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5. Genes and environment in multiple sclerosis: Impact of temporal changes in the sex ratio on recurrence risks.

Author

Sadovnick, A Dessa, Yee, Irene M, Criscuoli, Maria, and DeLuca, Gabriele C

Subjects
*SEX ratio, *MULTIPLE sclerosis, *ENVIRONMENTAL exposure, *HOME environment, *FAMILY history (Medicine)
Abstract

Objective: To evaluate the impact of temporal increase of female to male (F:M) sex ratio for persons with multiple sclerosis (MS) on the familial risk (empiric recurrence risks or RRs) for biological relatives of affected individuals. Methods: Detailed family histories were systematically obtained from people with MS attending the University of British Columbia Hospital MS Clinic. The study cohort was born in 1970 or more recently. Data were collected from 1 September 2015 to 31 January 2019. The study was designed to allow only one proband per family. Age-corrected RRs for biological relatives of probands were calculated based on a modification of the maximum-likelihood approach. Results: Data analyses were possible for 746 unique probands (531 females; 215 males) and 19,585 of their biological relatives. RRs were temporally impacted. Conclusion: Both genetic sharing and environmental factors are important in determining RRs. It appears that there is an increase in MS risk due to environmental factors in later life (i.e. not shared family environment). Environmental exposures in genetically predisposed individuals might be driving the MS risk. The increase in F:M ratio of RRs for sisters/brothers of female probands over time is likely due to environmental differences. [ABSTRACT FROM AUTHOR]

Published
2022
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6. Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Author

Neurociencias, Bioquímica y biología molecular, Neurozientziak, Biokimika eta biologia molekularra, Vilariño Güell, Carles, Zimprich, Alexander, Martinelli Boneschi, Filippo, Herculano, Bruno, Wang, Zhe, Matesanz, Fuencisla, Urcelay, Elena, Vandenbroeck, Koen, Leyva, Laura, Gris, Denis, Massaad, Charbel, Quandt, Jacqueline A., Traboulsee, Anthony L., Encarnacion, Mary, Bernales, Cecily Q., Follett, Jordan, Yee, Irene M., Criscuoli, Maria G., Deutschlander, Angela, Reinthaler, Eva M., Zrzavy, Tobias, Mascia, Elisabetta, Zauli, Andrea, Esposito, Federica, Alcina, Antonio, Izquierdo, Guillermo, Espino Paisan, Laura, Mena Lucía, Jorge, Rodríguez-Antigüedad Zarranz, Alfredo, Urbaneja Romero, Patricia, Ortega Pinazo, Jesús, Song, Weihong, Sadovnick, A. Dessa, Neurociencias, Bioquímica y biología molecular, Neurozientziak, Biokimika eta biologia molekularra, Vilariño Güell, Carles, Zimprich, Alexander, Martinelli Boneschi, Filippo, Herculano, Bruno, Wang, Zhe, Matesanz, Fuencisla, Urcelay, Elena, Vandenbroeck, Koen, Leyva, Laura, Gris, Denis, Massaad, Charbel, Quandt, Jacqueline A., Traboulsee, Anthony L., Encarnacion, Mary, Bernales, Cecily Q., Follett, Jordan, Yee, Irene M., Criscuoli, Maria G., Deutschlander, Angela, Reinthaler, Eva M., Zrzavy, Tobias, Mascia, Elisabetta, Zauli, Andrea, Esposito, Federica, Alcina, Antonio, Izquierdo, Guillermo, Espino Paisan, Laura, Mena Lucía, Jorge, Rodríguez-Antigüedad Zarranz, Alfredo, Urbaneja Romero, Patricia, Ortega Pinazo, Jesús, Song, Weihong, and Sadovnick, A. Dessa

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients. Author summary Although the majority of patients diagnosed with multiple sclerosis do not have a family history of disease, 13% report having a close relative also diagnosed with multiple sclerosis. In these families, the cause of multiple sclerosis can be largely attributed to a single genetic variant that is transmitted through generations. In this study we analyzed DNA from 132 patients from 34 families, resulting in the identification of 12 rare genetic variants that are largely responsible for the onset of multiple sclerosis in these families. These variants are located in genes implicated in specific immunological pathways, and suggest the biological mechanisms that trigger the onset of multiple sclerosis. These genes and variants provide the means for the generation of cellular and animal models of human disease, and highlight biological targets for the development of novel treatment

Published
2019

7. Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

Author

Vilariño-Güell, Carles, primary, Zimprich, Alexander, additional, Martinelli-Boneschi, Filippo, additional, Herculano, Bruno, additional, Wang, Zhe, additional, Matesanz, Fuencisla, additional, Urcelay, Elena, additional, Vandenbroeck, Koen, additional, Leyva, Laura, additional, Gris, Denis, additional, Massaad, Charbel, additional, Quandt, Jacqueline A., additional, Traboulsee, Anthony L., additional, Encarnacion, Mary, additional, Bernales, Cecily Q., additional, Follett, Jordan, additional, Yee, Irene M., additional, Criscuoli, Maria G., additional, Deutschländer, Angela, additional, Reinthaler, Eva M., additional, Zrzavy, Tobias, additional, Mascia, Elisabetta, additional, Zauli, Andrea, additional, Esposito, Federica, additional, Alcina, Antonio, additional, Izquierdo, Guillermo, additional, Espino-Paisán, Laura, additional, Mena, Jorge, additional, Antigüedad, Alfredo, additional, Urbaneja-Romero, Patricia, additional, Ortega-Pinazo, Jesús, additional, Song, Weihong, additional, and Sadovnick, A. Dessa, additional

Published
2019
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10. Purinergic receptorsP2RX4andP2RX7in familial multiple sclerosis

Author

Sadovnick, A Dessa, primary, Gu, Ben J, additional, Traboulsee, Anthony L, additional, Bernales, Cecily Q, additional, Encarnacion, Mary, additional, Yee, Irene M, additional, Criscuoli, Maria G, additional, Huang, Xin, additional, Ou, Amber, additional, Milligan, Carol J, additional, Petrou, Steven, additional, Wiley, James S, additional, and Vilariño-Güell, Carles, additional

Published
2017
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12. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

Author

Medicina, Neurociencias, Medikuntza, Neurozientziak, Sadovnick, A. Dessa, Traboulsee, Anthony L., Bernales, Cecily Q., Ross, Jay P., Forwell, Amanda L., Yee, Irene M., Guillot-Noel, Lena, Fontaine, Bertrand, Cournu-Rebeix, Isabelle, Alcina, Antonio, Fedetz, María, Izquierdo, Guillermo, Matesanz, Fuencisla, Hilven, Kelly, Goris, An, Astobiza Pérez, Janire, Alloza Moral, Iraide, Rodríguez-Antigüedad Zarranz, Alfredo, Vandenbroeck, Koen, Akkad, Denis A., Aktas, Orhan, Blaschke, Paul, Buttmann, Mathias, Chan, Andrew, Epplen, Joerg T., Gerdes, Lisa-Ann, Kroner, Antje, Kubisch, Christian, Kümpfel, Tania, Lohse, Peter, Rieckmann, Peter, Zettl, Uwe K., Zipp, Frauke, Bertram, Lars, Lill, Christina M., Fernández, Óscar, Urbaneja, Patricia, Leyva, Laura, Alvarez-Cermeño, José Carlos, Arroyo, Rafael, Garagorri, Aroa M., García-Martínez, Angel, Villar, Luisa M., Urcelay, Elena, Malhotra, Sunny, Montalbán, Xavier, Comabella, Manuel, Berger, Thomas, Fazekas, Franz, Reindl, Markus, Schmied, Mascha C., Zimprich, Alexander, Vilariño-Güell, Carles, Medicina, Neurociencias, Medikuntza, Neurozientziak, Sadovnick, A. Dessa, Traboulsee, Anthony L., Bernales, Cecily Q., Ross, Jay P., Forwell, Amanda L., Yee, Irene M., Guillot-Noel, Lena, Fontaine, Bertrand, Cournu-Rebeix, Isabelle, Alcina, Antonio, Fedetz, María, Izquierdo, Guillermo, Matesanz, Fuencisla, Hilven, Kelly, Goris, An, Astobiza Pérez, Janire, Alloza Moral, Iraide, Rodríguez-Antigüedad Zarranz, Alfredo, Vandenbroeck, Koen, Akkad, Denis A., Aktas, Orhan, Blaschke, Paul, Buttmann, Mathias, Chan, Andrew, Epplen, Joerg T., Gerdes, Lisa-Ann, Kroner, Antje, Kubisch, Christian, Kümpfel, Tania, Lohse, Peter, Rieckmann, Peter, Zettl, Uwe K., Zipp, Frauke, Bertram, Lars, Lill, Christina M., Fernández, Óscar, Urbaneja, Patricia, Leyva, Laura, Alvarez-Cermeño, José Carlos, Arroyo, Rafael, Garagorri, Aroa M., García-Martínez, Angel, Villar, Luisa M., Urcelay, Elena, Malhotra, Sunny, Montalbán, Xavier, Comabella, Manuel, Berger, Thomas, Fazekas, Franz, Reindl, Markus, Schmied, Mascha C., Zimprich, Alexander, and Vilariño-Güell, Carles

Abstract

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p. G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.931.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

Published
2016

13. Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Author

Wang, Zhe, primary, Sadovnick, A. Dessa, additional, Traboulsee, Anthony L., additional, Ross, Jay P., additional, Bernales, Cecily Q., additional, Encarnacion, Mary, additional, Yee, Irene M., additional, de Lemos, Madonna, additional, Greenwood, Talitha, additional, Lee, Joshua D., additional, Wright, Galen, additional, Ross, Colin J., additional, Zhang, Si, additional, Song, Weihong, additional, and Vilariño-Güell, Carles, additional

Published
2016
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14. Case-Control Studies Are Not Familial Studies

Author

Wang, Zhe, primary, Sadovnick, A. Dessa, additional, Traboulsee, Anthony L., additional, Ross, Jay P., additional, Bernales, Cecily Q., additional, Encarnacion, Mary, additional, Yee, Irene M., additional, de Lemos, Madonna, additional, Greenwood, Talitha, additional, Lee, Joshua D., additional, Wright, Galen, additional, Ross, Colin J., additional, Zhang, Si, additional, Song, Weihong, additional, and Vilariño-Güell, Carles, additional

Published
2016
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15. Editorial Note to:Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Author

Wang, Zhe, primary, Sadovnick, A. Dessa, additional, Traboulsee, Anthony L., additional, Ross, Jay P., additional, Bernales, Cecily Q., additional, Encarnacion, Mary, additional, Yee, Irene M., additional, de Lemos, Madonna, additional, Greenwood, Talitha, additional, Lee, Joshua D., additional, Wright, Galen, additional, Ross, Colin J., additional, Zhang, Si, additional, Song, Weihong, additional, and Vilariño-Güell, Carles, additional

Published
2016
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16. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

Author

Sadovnick, A Dessa, primary, Traboulsee, Anthony L, additional, Bernales, Cecily Q, additional, Ross, Jay P, additional, Forwell, Amanda L, additional, Yee, Irene M, additional, Guillot-Noel, Lena, additional, Fontaine, Bertrand, additional, Cournu-Rebeix, Isabelle, additional, Alcina, Antonio, additional, Fedetz, Maria, additional, Izquierdo, Guillermo, additional, Matesanz, Fuencisla, additional, Hilven, Kelly, additional, Dubois, Bénédicte, additional, Goris, An, additional, Astobiza, Ianire, additional, Alloza, Iraide, additional, Antigüedad, Alfredo, additional, Vandenbroeck, Koen, additional, Akkad, Denis A, additional, Aktas, Orhan, additional, Blaschke, Paul, additional, Buttmann, Mathias, additional, Chan, Andrew, additional, Epplen, Joerg T, additional, Gerdes, Lisa-Ann, additional, Kroner, Antje, additional, Kubisch, Christian, additional, Kümpfel, Tania, additional, Lohse, Peter, additional, Rieckmann, Peter, additional, Zettl, Uwe K, additional, Zipp, Frauke, additional, Bertram, Lars, additional, Lill, Christina M, additional, Fernandez, Oscar, additional, Urbaneja, Patricia, additional, Leyva, Laura, additional, Alvarez-Cermeño, Jose Carlos, additional, Arroyo, Rafael, additional, Garagorri, Aroa M, additional, García-Martínez, Angel, additional, Villar, Luisa M, additional, Urcelay, Elena, additional, Malhotra, Sunny, additional, Montalban, Xavier, additional, Comabella, Manuel, additional, Berger, Thomas, additional, Fazekas, Franz, additional, Reindl, Markus, additional, Schmied, Mascha C, additional, Zimprich, Alexander, additional, and Vilariño-Güell, Carles, additional

Published
2016
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18. Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis.

Author

Sadovnick, A Dessa, Gu, Ben J, Traboulsee, Anthony L, Bernales, Cecily Q, Encarnacion, Mary, Yee, Irene M, Criscuoli, Maria G, Huang, Xin, Ou, Amber, Milligan, Carol J, Petrou, Steven, Wiley, James S, and Vilariño‐Güell, Carles

Abstract

Genetic variants in the purinergic receptors P2RX4 and P2RX7 have been shown to affect susceptibility to multiple sclerosis (MS). In this study, we set out to evaluate whether rare coding variants of major effect could also be identified in these purinergic receptors. Sequencing analysis of P2RX4 and P2RX7 in 193 MS patients and 100 controls led to the identification of a rare three variant haplotype ( P2RX7 rs140915863:C>T [p.T205M], P2RX7 rs201921967:A>G [p.N361S], and P2RX4 rs765866317:G>A [p.G135S]) segregating with disease in a multi-incident family with six family members diagnosed with MS (logarithm of odds = 3.07). Functional analysis of this haplotype in HEK293 cells revealed impaired P2X7 surface expression ( P < 0.01), resulting in over 95% inhibition of adenosine triphosphate (ATP)-induced pore function ( P < 0.001) and a marked reduction in phagocytic ability ( P < 0.05). In addition, transfected cells showed 40% increased peak ATP-induced inward current ( P < 0.01), and a greater Ca2+ response to the P2X4 135S variant compared with wild type ( P < 0.0001). Our study nominates rare genetic variants in P2RX4 and P2RX7 as major genetic contributors to disease, further supporting a role for these purinergic receptors in MS and the disruption of transmembrane cation channels leading to impairment of phagocytosis as the pathological mechanisms of disease. [ABSTRACT FROM AUTHOR]

Published
2017
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19. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

Author

Sadovnick AD, Traboulsee AL, Bernales CQ, Ross JP, Forwell AL, Yee IM, Guillot-Noel L, Fontaine B, Cournu-Rebeix I, Alcina A, Fedetz M, Izquierdo G, Matesanz F, Hilven K, Dubois B, Goris A, Astobiza I, Alloza I, Antigüedad A, Vandenbroeck K, Akkad DA, Aktas O, Blaschke P, Buttmann M, Chan A, Epplen JT, Gerdes LA, Kroner A, Kubisch C, Kümpfel T, Lohse P, Rieckmann P, Zettl UK, Zipp F, Bertram L, Lill CM, Fernandez O, Urbaneja P, Leyva L, Alvarez-Cermeño JC, Arroyo R, Garagorri AM, García-Martínez A, Villar LM, Urcelay E, Malhotra S, Montalban X, Comabella M, Berger T, Fazekas F, Reindl M, Schmied MC, Zimprich A, and Vilariño-Güell C

Subjects
Adult, Aged, Amino Acid Sequence, Case-Control Studies, Chromosomes, Human, Pair 6 metabolism, Exome, Female, Gene Expression, Genotype, Humans, Male, Middle Aged, Multiple Sclerosis pathology, Pedigree, Risk Factors, Sequence Alignment, Sequence Homology, Amino Acid, Chromosomes, Human, Pair 6 chemistry, Multiple Sclerosis genetics, Plasminogen genetics, Polymorphism, Single Nucleotide
Abstract

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility., (Copyright © 2016 Sadovnick et al.)

Published
2016
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