Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls

Benedetto Simone; Valerio De Stefano; Emanuele Leoncini; Jeppe Zacho; Ida Martinelli; Joseph Emmerich; Elena Rossi; Aaron R. Folsom; Wassim Y. Almawi; Pierre Y. Scarabin; Martin Den Heijer; Mary Cushman; Silvana Penco; Amparo Vaya; Pantep Angchaisuksiri; Gulfer Okumus; Donato Gemmati; Simona Cima; Nejat Akar; Kivilcim I. Oguzulgen; Véronique Ducros; Christoph Lichy; Consuelo Fernandez-Miranda; Andrzej Szczeklik; José A. Nieto; Jose Domingo Torres; Véronique Le Cam-Duchez; Petar Ivanov; Carlos Cantu-Brito; Veronika M. Shmeleva; Mojka Stegnar; Dotun Ogunyemi; Suhair S. Eid; Nicola Nicolotti; Emma De Feo; Walter Ricciardi; Stefania Boccia

doi:10.1007/s10654-013-9825-8

Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls

Benedetto Simone, Valerio De Stefano, Emanuele Leoncini, Jeppe Zacho, Ida Martinelli, Joseph Emmerich, Elena Rossi, Aaron R. Folsom, Wassim Y. Almawi, Pierre Y. Scarabin, Martin Den Heijer, Mary Cushman, Silvana Penco, Amparo Vaya, Pantep Angchaisuksiri, Gulfer Okumus, Donato Gemmati, Simona Cima, Nejat Akar, Kivilcim I. OguzulgenVéronique Ducros, Christoph Lichy, Consuelo Fernandez-Miranda, Andrzej Szczeklik, José A. Nieto, Jose Domingo Torres, Véronique Le Cam-Duchez, Petar Ivanov, Carlos Cantu-Brito, Veronika M. Shmeleva, Mojka Stegnar, Dotun Ogunyemi, Suhair S. Eid, Nicola Nicolotti, Emma De Feo, Walter Ricciardi, Stefania Boccia

Epidemiology & Community Health

Research output: Contribution to journal › Article › peer-review

145 Scopus citations

Abstract

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

Original language	English (US)
Pages (from-to)	621-647
Number of pages	27
Journal	European Journal of Epidemiology
Volume	28
Issue number	8
DOIs	https://doi.org/10.1007/s10654-013-9825-8
State	Published - Aug 2013

Bibliographical note

Funding Information:
Acknowledgments The authors gratefully acknowledge funding from the Italian Ministry for Education and University (PRIN 2007) for the project: Health Technology Assessment per gli screening genetici: lo studio dell’appropriatezza dei test genetici di suscettibilità alla malattia tromboembolica venosa come modello di studio (health thechnology assessment for genetic screening tests: appropriateness of susceptibility genetic tests to venous thromboembolism as a model of study). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN2682011000 09C, HHSN268201100010C, HHSN268201100011C, and HHSN268 201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/ publications/WHI_investigators_shortlist.pdf. The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org.

Keywords

Factor V Leiden
Genetic susceptibility
Methylenetetrahydrofolate reductase C677T
Prothrombin G202010A
Venous thromboembolism

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Simone, B., De Stefano, V., Leoncini, E., Zacho, J., Martinelli, I., Emmerich, J., Rossi, E., Folsom, A. R., Almawi, W. Y., Scarabin, P. Y., Den Heijer, M., Cushman, M., Penco, S., Vaya, A., Angchaisuksiri, P., Okumus, G., Gemmati, D., Cima, S., Akar, N., ... Boccia, S. (2013). Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls. European Journal of Epidemiology, 28(8), 621-647. https://doi.org/10.1007/s10654-013-9825-8

Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls. / Simone, Benedetto; De Stefano, Valerio; Leoncini, Emanuele et al.
In: European Journal of Epidemiology, Vol. 28, No. 8, 08.2013, p. 621-647.

Research output: Contribution to journal › Article › peer-review

Simone, B, De Stefano, V, Leoncini, E, Zacho, J, Martinelli, I, Emmerich, J, Rossi, E, Folsom, AR, Almawi, WY, Scarabin, PY, Den Heijer, M, Cushman, M, Penco, S, Vaya, A, Angchaisuksiri, P, Okumus, G, Gemmati, D, Cima, S, Akar, N, Oguzulgen, KI, Ducros, V, Lichy, C, Fernandez-Miranda, C, Szczeklik, A, Nieto, JA, Torres, JD, Le Cam-Duchez, V, Ivanov, P, Cantu-Brito, C, Shmeleva, VM, Stegnar, M, Ogunyemi, D, Eid, SS, Nicolotti, N, De Feo, E, Ricciardi, W & Boccia, S 2013, 'Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls', European Journal of Epidemiology, vol. 28, no. 8, pp. 621-647. https://doi.org/10.1007/s10654-013-9825-8

Simone B, De Stefano V, Leoncini E, Zacho J, Martinelli I, Emmerich J et al. Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls. European Journal of Epidemiology. 2013 Aug;28(8):621-647. doi: 10.1007/s10654-013-9825-8

Simone, Benedetto ; De Stefano, Valerio ; Leoncini, Emanuele et al. / Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T : A meta-analysis involving over 11,000 cases and 21,000 controls. In: European Journal of Epidemiology. 2013 ; Vol. 28, No. 8. pp. 621-647.

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title = "Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls",

abstract = "Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.",

keywords = "Factor V Leiden, Genetic susceptibility, Methylenetetrahydrofolate reductase C677T, Prothrombin G202010A, Venous thromboembolism",

author = "Benedetto Simone and {De Stefano}, Valerio and Emanuele Leoncini and Jeppe Zacho and Ida Martinelli and Joseph Emmerich and Elena Rossi and Folsom, {Aaron R.} and Almawi, {Wassim Y.} and Scarabin, {Pierre Y.} and {Den Heijer}, Martin and Mary Cushman and Silvana Penco and Amparo Vaya and Pantep Angchaisuksiri and Gulfer Okumus and Donato Gemmati and Simona Cima and Nejat Akar and Oguzulgen, {Kivilcim I.} and V{\'e}ronique Ducros and Christoph Lichy and Consuelo Fernandez-Miranda and Andrzej Szczeklik and Nieto, {Jos{\'e} A.} and Torres, {Jose Domingo} and {Le Cam-Duchez}, V{\'e}ronique and Petar Ivanov and Carlos Cantu-Brito and Shmeleva, {Veronika M.} and Mojka Stegnar and Dotun Ogunyemi and Eid, {Suhair S.} and Nicola Nicolotti and {De Feo}, Emma and Walter Ricciardi and Stefania Boccia",

note = "Funding Information: Acknowledgments The authors gratefully acknowledge funding from the Italian Ministry for Education and University (PRIN 2007) for the project: Health Technology Assessment per gli screening genetici: lo studio dell{\textquoteright}appropriatezza dei test genetici di suscettibilit{\`a} alla malattia tromboembolica venosa come modello di studio (health thechnology assessment for genetic screening tests: appropriateness of susceptibility genetic tests to venous thromboembolism as a model of study). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN2682011000 09C, HHSN268201100010C, HHSN268201100011C, and HHSN268 201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/ publications/WHI_investigators_shortlist.pdf. The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org.",

year = "2013",

month = aug,

doi = "10.1007/s10654-013-9825-8",

language = "English (US)",

volume = "28",

pages = "621--647",

journal = "European Journal of Epidemiology",

issn = "0393-2990",

publisher = "Springer Netherlands",

number = "8",

}

TY - JOUR

T1 - Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T

T2 - A meta-analysis involving over 11,000 cases and 21,000 controls

AU - Simone, Benedetto

AU - De Stefano, Valerio

AU - Leoncini, Emanuele

AU - Zacho, Jeppe

AU - Martinelli, Ida

AU - Emmerich, Joseph

AU - Rossi, Elena

AU - Folsom, Aaron R.

AU - Almawi, Wassim Y.

AU - Scarabin, Pierre Y.

AU - Den Heijer, Martin

AU - Cushman, Mary

AU - Penco, Silvana

AU - Vaya, Amparo

AU - Angchaisuksiri, Pantep

AU - Okumus, Gulfer

AU - Gemmati, Donato

AU - Cima, Simona

AU - Akar, Nejat

AU - Oguzulgen, Kivilcim I.

AU - Ducros, Véronique

AU - Lichy, Christoph

AU - Fernandez-Miranda, Consuelo

AU - Szczeklik, Andrzej

AU - Nieto, José A.

AU - Torres, Jose Domingo

AU - Le Cam-Duchez, Véronique

AU - Ivanov, Petar

AU - Cantu-Brito, Carlos

AU - Shmeleva, Veronika M.

AU - Stegnar, Mojka

AU - Ogunyemi, Dotun

AU - Eid, Suhair S.

AU - Nicolotti, Nicola

AU - De Feo, Emma

AU - Ricciardi, Walter

AU - Boccia, Stefania

N1 - Funding Information: Acknowledgments The authors gratefully acknowledge funding from the Italian Ministry for Education and University (PRIN 2007) for the project: Health Technology Assessment per gli screening genetici: lo studio dell’appropriatezza dei test genetici di suscettibilità alla malattia tromboembolica venosa come modello di studio (health thechnology assessment for genetic screening tests: appropriateness of susceptibility genetic tests to venous thromboembolism as a model of study). The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN2682011000 09C, HHSN268201100010C, HHSN268201100011C, and HHSN268 201100012C). The authors thank the staff and participants of the ARIC study for their important contributions. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http://www.whiscience.org/ publications/WHI_investigators_shortlist.pdf. The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grant HL080295 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org.

PY - 2013/8

Y1 - 2013/8

N2 - Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

AB - Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

KW - Factor V Leiden

KW - Genetic susceptibility

KW - Methylenetetrahydrofolate reductase C677T

KW - Prothrombin G202010A

KW - Venous thromboembolism

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ER -

Risk of venous thromboembolism associated with single and combined effects of Factor v Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: A meta-analysis involving over 11,000 cases and 21,000 controls

Abstract

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Keywords

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