (7.5) OR (95% CI)b 0.7 (0.5-1.1) 0.7 (0.5-1.0) 95% CI: 95% confidence interval. a For TA or AA versus TT. Login to comment
80 These results on the factor XIII-A Val34Leu polymorphism are in agreement with those of several previous studies that demonstrated a lower risk of VTE in patients heterozygous for the factor XIII 34Leu allele [6,14]. Login to comment
97 In addition, the genotype frequencies found in this control group were similar to those previously reported in Caucasian healthy populations for both the fibrinogen Aα-Thr312Ala polymorphism [9, 18,19] and the FXIII-A Val34Leu polymorphism [15,20]. Login to comment