Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study

Gie Ken-Dror; Ida Martinelli; Elvira Grandone; Sini Hiltunen; Erik Lindgren; Maurizio Margaglione; Veronique Le Cam Duchez; Aude B. Triquenot; Marialuisa Zedde; Michelangelo Mancuso; Ynte M. Ruigrok; Bradford B. Worrall; Jennifer J. Majersik; Jukka Putaala; Elena Haapaniemi; Susanna Zuurbier; Matthijs C. Brouwer; Serena M. Passamonti; Maria Abbattista; Paolo Bucciarelli; Robin Lemmens; Emanuela Pappalardo; Paolo Costa; Marina Colombi; Diana Aguiar De Sousa; Sofia G. Rodrigues; Patrícia Canhao; Aleksander Tkach; Rosa Santacroce; Giovanni Favuzzi; Antonio Arauz; Donatella Colaizzo; Konstantinos Spengos; Amanda Hodge; Reina Ditta; Alessandro Pezzini; Jonathan M. Coutinho; Vincent N. Thijs; Katarina Jood; Guillaume Pare; Turgut Tatlisumak; José M. Ferro; Pankaj Sharma

doi:10.1212/WNL.0000000000209445

Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study

Gie Ken-Dror, Ida Martinelli, Elvira Grandone, Sini Hiltunen, Erik Lindgren, Maurizio Margaglione, Veronique Le Cam Duchez, Aude B. Triquenot, Marialuisa Zedde, Michelangelo Mancuso, Ynte M. Ruigrok, Bradford B. Worrall, Jennifer J. Majersik, Jukka Putaala, Elena Haapaniemi, Susanna Zuurbier, Matthijs C. Brouwer, Serena M. Passamonti, Maria Abbattista, Paolo BucciarelliRobin Lemmens, Emanuela Pappalardo, Paolo Costa, Marina Colombi, Diana Aguiar De Sousa, Sofia G. Rodrigues, Patrícia Canhao, Aleksander Tkach, Rosa Santacroce, Giovanni Favuzzi, Antonio Arauz, Donatella Colaizzo, Konstantinos Spengos, Amanda Hodge, Reina Ditta, Alessandro Pezzini, Jonathan M. Coutinho, Vincent N. Thijs, Katarina Jood, Guillaume Pare, Turgut Tatlisumak, José M. Ferro, Pankaj Sharma^*

^*Corresponding author for this work

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

Abstract

BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

Original language	English
Article number	e209445
Journal	Neurology
Volume	102
Issue number	11
DOIs	https://doi.org/10.1212/WNL.0000000000209445
Publication status	Published - 11 Jun 2024

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Ken-Dror, G., Martinelli, I., Grandone, E., Hiltunen, S., Lindgren, E., Margaglione, M., Le Cam Duchez, V., Triquenot, A. B., Zedde, M., Mancuso, M., Ruigrok, Y. M., Worrall, B. B., Majersik, J. J., Putaala, J., Haapaniemi, E., Zuurbier, S., Brouwer, M. C., Passamonti, S. M., Abbattista, M., ... Sharma, P. (2024). Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study. Neurology, 102(11), Article e209445. https://doi.org/10.1212/WNL.0000000000209445

@article{1a764603ac43411caed20da69cf5a76a,

title = "Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study",

abstract = "BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.",

author = "Gie Ken-Dror and Ida Martinelli and Elvira Grandone and Sini Hiltunen and Erik Lindgren and Maurizio Margaglione and {Le Cam Duchez}, Veronique and Triquenot, {Aude B.} and Marialuisa Zedde and Michelangelo Mancuso and Ruigrok, {Ynte M.} and Worrall, {Bradford B.} and Majersik, {Jennifer J.} and Jukka Putaala and Elena Haapaniemi and Susanna Zuurbier and Brouwer, {Matthijs C.} and Passamonti, {Serena M.} and Maria Abbattista and Paolo Bucciarelli and Robin Lemmens and Emanuela Pappalardo and Paolo Costa and Marina Colombi and {De Sousa}, {Diana Aguiar} and Rodrigues, {Sofia G.} and Patr{\'i}cia Canhao and Aleksander Tkach and Rosa Santacroce and Giovanni Favuzzi and Antonio Arauz and Donatella Colaizzo and Konstantinos Spengos and Amanda Hodge and Reina Ditta and Alessandro Pezzini and Coutinho, {Jonathan M.} and Thijs, {Vincent N.} and Katarina Jood and Guillaume Pare and Turgut Tatlisumak and Ferro, {Jos{\'e} M.} and Pankaj Sharma",

note = "Publisher Copyright: {\textcopyright} 2024 American Academy of Neurology.",

year = "2024",

month = jun,

day = "11",

doi = "10.1212/WNL.0000000000209445",

language = "English",

volume = "102",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams & Wilkins",

number = "11",

}

Ken-Dror, G, Martinelli, I, Grandone, E, Hiltunen, S, Lindgren, E, Margaglione, M, Le Cam Duchez, V, Triquenot, AB, Zedde, M, Mancuso, M, Ruigrok, YM, Worrall, BB, Majersik, JJ, Putaala, J, Haapaniemi, E, Zuurbier, S, Brouwer, MC, Passamonti, SM, Abbattista, M, Bucciarelli, P, Lemmens, R, Pappalardo, E, Costa, P, Colombi, M, De Sousa, DA, Rodrigues, SG, Canhao, P, Tkach, A, Santacroce, R, Favuzzi, G, Arauz, A, Colaizzo, D, Spengos, K, Hodge, A, Ditta, R, Pezzini, A, Coutinho, JM, Thijs, VN, Jood, K, Pare, G, Tatlisumak, T, Ferro, JM & Sharma, P 2024, 'Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study', Neurology, vol. 102, no. 11, e209445. https://doi.org/10.1212/WNL.0000000000209445

TY - JOUR

T1 - Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis

T2 - The BEAST Study

AU - Ken-Dror, Gie

AU - Martinelli, Ida

AU - Grandone, Elvira

AU - Hiltunen, Sini

AU - Lindgren, Erik

AU - Margaglione, Maurizio

AU - Le Cam Duchez, Veronique

AU - Triquenot, Aude B.

AU - Zedde, Marialuisa

AU - Mancuso, Michelangelo

AU - Ruigrok, Ynte M.

AU - Worrall, Bradford B.

AU - Majersik, Jennifer J.

AU - Putaala, Jukka

AU - Haapaniemi, Elena

AU - Zuurbier, Susanna

AU - Brouwer, Matthijs C.

AU - Passamonti, Serena M.

AU - Abbattista, Maria

AU - Bucciarelli, Paolo

AU - Lemmens, Robin

AU - Pappalardo, Emanuela

AU - Costa, Paolo

AU - Colombi, Marina

AU - De Sousa, Diana Aguiar

AU - Rodrigues, Sofia G.

AU - Canhao, Patrícia

AU - Tkach, Aleksander

AU - Santacroce, Rosa

AU - Favuzzi, Giovanni

AU - Arauz, Antonio

AU - Colaizzo, Donatella

AU - Spengos, Konstantinos

AU - Hodge, Amanda

AU - Ditta, Reina

AU - Pezzini, Alessandro

AU - Coutinho, Jonathan M.

AU - Thijs, Vincent N.

AU - Jood, Katarina

AU - Pare, Guillaume

AU - Tatlisumak, Turgut

AU - Ferro, José M.

AU - Sharma, Pankaj

PY - 2024/6/11

Y1 - 2024/6/11

N2 - BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

AB - BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

UR - http://www.scopus.com/inward/record.url?scp=85193565038&partnerID=8YFLogxK

U2 - 10.1212/WNL.0000000000209445

DO - 10.1212/WNL.0000000000209445

M3 - Article

C2 - 38759137

AN - SCOPUS:85193565038

SN - 0028-3878

VL - 102

JO - Neurology

JF - Neurology

IS - 11

M1 - e209445

ER -

Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study

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