C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

James Rooney; Isabella Fogh; Henk-Jan Westeneng; Alice Vajda; Russell McLaughlin; Mark Heverin; Ashley Jones; Ruben van Eijk; Andrea Calvo; Letizia Mazzini; Christopher Shaw; Karen Morrison; Pamela J Shaw; Wim Robberecht; Phillip Van Damme; Ammar Al-Chalabi; Leonard van den Berg; Adriano Chiò; Jan Veldink; Orla Hardiman

doi:10.1136/jnnp-2016-314093

C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

James Rooney, Isabella Fogh, Henk-Jan Westeneng, Alice Vajda, Russell McLaughlin, Mark Heverin, Ashley Jones, Ruben van Eijk, Andrea Calvo, Letizia Mazzini, Christopher Shaw, Karen Morrison, Pamela J Shaw, Wim Robberecht, Phillip Van Damme, Ammar Al-Chalabi, Leonard van den Berg, Adriano Chiò, Jan Veldink, Orla Hardiman

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

35 Citations (Scopus)

Abstract

INTRODUCTION: The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset.

METHODS: C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance.

RESULTS: 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96).

CONCLUSIONS: This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration.

Original language	English
Number of pages	7
Journal	Journal of neurology, neurosurgery, and psychiatry
Early online date	23 Sept 2016
DOIs	https://doi.org/10.1136/jnnp-2016-314093
Publication status	E-pub ahead of print - 23 Sept 2016

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10.1136/jnnp-2016-314093

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Rooney, J., Fogh, I., Westeneng, H.-J., Vajda, A., McLaughlin, R., Heverin, M., Jones, A., van Eijk, R., Calvo, A., Mazzini, L., Shaw, C., Morrison, K., Shaw, P. J., Robberecht, W., Van Damme, P., Al-Chalabi, A., van den Berg, L., Chiò, A., Veldink, J., & Hardiman, O. (2016). C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis. Journal of neurology, neurosurgery, and psychiatry. Advance online publication. https://doi.org/10.1136/jnnp-2016-314093

@article{64b40090a9cb4ad689ff9caa122df61f,

title = "C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis",

abstract = "INTRODUCTION: The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset.METHODS: C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance.RESULTS: 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96).CONCLUSIONS: This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration.",

author = "James Rooney and Isabella Fogh and Henk-Jan Westeneng and Alice Vajda and Russell McLaughlin and Mark Heverin and Ashley Jones and {van Eijk}, Ruben and Andrea Calvo and Letizia Mazzini and Christopher Shaw and Karen Morrison and Shaw, {Pamela J} and Wim Robberecht and {Van Damme}, Phillip and Ammar Al-Chalabi and {van den Berg}, Leonard and Adriano Chi{\`o} and Jan Veldink and Orla Hardiman",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2016",

month = sep,

day = "23",

doi = "10.1136/jnnp-2016-314093",

language = "English",

journal = "Journal of neurology, neurosurgery, and psychiatry",

issn = "0022-3050",

publisher = "BMJ Publishing Group",

}

Rooney, J, Fogh, I, Westeneng, H-J, Vajda, A, McLaughlin, R, Heverin, M, Jones, A, van Eijk, R, Calvo, A, Mazzini, L, Shaw, C, Morrison, K, Shaw, PJ, Robberecht, W, Van Damme, P, Al-Chalabi, A, van den Berg, L, Chiò, A, Veldink, J & Hardiman, O 2016, 'C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis', Journal of neurology, neurosurgery, and psychiatry. https://doi.org/10.1136/jnnp-2016-314093

TY - JOUR

T1 - C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

AU - Rooney, James

AU - Fogh, Isabella

AU - Westeneng, Henk-Jan

AU - Vajda, Alice

AU - McLaughlin, Russell

AU - Heverin, Mark

AU - Jones, Ashley

AU - van Eijk, Ruben

AU - Calvo, Andrea

AU - Mazzini, Letizia

AU - Shaw, Christopher

AU - Morrison, Karen

AU - Shaw, Pamela J

AU - Robberecht, Wim

AU - Van Damme, Phillip

AU - Al-Chalabi, Ammar

AU - van den Berg, Leonard

AU - Chiò, Adriano

AU - Veldink, Jan

AU - Hardiman, Orla

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2016/9/23

Y1 - 2016/9/23

N2 - INTRODUCTION: The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset.METHODS: C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance.RESULTS: 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96).CONCLUSIONS: This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration.

AB - INTRODUCTION: The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset.METHODS: C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance.RESULTS: 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96).CONCLUSIONS: This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration.

U2 - 10.1136/jnnp-2016-314093

DO - 10.1136/jnnp-2016-314093

M3 - Article

C2 - 27663272

SN - 0022-3050

JO - Journal of neurology, neurosurgery, and psychiatry

JF - Journal of neurology, neurosurgery, and psychiatry

ER -

C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

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