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C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis

C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis
C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis
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.
Rooney, James
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Fogh, Isabella
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Westeneng, Henk-Jan
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Vajda, Alice
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McLaughlin, Russell
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Heverin, Mark
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Jones, Ashley
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van Eijk, Ruben
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Calvo, Andrea
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Mazzini, Letizia
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Shaw, Christopher
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Morrison, Karen
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Shaw, Pamela J.
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Robberecht, Wim
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Van Damme, Phillip
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Al-Chalabi, Ammar
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van den Berg, Leonard
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Chio, Adriano
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Veldink, Jan
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Hardiman, Orla
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Rooney, James
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Fogh, Isabella
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Westeneng, Henk-Jan
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Vajda, Alice
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McLaughlin, Russell
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Heverin, Mark
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Jones, Ashley
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van Eijk, Ruben
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Calvo, Andrea
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Mazzini, Letizia
71dbc368-53fe-47a4-92de-06b4563810bb
Shaw, Christopher
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Morrison, Karen
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Shaw, Pamela J.
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Robberecht, Wim
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Van Damme, Phillip
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Al-Chalabi, Ammar
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van den Berg, Leonard
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Chio, Adriano
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Veldink, Jan
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Hardiman, Orla
95816121-f024-4ca0-bc95-426d778e5b80

Rooney, James, Fogh, Isabella, Westeneng, Henk-Jan, Vajda, Alice, McLaughlin, Russell, Heverin, Mark, Jones, Ashley, van Eijk, Ruben, Calvo, Andrea, Mazzini, Letizia, Shaw, Christopher, Morrison, Karen, Shaw, Pamela J., Robberecht, Wim, Van Damme, Phillip, Al-Chalabi, Ammar, van den Berg, Leonard, Chio, Adriano, Veldink, Jan and Hardiman, Orla (2017) C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis. Journal of Neurology, Neurosurgery & Psychiatry, 88. (doi:10.1136/jnnp-2016-314093).

Record type: Article

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.

Full text not available from this repository.

More information

Accepted/In Press date: 30 August 2016
e-pub ahead of print date: 23 September 2016
Published date: 1 April 2017

Identifiers

Local EPrints ID: 416118
URI: http://eprints.soton.ac.uk/id/eprint/416118
PURE UUID: 078d729d-8351-4205-bf87-f82a81a6b88c
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 04 Dec 2017 17:30
Last modified: 07 Oct 2020 02:09

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Contributors

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

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