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  Canhão; 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 Bucciarelli

Robin Lemmens, Emanuela Pappalardo, Paolo Costa, Marina Colombi, Diana Aguiar de Sousa, Sofia G. Rodrigues, Patrícia Canhão, 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

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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
Journal	Neurology
Volume	102
Issue number	11
Early online date	17 May 2024
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., M. Ruigrok, Y., 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). https://doi.org/10.1212/WNL.0000000000209445

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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 = "\{Ken Dror\}, Gie 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 \{M. Ruigrok\}, Ynte 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 \{Aguiar de Sousa\}, Diana and Rodrigues, \{Sofia G.\} and Patr{\'i}cia Canh{\~a}o 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 \{N Thijs\}, Vincent and Katarina Jood and Guillaume Pare and Turgut Tatlisumak and Ferro, \{Jos{\'e} M\} and Pankaj Sharma",

year = "2024",

month = jun,

day = "11",

doi = "10.1212/WNL.0000000000209445",

language = "English",

volume = "102",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and 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, M. Ruigrok, Y, 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, Aguiar de Sousa, D, Rodrigues, SG, Canhão, P, Tkach, A, Santacroce, R, Favuzzi, G, Arauz, A, Colaizzo, D, Spengos, K, Hodge, A, Ditta, R, Pezzini, A, Coutinho, JM, N Thijs, V, 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. 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 - M. Ruigrok, Ynte

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 - Aguiar de Sousa, Diana

AU - Rodrigues, Sofia G.

AU - Canhão, 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 - N Thijs, Vincent

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.

U2 - 10.1212/WNL.0000000000209445

DO - 10.1212/WNL.0000000000209445

M3 - Article

SN - 0028-3878

VL - 102

JO - Neurology

JF - Neurology

IS - 11

ER -