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UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort

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Abstract

To investigate the association of functional variants of the human UNC13A gene with the risk of ALS, survival and the disease progression rate in a Spanish ALS cohort. 136 sporadic ALS (sALS) patients and 487 healthy controls were genotyped for the UNC13A rs12608932 variant. Clinical characterization of ALS patients included gender, age at first symptom, initial topography, disease progression rate, and survival. Genetic association was analyzed under five inheritance models. The sALS patients with the rs12608932CC genotype had an increased risk of ALS under a recessive genetic model [OR 2.16; 95 % CI (1.23, 3.8), p = 0.009; corrected p = 0.028]. Genotypes with a C allele are also associated with increased risk [OR 1.47; 95 % CI (1.11, 1.95); p = 0.008; corrected p = 0.023] under an additive model. sALS patients with a C/C genotype had a shorter survival than patients with A/A and A/C genotypes [HR 1.44; 95 % CI (1.11, 1.873); p = 0.007] under a recessive model. In an overdominant model, heterozygous patients had a longer survival than homozygous patients [HR 0.36; 95 % CI (0.22, 0.59); p = 0.001]. The rs12608932 genotypes modify the progression of symptoms measured using the ALSFRS-R. No association with age of onset, initial topography or rate of decline in FVC was found. Our results show that rs12608932 is a risk factor for ALS in the Spanish population and replicate the findings described in other populations. The rs12608932 is a modifying factor for survival and disease progression rate in our series. Our results also corroborated that it did not influence the age of onset.

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Acknowledgments

The authors are indebted to the patients and their relatives for their cooperation. The authors are grateful to the Spanish National DNA Bank (Salamanca, Spain) for supplying control samples and Dr. Josep Saura and Marta Pulido for their results of Munc13-1 gene expression in mice. JG is the recipient of a grant from the Spanish Fondo de Investigaciones Sanitarias (PI10-01070 and FIS PI13-01272-FEDER), and an Interlaken Research Awards Program. This work was supported by grant IPT-2012-0614-010000 from the Ministerio de Economia y Competitividad and by grant 2014SGR1115 from the Generalitat de Catalunya to MJR, Spain.

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Authors and Affiliations

  1. Biochemistry and Molecular Biology Unit, Department of Physiological Sciences I, Faculty of Medicine, IDIBAPS, Universitat de Barcelona, Casanova 143, 08036, Barcelona, Spain

    Jose Manuel Vidal-Taboada, Alan Lopez-Lopez, Nicole Mahy & Manuel J. Rodríguez

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Barcelona, Spain

    Jose Manuel Vidal-Taboada, Alan Lopez-Lopez, Nicole Mahy & Manuel J. Rodríguez

  3. ALS Unit, Neurology Department, Hospital Universitari Vall d’Hebron, VHIR, Medicine Department, Autonomous University of Barcelona, FEDER, Passeig Vall d’Hebron 119, 08035, Barcelona, Spain

    Maria Salvado, Laura Lorenzo, Cecilia Garcia & Josep Gamez

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  1. Jose Manuel Vidal-Taboada
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  2. Alan Lopez-Lopez
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  3. Maria Salvado
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  7. Manuel J. Rodríguez
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Correspondence to Jose Manuel Vidal-Taboada or Josep Gamez.

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Ethical statement

This genetic study was approved by the local IRBs at the Vall d’Hebron Research Institute and the Spanish National DNA Bank. The study has been conducted according to the principles expressed in the Declaration of Helsinki. All patients gave their informed written consent to participation in the study prior to their inclusion in the study, and a blood sample for genetic analysis was obtained from all of them.

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Vidal-Taboada, J.M., Lopez-Lopez, A., Salvado, M. et al. UNC13A confers risk for sporadic ALS and influences survival in a Spanish cohort. J Neurol 262, 2285–2292 (2015). https://doi.org/10.1007/s00415-015-7843-z

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